of diabetes pathogenesis. common form of familial diabetes in India. 2 Diabetes in Asian Indian Population and related research initiatives in …
Kamla-Raj 2006
Int J Hum Genet, 61: 1-13 2006
Genetic Epidemiology of Adult Onset Type 2 Diabetes in Asian Indian Population: Past, Present and Future
Swapan Kumar Das Division of Endocrinology and Metabolism, Department of Medicine, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205, USA Telephone: 501-257-4859, , Fax: 501-257-5389, Email: swkuda@yahoocom, Personal URL: wwwgeocitiescom/swkuda
KEYWORDS Type 2 diabetes; IGT; Linkage; Association; insulin resistance ABSTRACT Incidence and prevalence of Type 2 Diabetes mellitus T2DM continue to rise in Indian populations Despite known roles for obesity, sedentary lifestyles and diet, genetic predisposition accounts for significant risk The identification of susceptibility loci for both monogenic and typical oligogenic diabetes have introduced novel genes, pathways and mechanisms of diabetes pathogenesis Very little data is available on T2DM susceptibility loci in Asian Indian population An extensive consortium based approach is required to identify the susceptibility locus and genes responsible for common form of familial diabetes in India By defining the genetic susceptibility loci, such
studies will eventually facilitate a direct, systematic exploration of the interactions of environmental factors, obesity, insulin resistance, and genetic predisposition in the pathogenesis of T2DM and prediabetic traits and also will open new pathways of exploration and therapy This article is a systematic review of genetic epidemiology of adult onset Type 2 Diabetes in Asian Indian Population and related research initiatives in India and abroad Arise, Awake, and stop not till the goal is achieved -Swami Vivekananda
INTRODUCTION Type 2 diabetes mellitus T2DM; MIM125853 encompasses a diverse set of diseases marked by elevated levels of plasma glucose Extensive studies in humans and animal models have led to a model for the pathogenesis of type 2 diabetes T2DM in which early and persistent insulin resistance in insulin target tissues in combination with the progressive decline in glucose stimulated insulin secretion from the pancreatic -cells results in postprandial hyperglycemia Subsequently, overt fasting hyperglycemia surfaces with hepatic insulin resistance and elevated hepatic glucose production Details of this general schema remain uncertain; however, both animal models and
monogenic causes of T2DM suggest complex pathways in which insulin action and insulin secretion are intertwined Thus, Type 2 diabetes is likely to be a heterogeneous disorder that may result from defects in one or more diverse molecular pathways Rare monogenic forms of T2DM mostly MODY account for only 5 of diabetes Most monogenic forms of diabetes are caused by defects in insulin secretion as compared to syndromic or common multifactorial T2DM in which insulin resistance and obesity play the major role
Three key defects mark the onset of hyperglycemia in T2DM: increased hepatic glucose production, diminished insulin secretion, and impaired insulin action Unfortunately, at the time of hyperglycemia, glucose and possibly lipid toxicity obscure the primary defects Prospective and cross-sectional analyses of euglycemic individuals at risk relatives of T2DM individuals circumvent this dilemma, and suggest a key early and predictive role of reduced insulin sensitivity in T2DM pathogenesis Nonetheless, few individuals with genetic insulin resistance develop diabetes, and 25 of nondiabetic individuals may have insulin sensitivity as low as that seen in T2DM The increase in hepatic
glucose production is a late event, occurring only at the onset of hyperglycemia and glucose intolerance Consequently, the importance and timing of a -cell defect have been hotly debated Obese individuals, those with a family history of diabetes, and individuals with impaired glucose tolerance IGT are all characterized by absolute hyperinsulinemia until the development of overt hyperglycemia In contrast, when -cell function is viewed in the context of reduced insulin sensitivity, considerable data support the early failure of insulin secretion in T2DM pathogenesis Animal models also support this concept: both reduced insulin secretion and
2 reduced -cell mass precede diabetes in the GK rat model, yet an experimental mouse with isolated, pro-found muscle and adipose tissue insulin resistance develops only IGT without overt diabetes Despite much study, the signals that cause normal -cell compensation and hyperinsulinemia, the mechanisms of this compensation, the point in the pathogenesis of T2DM where this compensatory mechanism fails, and the etiology of this failure all remain subjects of speculation Insulin sensitivity and insulin secretion deteriorate in parallel in most human
T2DM The remarkable difficulty in uncoupling these two defects may suggest a common mechanism Despite the diverse phenotypic nature of T2DM, monozygotic and dizygotic twin studies, family studies, and marked differences in disease prevalence across populations all provide convincing evidence for an important role of genetic susceptibility loci in T2DM pathogenesis Based on epidemiological data, the total sibling relative risk s has been estimated at 3-4, although the number of loci that contribute to this risk is unclear Barroso 2005; Elbein 2002; Kahn et al 1996; McCarthy 2004; ORahilly et al 2005; Permutt et al 2005 Identification of the genetic components of type 2 diabetes is the most important area of diabetes research because elucidation of the diabetes genes alleles will influence all efforts toward a mechanistic understanding of the disease, its complications, and its treatment, cure, and prevention Olefsky 2002 EPIDEMIOLOGY OF T2DM IN INDIA The worldwide prevalence of diabetes for all age-groups was estimated to be 28 in 2000 and is predicted to be 44 in 2030 by the World health Organization WHO Wild et al 2004 The total number of people with diabetes is projected to rise
from 171 million in 2000 to 366 million in 2030 WHO has predicted that India would experience the largest increase 48 increase in total population and 168 increase in population with 65 years of age in type 2 diabetes and would have the greatest number of diabetic individuals in the world by the year 2030 317 million in 2000 to 794 million in 2030 Data on the prevalence of type 2 DM in subcontinental Indians is limited, considering the socio-economic and rural-urban disparity, and
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the great cultural, geographical and racial diversity of our country The WHO 2030 prediction on India was extrapolated from the National Urban Diabetes Survey NUDS published by Diabetes Epidemiology Study Group in India DESI Ramachandran et al 2001 This Study was conducted on 11,216 subjects 20 years or older, from six metropolitan cities Chennai, Bangalore, Hyderabad, Mumbai, Calcutta and New Delhi Age standardized prevalence of diabetes and impaired glucose tolerance were found to be 121 and 140 respectively in NUDS study with no gender difference Subjects under 40 years of age had a higher prevalence of IGT than diabetes 128 vs 46, p00001 Diabetes showed positive and independent
association with Body Mass Index BMI, Waist to Hip Ratio WHR, family history, sedentary physical activity etc The DECODE -DECODA study group on behalf of the European Diabetes Epidemiology Group and the International Diabetes Epidemiology Group found that DM prevalence in Indians starts increasing at a BMI of 15-20 kg/m2 compared with greater than 25 kg/m2 in Chinese, Japanese and Europeans DECODE-DECODA Study Group 2003 Lack of proper representation from different socioeconomic and geographic regions eg overrepresentation from higher economic group population from metro cities is probably a major factor for over or under estimation of DM prevalence in India by different published epidemiological studies Recently a random multistage cross-sectional population survey was undertaken to determine the prevalence of type 2 diabetes mellitus DM in subjects aged 25 years and above in India by the Diabetes India group, Mumbai called Prevalence of Diabetes in India study PODIS Sadikot et al 2004 The study was carried out in 77 centers 42 urban and 35 rural to reflect the size and heterogeneity of the Indian population 18 363 9008 male and 9355 female subjects were studied of which 10 617
5379 males and 5238 females were from urban areas and 7746 3629 males and 4117 females from rural areas Blood samples were taken after 1012 hr of fasting and 2 hr after 75 g of oral glucose intake Subjects were categorized as having impaired fasting glycemia IFG or DM using the 1997 American Diabetes Association ADA or having impaired glucose tolerance IGT or DM using the 1999 WHO criteria The
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age and gender-standardized prevalence rate for DM using the ADA criteria was 36 whilst that using the WHO criteria was 43 for total Indian cohort This study observed a significant difference in DM prevalence between rural and urban population The respective standardized prevalence of DM, using the two criteria was 47 and 56, respectively in the urban Indian population and 20 and 27 in the rural Indian population The standardized prevalence rate for IGT in the total Indian, urban and rural populations was 52, 63 and 37, respectively under WHO criteria This study showed that use of the ADA criteria would underestimate the prevalence of DM by not diagnosing subjects showing a poor response to a glucose challenge Other than differences in
DM prevalence between urban and rural region, this study also observed significant difference of DM prevalence between different geographical regions of India West 402 and 434 and South 383 and 442 showed significantly higher prevalence of DM and IFG compared to North 312 and 367 , East 279 and 276 and Central 258 and 239 region This difference in DM prevalence is more striking in urban regions as compared to rural regions There was no significant difference in IFG prevalence in rural regions of different geographic zones personal communication Diabetes India GENETICS OF T2DM Although physiologic and epidemiologic studies provide clues to the pathophysiology underlying T2DM, the molecular mechanisms for the strong genetic predisposition cannot be explained Many laboratories have chosen a genetic approach to define early T2DM pathophysiology This approach is supported by: 1 The observation of a wide spectrum of diabetes prevalence in different ethnic groups world wide Part of this observed ethnic variability can be attributed to non-genetic environmental and cultural factors; however, the observation that the disease prevalence varies substantially among ethnic groups that share
similar environment, supports the idea of genetic factors contributing to disease predisposition 2 Apart form genes, families share environments, culture and habits, yet familial aggregation of the disease is another source of
evidence for a genetic contribution to the disease Different observations like the nearly 4-fold increased risk for T2DM in siblings of a diabetic proband compared with the general population S of 35 to 4, the increase in risk of T2DM in the offspring of one affected parent to an odds ratio OR of 3435 and to 61 if both parents are affected etc substantiate the role of genetic factors in T2DM etiology 3 Twin studies suggesting that T2DM susceptibility can be explained by only a few genetic loci oligogenic inheritance Several studies of twin concordance rates have been undertaken in T2DM, and estimates for concordance rates ranged from 020 to 091 in Monozygotic MZ, while in Dizygotic DZ the range was 010043 In spite of several caveats in twin studies, the evidence is compelling that T2DM has a substantial genetic component Barroso 2005 4 Data from different laboratories supporting a genetic basis for insulin sensitivity and insulin secretion Single gene causes
of T2DM, account for fewer than 5 of all cases Interestingly, most single gene disorders impair insulin secretion or cell mass rather than insulin action Researchers world wide have undertaken genome-wide linkage mapping studies in multiple populations to identify loci for common T2DM susceptibility genes or related quanti-tative traits including insulin sensitivity, insulin secretion, and obesity Loci for T2DM have been reported on chromosomes 1q21, 2q, 3, 5, 11q, 12q, and 20q, among others Stern 2002 NIDDM1 was mapped to 2q in Hispanic sib pairs Hanis 1996 and subsequently localized the gene to calpain10 CAPN10 using linkage disequilibrium Horikawa 2000 Among the best replicated regions is chromosome 1q21-q24, which was mapped independently in Utah Caucasians and in Pima Indians and confirmed in English, French, Amish, Chinese and several other studies To date, more than 50 linkage studies genome wide and fine mapping on smaller intervals have been conducted in a variety of populations with a number of chromosome regions demonstrating at least suggestive evidence for linkage LOD 2, but only a few regions have shown significant evidence for linkage LOD 36 Fewer regions still
have been replicated in multiple studies Linkage studies in T2DM are facing similar problems as encountered in other complex
4 diseases ie, a lack of replication of peaks of linkage and difficulty in identifying the underlying genes Progress in gene identification for more common, multifactorial forms of type 2 diabetes has been slower, but there is now compelling evidence that common variants in the PPARG, KCNJ11, CAPN10 and HNF4 genes influence T2DM susceptibility Three common intronic variants of CAPN10 that showed linkage to T2DM in Hispanics, were associated with T2DM in Hispanics and Finns, altered gene transcription, and reduced muscle mRNA levels However, its role in other populations is unclear Non-coding variants of the sulfonylurea receptor gene ABCC8 were associated with altered insulin secretion and T2DM in multiple populations The Pro12Ala variant of the PPAR2 gene has been associated with alterations in BMI, insulin sensitivity, and most recently diabetes risk Several studies suggest a role for the glycogen targeting subunit of type 1 protein phosphatase PPP1R3 in insulin sensitivity and T2DM Evidence is less clear for the insulin VNTR and a common variant of
insulin receptor substrate 1 IRS1, Gly972Arg that may impair insulin secretion and action Recent independent publication from Finnish and Ashkenazi Jews population showed polymorphisms near P2 promoter of HNF4 that is associated with Type 2 Diabetes In genetic association database http://geneticassociation dbnihgov/ 562 entries as of August 2005 can be obtained after a search using Type 2 diabetes as broad phenotype category keyword and 124 entries after filtering for positive association [Association Y/N? Y] Associations of many of those variants have not been replicated in other population or another cohort and experimental evidence towards elucidating the role of most of those variants in common multifactorial form of T2DM pathogenesis is lacking Asian Indians people from India, Pakistan, Bangladesh, Sri Lanka etc have surprisingly high prevalence of type 2 diabetes compared to Caucasians The high racial predisposition is evident from the studies in native Indians as well as migrant populations in any part of the world However, the incidence of obesity, an important risk factor in the development of type 2 diabetes, is significantly lower in Asian Indians compared to Caucasians
Though westernization of lifestyle with dietary changes and lack of exercise may
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play a role in increased prevalence of type 2 diabetes in migrant Asian Indians, various epidemiological studies have shown that these factors alone are not sufficient to explain this finding Excessive insulin resistance in Asian Indians compared to Caucasians may be one of the contributing factor This difference in the degree of insulin resistance may be explained by either an environmental or a genetic factor or by combination of both Abate and Chandalia 2001; Dhawan 1994; Gopalan 2001; Mohan 2004; Radha et al 2003; Ramachandran et al 2004; Ramachandran 2005; Snehalatha 2003 Search for T2DM genes in Asian Indian Population To date, only one published genome wide linkage analysis towards finding the T2DM loci in Asian Indian population is available A 10cM density genome wide scan with 403 microsatellite markers was performed in a set of 99 complex families including 535 individuals of NorthEastern Indian origin Hindu or Muslims, whose ancestors had migrated from the port of Calcutta ascertained from Mauritius and in a second cohort of 35 complex Tamil Indian families ascertained
through at least two T2DM affected individuals from Pondichery, India Francke et al 2001 Model free two point and multipoint linkage analysis was performed using the Mapmaker-sibs MLS and maximum-likelihood binominal MLB for autosomal markers A suggestive linkage with T2DM was observed for 3q22 region MLS LOD 206 at marker D3S1292 16485cM, 1 LOD interval 15668-17388 cM, 1q44 region MLS LOD214 at marker D1S2836 31892cM and 8q23 region MLS LOD173 at marker D8S1784 13188cM in Mauritian pedigrees Dense marker analysis on chromosome 8q23 improved the linkage for T2DM at 12198 cM D8S1779, MLS LOD 255, 1 LOD interval 10967-14309cM Nominal replication of T2DM linkage was observed only for 3q22 region MLS LOD136 at marker D3S1292 and a weak evidence for a novel linkage region at D16S407 MLS LOD 114, 16p13-pter in Pondicherian pedigrees Ordered-subset analysis based on family body mass index ranking showed a suggestive evidence for linkage with T2DM at position 273cM on chromosome 2q37 D2S125, 273cM, MLS303 including 24 Mauritian T2DM families with the lowest BMI Other interesting
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regions that emerged through the same analysis are 8q23
D8S514, 129cM, MLS226, 16q12 D16S415, 67cM, MLS196 and 19p133 D19S414, 15cM, MLS220 Recently a study has been undertaken by University of Pittsburgh, USA and Guru Nanak Dev University, India in Khatri Sikh population North Indian which promises a genome wide search to map Asian Indian diabetes T2DM susceptibility gene by family based linkage study Sanghera et al 2005 Some genetic studies have been performed on Indian Type 2 diabetic subjects in the southern part of India, but most of those studies are under powered, ill designed, and used monogenic disease approach to solve complex disease genetics Many of these studies looked at one or two exonic mutation in casecontrol association study approach, but they are too rare to account for common familial form of T2DM in Indian population, although may explain certain rare monogenic forms of T2DM Except a few reports Das and Maji 1999; Dixit et al 2005; Gill et al 1990, 1991; Hitman et al 1987; Inamdar 2000 most of the genetic association studies are on Asian Indians of South Indian Dravidian origin Considering the high genetic/ ethnic heterogeneity in this geographic region those studies are extremely inadequate Study of PuVII RFLP
site in Islet amyloid polypeptide IAPP or amylin gene failed to find any significant association with T2DM in a wellcharacterized population of 62 unrelated Dravidian subjects with non-insulin-dependent diabetes mellitus and 56 normal Dravidian controls McCarthy 1992 form South India McCarthy 1993 also studied the role of glucokinase GCK gene in a cohort of 168 South Indian Type 2 diabetic subjects and 70 racially-matched control subjects Out of two CAn marker studied GCK3 marker showed a significant difference between the Type 2 diabetic subjects and control subjects p 0009 with an increase of the z allele 780 vs 664 and a decrease of the z 2 allele 137 vs 250 amongst the diabetic subjects Linkage analysis was negative for this region Hitman et al 1995 examined the role of a missense mutation in the insulin receptor substrate-1 gene IRS-1 at codons 972 glycine to arginine with restriction enzymes BstN1 in a population from South India and failed to find any significant association with T2DM Baker et al 1994 observed a significant difference in genotype distribution of apolipoprotein D apo
D genotypes between diabetic subjects n 110 and controls n 88; p 0004 of South Indian
ethnicity studied through Taq 1 polymorphism analysis Pontiroli et al 1996 evaluated the allele and genotype frequencies of GLUT1 and GLUT4 restriction fragment length polymorphism RFLP, revealed by digestion with XbaI for GLUT1 and KpnI for GLUT4, in Asian Indian population Positive results were found for the XbaI RFLP and showed an association of allele 1 with type 2 diabetes Cassell et al 1999 investigated the exon 8 insertiondeletion variant of UCP2 gene as a marker for glucose and body weight homeostasis in 453 South Indian subjects and found an association in women between the UCP2 exon variant and body mass index p 0018 These findings were replicated in a separate group of South Indian subjects n 143, p 0001 irrespective of sex No association was found between UCP2 and Type II noninsulin-dependent diabetes Leprêtre et al 1998 reported a study of 10 candidate genes presumably involved in diabetes or insulin resistance or obesity among Pondicherian Tamil Indians Forty-nine families with at least two affected patients in the sibship 567 individuals were selected and tested by PCRRFLP techniques for reported mutations in 10 diabetes or obesity candidate genes namely: glucagon
receptor GCG-R, insulin receptor substrate 1 IRS-1, insulin receptor INSR, human b3 adrenergic receptorHb3AR, fatty acid binding protein 2 FABP2, mitochondrial tRNALeuUUR, sulphonylurea receptor SUR22, human uncoupling protein UCP1 and the glycogen associated regulatory subunit of protein phosphatase-1 PPP1R3 No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands No evidence of association between any of these gene variants and non-insulindependent diabetes mellitus NIDDM or quantitative traits related to NIDDM including body mass index, waist/hip ratio, insulinaemia, glycaemia, triglycerides and total cholesterol was found in this cohort However, this study cannot exclude that these genes may contribute to the polygenic background of the metabolic syndrome in Pondichery, India Using Starch gel electrophoresis Das and Maji 1999 studied the Phosphoglucomutase PGM1 and Glyoxalase I GLO enzyme isoforms in an East Indian Bengali speaking cohort of
6 195 NIDDM and 195 control individuals, but failed to find any genotypic association Cassell et al 2002 evaluated whether 4 SNP UCSNP 44, 43, 19 and 63, haplotype or haplotype
combination of Calpain 10 CAPN10 gene contribute to increased susceptibility to impaired fasting glucose IFG/impaired glucose tolerance IGT and type 2 diabetes in a South Indian population Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey 691 with normal glucose tolerance, 128 with IFG/IGT, and 182 with T2DM Family-based association studies did not reveal any excess transmission for any of the four individual SNP alleles to probands with type 2 diabetes, also found no evidence of excess transmission of any haplotype to type 2 diabetic offspring In the urban survey, there was no difference between the genotype frequencies of normoglycemic control subjects, IFG/IGT, and T2DM for the UCSNP44, 43 and 19 variants However, the presence of the uncommon allele 2 T of UCSNP63 was significantly increased in IFG/IGT subjects, with a frequency of 17 compared with control subjects 4, P0001 Although there was only a slight nonsignificant increase in frequency of allele 2 in the unrelated type 2 diabetic subjects 59, there was a significant increase 11 in the type 2 diabetic probands P002 Analysis of
the five common haplotypes found the frequency of the 1112 haplotype also significantly increased in both the urban IFG/IGT subjects global P 0001 and the probands global P 0004 Interestingly in this study UCSNP19 was not P 0009 in Hardy-Weinberg equilibrium Further analysis found that the 1112/1121 heterozygous haplotype combination was associated with an increased risk of IFG/IGT in urban subjects OR 1074, P 0001 and urban type 2 diabetic subjects OR652, P 0015 and probands OR578, P 0025 Due to relative infrequency frequency 005-009 of the at-risk combinations in the South Indian population this study suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes Analysis of the same population genotype data set by North et al 2003 using a neural network based method revealed arguably stronger evidence of association for UCSNP63 of CAPN10 Venkatesan et al 2003 examined the relation of Pro12Ala variant in PPAR-2 in Type 2
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diabetes, insulin resistance and obesity This variant was examined using PCR-RFLP technique on 1145 randomized subjects from the population based ongoing Chennai Urban Rural Epidemiological Study CURES 1015
subjects 886 had the PPAR-2 Pro12Pro genotype 125 subjects 109 had Pro12Ala genotype and 5 subjects 04 had Ala12Ala genotype In males, the prevalence of Pro12Ala was more in controls 144 compared to Insulin resistant IR 93, p 050, Impaired Glucose Tolerant IGT 89, p 061 and Diabetic 68, p 0076 subjects, suggesting a protective role of this polymorphism However, no such trend was seen in females Further, the Pro12Ala did not show any association with BMI Authors also investigated the interaction between the Pro12Ala of PPAR-2 and Gly482Ser of PGC-1 PPAR-gamma coactivator-1 gene Gly482Ser polymorphism was genotyped also by using PCR-RFLP in a subset of these samples n163 In this preliminary study no indication for the additive effects of the two polymorphisms on the diabetes status was observed Further in a cohort of 87 type 2 diabetic subjects and 81 subjects with Normal Glucose Tolerance NGT of CURES study Mohan et al 2005 analyzed Thr394Thr GA, Gly482Ser and A2962G polymorphism of PGC-1 gene and found that Thr394Thr polymorphism in the PGC-1 gene is associated p0001 with higher visceral and central abdominal fat and with type 2 diabetes in urban Asian Indians There was no
association between Gly482Ser or A2962G polymorphisms and body fat distribution Abate et al 2003 studied if plasma cell membrane glycoprotein PC-1 K121Q and insulin receptor substrate-1 IRS-1 G972A polymorphisms contribute significantly to susceptibility to insulin resistance in Asian Indians This study recruited 638 individuals originated from the Asian Indian subcontinent India, Pakistan, and Bangladesh by public advertisement and offering free screening for cardiovascular risk factors at University of Texas Southwestern Lipid and Heart Disease Risk Management Clinic Dallas, TX A significantly higher insulin area under the curve during oral glucose tolerance testing P 00001 and lower insulin sensitivity during hyperinsulinemic-euglycemic clamps P 004 were found in Asian Indians with PC-1 121Q variant compared with Asian Indians with wild-type PC-1 IRS-1 G972A was not associated
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with any change in insulin sensitivity This study concluded that the PC-1 K121Q polymorphism associates with primary insulin resistance in migrant Asian Indians and relatively high frequency of this polymorphism thus may be one factor contributing
to insulin resistance susceptibility in Asian Indians Chiu et al 2000 investigated the role of the GA polymorphism in the hepatic glucokinase GCK promoter on insulin sensitivity and beta cell function in 63 normotensive Asian Indians with normal glucose tolerance recruited from local Indian temples of metropolitan Los Angeles area Compared to the GG group, the GA/AA group had a lower hepatic insulin sensitivity ISIH p0002, a lower total body insulin sensitivity ISIM p0009, a higher Beta cell function B p0014 measured under Homeostasis model assessment, and a higher insulingenic index dI/dG p0030 Multivariate analysis revealed that this polymorphism is an independent determinant for ISIH p0019 and along with age, waist-hip ratio, gender, and diastolic blood pressure accounted for 515 of the variation of ISIH However, this polymorphism was a weak, but independent determinant for ISIM p0089 and B p0083 Furthermore, it had no independent effect on dI/dG p0135 These data suggest that the GA polymorphism in the hepatic GCK promoter is associated with hepatic insulin resistance in Asian Indians Jackson et al 2004 investigated the role of three polymorphisms in three genes namely: Ala45Thr
polymorphism of neurogenic differentiation-1 [NEUROD1], Ser199Phe polymorphism of Neurogenin-3 [NEUROG3] and Ala98Val polymorphism of Hepatic nuclear factor1 [TCF1or HNF-1] in T2DM They have also studied the effect of interactions between these variants using PCR/RFLP assays in 454 subjects recruited as part of a population survey in South India Additionally, 97 South Indian parentoffspring trios were studied OnlyTCF1 polymorphism showed genotypic p0037 as well as allelic p002 association with T2DM in case-control study The families were not studied because there was insufficient power for analysis due to the low variant allele frequency of TCF1 polymorphism NEUROD-1 and NEUROG3 markers were not significant in both case-control and family based study Polymorphisms of all three genes were associated with either fasting blood glucose FBG and/or 2-h blood glucose BG in either the total data set or when restricted
to a normoglycemic population A monotonically increasing effect, dependent on the total number of risk-associated alleles carried, was observed across the whole population P 00001 for FBG and 2-h BG which indicates the possible role of these polymorphisms in overall glucose
intolerance in South Indian population Abate et al 2005 evaluated the role of Ectonucleotide pyrophosphate phosphodiesterase or ENPP1 also called Plasma cell glycoprotein-1, PC-1 genes exon4 K121Q polymorphism in prediction of type2 diabetes in two Asian Indian populations that differ in susceptibility to diabetes and environmental exposure Two cohorts included 679 nonimmigrant South Asians participants of the Chennai Urban Rural Epidemiological Study CURES living in Chennai, India 223 with type 2 diabetes and 1,083 migrant new immigrants or first generation from India, Pakistan, or Bangladesh South Asians living in Dallas, Texas 121 with type 2 diabetes recruited by public advertisement and by offering free screening for cardiovascular risk factors at the University of Texas Southwestern Lipid and Heart Disease Risk Management Clinic Patients with type 2 diabetes were included in these cohorts if they had diabetes onset before the age of 60 years The prevalence of subjects carrying the polymorphic ENPP1 121Q allele was 25 in the nondiabetic group and 34 in the diabetic group of South Asians living in Chennai P001 The prevalence in the nondiabetic and diabetic groups were 33 and 45
P001 for the South Asians living in Dallas This study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in South Asians In most of these published Type 2 diabetes genetic association studies investigators selected these variations in putative functional candidate genes, which might affect insulin signaling cascade directly or indirectly Due to lack of high throughput genotyping techniques and data analysis algorithm none of these studies have implemented unbiased genome wide association analysis or extensive linkage disequilibrium LD based approach Recent findings have revived interest in the role played by the brain in both glucose homeostasis and the mechanism linking obesity to type2 diabetes Also there is mounting evidence of changes in -cell mass genes involved in -cell growth and survival and concomitant change of insulin
8 secretion in the pathogenesis of type2 diabetes A whole genome association study followed by an advanced pathway analysis can only lead to an unbiased conclusion about genes involved and mode of their interactions in T2DM pathogenesis in Asian Indians Search for Genetic Factors Associated with Diabetic
Complications in Asian Indians Microvascular and macrovascular complications in relation to diabetes mellitus are responsible for major morbidity and mortality Prevention of these complications should be the aim while managing diabetes Retinopathy, nephropathy and neuropathy are microvascular complications and macrovascular complication affects the heart, brain and foot Maji 2004 Ethnic differences in prevalence of diabetic complications indicate the involvement of genetic factors in these phenotypes Several studies suggest that genetic factors could be promoting the severity and rapidity of onset of micro and macrovascular complications in diabetic patients Rema M et al 2002 Hawrami 1991 by southern blot hybridization technique tried to evaluate the role of several HLA region markers for predisposition to diabetic retinopathy in a cohort of South Indian Type 2 non-insulin-dependent diabetic patients Patients were subdivided into those with exudative maculopathy n 53, proliferative retinopathy n 40 and patients free from diabetic retinopathy with a minimum disease duration of 15 years n 45 This study suggests that there is a genetic predisposition to proliferative retinopathy in
Type 2 non-insulindependent diabetes of South Indian origin and that this is determined by polymorphism of the heavy chain immunoglobulin genes [using restriction enzyme Pvu II and probe for the switch region of the immunoglobulin IgM heavy chain gene S mu] located on chromosome 14 Kumaramanickavel et al 2001 studied a dinucleotide microsatellite repeat length polymorphism [GT n] upstream to the promoter region of tumor necrosis factor TNF gene in an Indian cohort mixed south and north Indian ethnicity of 100 patient with diabetic retinopathy, 107 patients without retinopathy and 50 control individuals without diabetes or retinopathy to evaluate the role of this gene in susceptibility for the development of retinopathy In this study
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population authors observed 18 alleles ranging from 97 to 131 base pairs bp Allele 4 103 bp had a higher prevalence 981 in the Diabetic Non Retinopathy DNR group compared to that in the Diabetic Retinopathy DR group 25; P0002 and control group 2; P0039 When the allele 4 data were separated into those of north and south Indian patients, results were still significant, the P value for north Indians being 0003 and for the south Indians
being 0008 Patients with retinopathy and allele 8 111 bp had a tendency to develop proliferative diabetic retinopathy PDR In this study of Indian subjects, it is suggested that allele 4 is a low risk allele for developing retinopathy and allele 8 111 bp shows an association with PDR Considering the cohort size and number of observed alleles of the TNF microsatellite this study is extremely underpowered and also not in agreement with a previously published study of Hawrami et al 1996 on a Dravidian South Indian cohort Fifteen 15 alleles were observed for the same marker in a cohort of unselected NIDDM n 76, unselected IDDM n 99, non-diabetic controls n 96, NIDDM subjects with maculopathy MAC, n 55, NIDDM subjects with proliferative retinopathy PR, n 53, and Long term diabetic without retinopathy LTD, n 46, studied by Hawrami et al 1996 After correction for the number of alleles studied, only the allele 9 B9 had a significantly different distribution between patients with proliferative retinopathy and those without retinopathy p 004 Kumaramanickavel 2002 also studied a pentanucleotide microsatellite repeat located 25 kb upstream of the transcription start site of the inducible
nitric oxide synthase iNOS gene by polymersase chain reaction PCR in a cohort of 199 unrelated Asian Indian patients with 15 or more years of type 2 diabetesdivided into two groups: diabetic retinopathy and diabetic nonretinopathy This study identified eleven alleles ranging from 175 to 225 bp of which allele 210 bp was significantly associated with retinopathy p 0044, OR 203; 95 CI 096435 Alleles 200 and 220 bp were also significantly associated with no retinopathy and no serious retinopathy complications, respectively From this study authors concluded that in Asian Indian population, allele 210 bp of the iNOS gene is a high-risk allele for developing retinopathy and alleles 200 and 220 bp protect an
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individual from developing retinopathy or its complications In a similar study design polymorphisms in CAn di-nucleotide repeat present in upstream of the promoter of the aldose reductase ALR2 gene was studied by Kumaramanickavel et al 2003 to evaluate its association with diabetes retinopathy in the Asian Indian population 105 diabetic patients with retinopathy and 109 diabetic patients without retinopathy were screened and 13
alleles of this marker were identified The Z-2 allele 136 bp showed an association with the DR group 1381 with a significant p value p 0029 when compared with the DNR group 734 The Z-2 allele also showed a significant association with the DR patients who had proliferative retinopathy and maculopathy p 0004 This study infers Z-2 allele as a high-risk allele for diabetic retinopathy in the Asian Indian patients Gly82Ser polymorphism in exon 3 of the receptor for advanced glycation end products RAGE gene was studied by Kumaramanickavel et al 2002 in a cohort of 100 diabetic patients with retinopathy DR,100 diabetic patients without retinopathy DNR and 50 control individual of Asian Indian origin heterogeneous ethnicity by PCR-RFLP method The frequency of the Ser82 allele was significantly higher, 18 in the DNR group compared to 7 in the DR group P03 The same genotype was 2 in the control group This result suggests that Ser82 allele in the RAGE gene is a low-risk allele for developing DR in Asian Indian patients who have type II diabetes This report has not been replicated in any other Indian cohort and due to ethnic heterogeneity this observed association may be a type 1 statistical
error due to population stratification An ongoing population-based study called Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetic Study SNDREAMS 1 promises to estimate the prevalence of diabetes and diabetic retinopathy in urban Chennai, Tamil Nadu, South India, and also to elucidate the clinical, anthropometric, biochemical and genetic risk factors associated with diabetic retinopathy in an anticipated cohort of total of 5830 participants Agarwal et al 2005 South Asian type 2 diabetic patients have been shown to have a higher prevalence of nephropathy when compared to Europeans Viswanathan et al 2001 studied the association
of Angiotensin-converting enzyme ACE gene polymorphism and diabetic nephropathy in a cohort of 109 South Indian type 2 diabetic patients The patients were subdivided into two groups: nephropathic n86 and normoalbuminuric patients n23 ACE gene insertion I-Deletion D polymorphism was analyzed by PCR amplification The D allele was present in 802 of the nephropathic patients and 565 of the normoalbuminuric patients P0039; odds ratio 312This study showed a positive association between the D allele ID and DD genotype of the ACE polymorphism
and diabetic proteinuria in South Indian type 2 diabetic patients Dixit et al 2005 studied the association of Cholesteryl ester transfer protein CETP TaqI B, D442G, and Apolipoprotein E APOE Hha I polymorphisms with T2DM and its complications in a North Indian cohort of 136 patients and 264 healthy controls ascertained mostly from SGPGI, Lucknow, Uttar Pradesh Polymorphisms were detected using PCR-RFLP CETP TaqI B polymorphism was not associated with the T2DM but B1B2 genotype was significantly p0028 associated with high risk of hypertension in diabetic patients OR3068, 95 CI 1183-7958 In North Indians D442G variation in CETP gene was found to be absent Frequency of APOE HhaI polymorphism was also not different between patients and controls In diabetic patients having neuropathy and retinopathy significantly different levels of totalcholesterol [p0001 and p0029 respectively] and LDL-cholesterol [p0001 and p0001 respectively] were observed when compared to patients with T2DM only However, lipid levels did not show any correlation with the CETP TaqI B and APOE Hha I genetic polymorphisms This study suggests that CETP TaqI B and APOE HhaI polymorphism may not be associated with type
II diabetes mellitus in North Indian population; however CETP TaqI B polymorphism may be associated with hypertension along with T2DM Guettier et al 2005 evaluated the association between Ala54Thr polymorphism in the fatty acid-binding protein 2 FABP2 gene as well as the T455C and C482T polymorphisms in the apolipoprotein C-III APOC3 gene promoter with metabolic syndrome MS and dyslipidemia, defined according to National Cholesterol Education Program Adult Treatment Panel III in Asian-Indians 70 controls and 110 patients with
10 diabetes from the Chennai Urban Population Study This study showed that controls carrying FABP2 Thr54 were more likely to have MS than noncarriers P0031; odds ratio69 with a 95 confidence interval of 11, 439 Those carrying at least one polymorphic allele in both genes had a higher likelihood of having MS than wild type P0003; odds ratio 121 with a 95 confidence interval of 188, 776 Dyslipidemia was associated with the polymorphism as well The polymorphisms were not associated with MS in patients with diabetes Association of the polymorphisms with MS and dyslipidemia indicate their contribution to the high cardiovascular disease prevalence in this
population Indian Diabetes Research- working with Ostrich attitude Diabetes mellitus is described as Madhumeha in ancient Indian Sanskrit literature dealing with health care systems, and is duly acknowledged in modern medical texts However, detailed descriptions of the disease process and therapeutics prescribed in these classics could not get proper recognition Tiwari 2005 Arunachalam and Gunasekaran 2002 have mapped and evaluated diabetes research in India based on papers published during 19901999 and indexed in PubMed, Science Citation Index SCI and Biochemistry and Biophysics Citation Index BBCI and citations to each one of these papers up to 2000 They have also assessed the extent of international collaboration in diabetes research, based on papers indexed in SCI and BBCI There is an enormous mismatch between the disease burden and the share of research performed in India 837 unique papers from India consisting of 667 articles, 111 meeting abstracts, 31 letters, 25 notes and three editorials Nearly 596 of Indian papers are covered by SCI The 531 papers from India indexed in PubMed amount to 111 of the 47,877 papers from all over the world Indias share of diabetes papers in SCI
is 098 and in BBCI is 161 In 1995, over 14 of the worlds diabetes patients were in India and yet India accounted for about 1 of research in diabetes In all, 371 Indian diabetes papers have been cited 1657 times More than 55 of Indian papers were not cited at all India has published a very large percentage of their papers in lowimpact journals: 578 69 Indian papers in journals of impact factor IF less than 10 Two
SWAPAN KUMAR DAS
private research institutions attached to hospitals located in Chennai are among the leading producers of diabetes research papers in India Diabetes Research Centre, Chennai, founded in 1972, has published 74 papers, and of these 45 was cited 289 times Madras Diabetes Research Foundation the parent hospital was founded in 1991 has published 27 papers, of which 16 were cited 53 times More than 16 of the 534 Indian papers in diabetes indexed in SCI and BBCI 86 papers from 37 institutions had resulted from collaboration with foreign authors In diabetes research, India had collaborated with the UK in 40 papers and USA in 22 papers Similar situation prevails in the area of genetic epidemiology of T2DM research in India Most of the research in this area was
carried out on South Indian samples and with a few exceptions most of those research works are spearheaded by UK, US or French laboratories, as evidenced from the location of corresponding author of those publications and no acknowledgement to Indian Government funding agencies like Indian Council of Medical Research ICMR, Department of Biotechnology DBT, Department of Science and Technology DST or Council for Scientific and Industrial Research CSIR Under the mission mode programs of Department of Biotechnology, Government of India, a major proposal on molecular genetic studies of type2 diabetes and diabetic retinopathy has been developed at Madras Diabetes Research Foundation, Chennai http://dbtindia nicin/rd/humangenomehtml with objectives to identify and characterize various genes that predispose to Type2 diabetes and its intermediary phenotypes such as Insulin Resistance, impaired glucose tolerance, perform gene expression and protein profiling of components of the signaling molecules, analyze drug responses in different single nucleotide polymorphisms SNPs of PPAR- gene and elucidate genetic factors predisposing to diabetic retinopathy in India and to attempt clinico-genetic
correlations of DR phenotype The recent annual report of DBT indicate the progress of this project DBT 2004 2005 Annual Report 2005 but no research publication appeared till date in any Pubmed Indexed journal acknowledging this mission mode project of DBT, India A public-private knowledge alliance between Nicholas Piramal India Limited, Mumbai and Institute of Genomics and Integrative Biology
GENETIC EPIDEMIOLOGY OF ADULT ONSET TYPE 2 DIABETES
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a Council of Scientific and Industrial Research Laboratory was initiated on November 2001 as GENOMED project with a major research objective Flag Ship Project of developing biomarkers Genetic markers for Type 2 Diabetes Till the final closing of this three years project on January 2005, this project failed to publish any research article or patent which can be evidenced as achievement of this project Lessons can be learned from failures of such high investment projects, which may be useful for future successful project formulation and execution Incidence and prevalence of T2DM continue to rise in Indian populations Despite known roles for obesity, sedentary lifestyles, and diet, genetic predisposition accounts for significant risk The
identification of susceptibility loci for both monogenic and typical oligogenic diabetes have introduced novel genes, pathways and mechanisms of diabetes pathogenesis An extensive consortium based approach is required to identify the susceptibility locus and genes responsible for common form of familial diabetes in India By defining the genetic susceptibility loci, such studies will eventually facilitate a direct, systematic exploration of the interactions of environmental factors, obesity, insulin resistance, and genetic predisposition in the pathogenesis of T2DM and prediabetic traits and also will open new pathways of exploration and therapy It can be argued that India needs to strengthen research capabilities by increasing investment in these areas of research considerably Substantive facilitation of international collaboration in research and support of cross-disciplinary research between basic life sciences researchers and medical researchers will facilitate this process It is not the time to work with an Ostrich-attitude to avoid problems, but to face the problem and solve it to achieve the yet elusive goal Time has come for Indian researchers and research policy makers to
switch gear and give new direction towards taking diabetes research in India to global standard ACKNOWLEDGEMENT Author like to acknowledge Dr Steven C Elbein, University of Arkansas for Medical Sciences, Little Rock, USA; Dr Malabika Datta, Institute of Genomics and Integrative Biology, Delhi, India and Dr Madhumita Santra, The
Center for Genomic Application, Delhi, India for their valuable help in writing this manuscript REFERENCES
Abate N, Carulli L, Cabo-Chan Jr A, Chandalia M, Snell PG, Grundy SM 2003 Genetic Polymorphism PC1 K121Q and Ethnic Susceptibility to Insulin Resistance J ClinEndocrinol Meta, 88: 5927-5934 Abate N, Chandalia M 2001 Ethnicity and type 2 diabetes: Focus on Asian Indians J Diabetes Complications, 15: 320-7 Abate N, Chandalia M, Satija P, Adams-Huet B, Grundy SM, Sandeep S, Radha V, Deepa R, Mohan V 2005 ENPP1/PC-1 K121Q Polymorphism and Genetic Susceptibility to Type 2 Diabetes Diabetes, 54: 1207-1213 Agarwal S, Raman R, Paul PG, Rani PK, Uthra S, Gayathree R, McCarty C, Kumaramanickavel G, Sharma T 2005 Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetic Study SN-DREAMS 1: study design and research methodology Ophthalmic
Epidemiol, 12: 143-53 Arunachalamand S, Gunasekaran S 2002 Diabetes research in India and China today: From literaturebased mapping to health-care policy Current Science, 82: 1086-1097 Baker WA, Hitman GA, Hawrami K, McCarthy MI, Riikonen A, Tuomilehto-Wolf E, Nissinen A, Tuomilehto J, Mohan V, Viswanathan M 1994 Apolipoprotein D gene polymorphism: A new genetic marker for type 2 diabetic subjects in Nauru and south India Diabet Med, 11: 947-52 Barroso I 2005Genetics of Type 2 diabetes Diabet Med, 22: 517-535 Cassell PG, Jackson AE, North BV, Evans JC, Syndercombe-Court D, Phillips C, Ramachandran A, Snehalatha C, Gelding SV, Vijayaravaghan S, Curtis D, Hitman GA 2002 Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in south indians Diabetes, 51: 1622-1628 Cassell PG, Neverova M, Janmohamed S, Uwakwe N, Qureshi A, McCarthy MI, Saker PJ, Albon L, Kopelman P, Noonan K, Easlick J, Ramachandran A, Snehalatha C, Pecqueur C, Ricquier D, Warden C, Hitman GA 1999 An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes Diabetologia, 42: 688692 Chiu KC,
Chuang LM, Yoon C, Saad MF 2000 Hepatic glucokinase promoter polymorphism is associated with hepatic insulin resistance in Asian Indians BMC Genet, 1: 2 Das S, Maji D 1999Genetic markers association in Diabetes J Viv Inst Med Sci 22: 42-44 DBT 2004-2005 Annual Report 2005 Chapter 5, p113 DECODE-DECODA Study Group on behalf of the European Diabetes Epidemiology Group, and the International Diabetes Epidemiology Group c/o T Nakagami 2003Age, body mass index and Type 2 diabetes– associations modified by ethnicity Diabetologia, 46: 1063-1070
12
Dhawan J, Bray CL, Warburton R, Ghambhir DS, Morris J 1994 Insulin resistance, high prevalence of diabetes, and cardiovascular risk in immigrant Asians Genetic or environmental effect? Br Heart J, 72: 413-21 Dixit M, Bhattacharya S, Mittal B 2005 Association of CETP TaqI and APOE polymorphisms with type II diabetes mellitus in North Indians: a case control study BMC Endocrine Disorders, 5: 7 Elbein SC 2002 Perspective: the search for genes for type 2 diabetes in the post-genome era Endocrinology, 143: 2012-2018 Francke S, Manraj M, Lacquemant C, Lecoeur C, Lepretre F, passa P, Hebe A, Corset L, Yan SLK, lahmidi S, Jankee S, Gunness TK,
Ramjuttun US, Balgobin V, Dina C and Froguel P 2001 A genome-wide scan for coronary heart disease suggests in Indomauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27 Human Molecular Genetics, 10: 2751-2765 Gill PS, Chahal SM, Blangero J, Corruccini RS, Bansal IJ, Kaul SS, Bhalla V 1991 Genetic epidemiology of non-insulin-dependent diabetes mellitus in north India: preliminary analyses of some genetic markers in Punjabis Hum Biol , 63: 549-53 Gill PS, Pandey JP, Blangero J, Corruccini RS, Gill IS 1990 Genetic epidemiology of non-insulindependent diabetes mellitus NIDDM in north India: distribution of Gm and Km allotypes in Punjabis Dis Markers, 8: 59-67 Gopalan C 2001 Rising incidence of obesity, coronary heart disease and diabetes in the Indian urban middle class Possible role of genetic and environmental factors World Rev Nutr Diet, 90: 127-43 Guettier J-M, Georgopoulos A, Tsai MY, Radha V, Shanthirani S, Deepa R, Gross M, Rao G, Mohan V 2005 Polymorphisms in the Fatty Acid-Binding Protein 2 and Apolipoprotein C-III Genes Are Associated with the Metabolic Syndrome and Dyslipidemia in a South Indian Population The Journal
of Clinical Endocrinology Metabolism, 90: 17051711 Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, Shephard JM, Williams, SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzsch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, Lim LR, Linder T, Mereu LF, Xiang WK, Yamagata K, Yang Y, Bell G 1996 A genome-wide search for human non-insulindependent type 2 diabetes genes reveals a major susceptibility locus on chromosome 2 Nat Genet, 13: 161166 Hawrami K, Hitman GA, Rema M, Snehalatha C, Viswanathan M, Ramachandran A, Mohan V 1996 An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism Hum Immunol, 46: 49-54 Hawrami K, Mohan R, Mohan V, Hitman GA 1991 A genetic study of retinopathy in south Indian type 2 non-insulin-dependent diabetic patients Diabetologia, 34: 441-444 Hitman GA, Hawrami K, McCarthy MI, Viswanathan
SWAPAN KUMAR DAS M, Snehalatha C, Ramachandran A, Tuomilehto J, Tuomilehto-Wolf E, Nissinen A, Pedersen O 1995 Insulin receptor substrate-1 gene mutations in NIDDM;
implications for the study of polygenic disease Diabetologia, 38: 481-6 Hitman GA, Karir PK, Mohan V, Rao PV, Kohner EM, Levy JC, Mather H 1987 A genetic analysis of type 2 non-insulin-dependent diabetes mellitus in Punjabi Sikhs and British Caucasoid patients Diabet Med, 4: 526-30 Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M , Hinokio Y, Linder TH, Mashima H, Schwarz PEH, Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchari I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier L, Bogardus C, Groop L, Boerwinkle E, Hanis C and Bell GI 2000 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus Nat Genet, 26: 163-175 Inamdar PA, Kelkar SM, Devasagayam TP, Bapat MM 2000 Apolipoprotein E polymorphism in noninsulin-dependent diabetics of Mumbai, India and its effect on plasma lipids and lipoproteins Diabetes Res Clin Pract, 47: 217-23 Jackson AE, Cassell PG, North BV, Vijayaraghavan S, Gelding SV, Ramachandran A, Snehalatha C, Hitman GA Polymorphic Variations in the Neurogenic Differentiation-1, Neurogenin-3, and Hepatocyte Nuclear Factor-1alpha Genes Contribute to Glucose Intolerance in a South Indian Population
Diabetes, 53: 21222125 Kahn CR, Vicent D, Doria A 1996Genetics of NonInsulin-Dependent Type-II Diabetes Mellitus Annu Rev Med, 47: 50931 Kumaramanickavel G, Ramprasad VL, Sripriya S, Upadyay NK, Paul PG, Sharma T 2002 Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II diabetic Asian Indian patients Journal of Diabetes and Its Complications, 16: 391394 Kumaramanickavel G, Sripriya S, Ramprasad VL, Upadyay NK, Paul PG, Sharma T 2003 Z-2 aldose reductase allele and diabetic retinopathy in India Ophthalmic Genet, 24: 41-8 Kumaramanickavel G, Sripriya S, Vellanki RN, Upadyay NK, Badrinath SS, Arokiasamy T, Sukumar B, Vidhya A, Joseph B, Sharma T, Gopal L 2001Tumor necrosis factor allelic polymorphism with diabetic retinopathy in India Diabetes Res Clin Pract, 54: 89-94 Kumaramanickavel G, Sripriya S, Vellanki RN, Upadyay NK, Badrinath SS, Rajendran V, Sukumar B, Ramprasad VL, Sharma T 2002 Inducible nitric oxide synthase gene and diabetic retinopathy in Asian Indian patients Clin Genet, 61: 344-348 Leprêtre F, Vionnet N, Budhan S, Dina C, Powel KL, Génin E, Das AK, Nallam V, Passa P, Froguel P 1998 Genetic studies of polymorphisms in ten
noninsulin-dependent diabetes mellitus candidate genes in Tamil Indians from Pondichery Diabetes metabolism Paris, 23: 244-250 Maji D 2004 Prevention of microvascular and macrovascular complications in diabetes mellitus J Indian Med Assoc, 102: 426 -430 McCarthy MI 2004 Progress in defining the molecular
GENETIC EPIDEMIOLOGY OF ADULT ONSET TYPE 2 DIABETES basis of type 2 diabetes mellitus through susceptibility-gene identification Human Molecular Genetics, 13: R33-R41 McCarthy MI, Hitchins M, Hitman GA, Cassell P, Hawrami K, Morton N, MohanV, Ramachandran A, Snehalatha C, Viswanathan M 1993 Positive association in the absence of linkage suggests a minor role for the glucokinase gene in the pathogenesis of type 2 non-insulin-dependent diabetes mellitus amongst south Indians Diabetologia, 36: 633-41 McCarthy MI, Hitman GA, Mohan V, Ramachandran A, Snehalatha C, Viswanathan M 1992 The islet amyloid polypeptide gene and non-insulindependent diabetes mellitus in south Indians Diabetes Res Clin Pract 18: 31-34 Mohan V 2004 Why Are Indians More Prone to Diabetes? JAPI, 52: 468-474 Mohan V, Vimaleswaran KS, Anjana M, Radha V, Deepa R 2005 The Thr394Thr GA Polymorphism of PGC-1 gene is
associated with visceral fat and Type 2 Diabetes in Asian Indians American Diabetes Association Annual Meeting, Abstract Number: 1174-P North BV, Curtis D, Cassell PG, Hitman GA, Sham PC 2003 Assessing optimal neural network architecture for identifying disease-associated multi-marker genotypes using a permutation test, and application to calpain 10 polymorphisms associated with diabetes Annals of Human Genetics, 67: 348-356 ORahilly S, Barroso I, Wareham NJ 2005 Genetic Factors in Type 2 Diabetes: The End of the Beginning? Science, 307: 370-373 Olefsky JM 2001 Prospects for Research in Diabetes Mellitus JAMA, 285: 628-632 Permutt MA, Wasson J, Cox N 2005Genetic epidemiology of diabetes J Clin Investigation, 115: 14311439 Pontiroli AE, Capra F, Veglia F, Ferrari M, Xiang KS, Bell GI, Baroni MG, Galton DJ, Weaver JU, Hitman GA, Kopelman PG, Mohan V, Viswanathan M 1996 Genetic contribution of polymorphism of the GLUT1 and GLUT4 genes to the susceptibility to type 2 non-insulin-dependent diabetes mellitus in different populations Acta Diabetol, 33: 193-197 Radha V, Vimaleswaran KS, Deepa R, Mohan V 2003 The genetics of diabetes mellitus Indian J Med Res, 117: 225-238 Ramachandran A
2005 Epidemiology of Diabetes in India Three Decades of Research JAPI, 53: 3438 Ramachandran A, Snehalata C, Kapur A, Vijay V, Mohan V, Das AK, Rao PV, Yajnik CS, Kuamar KMP, Nair JD for the Diabetes Epidemiology Study Group in India DESI 2001 High prevalence of diabetes and
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impaired glucose tolerance in India: National Urban Diabetes Survey Diabetologia, 44: 1094-1101 Ramachandran A, Snehalatha C, Baskar ADS, Mary S, Sathish Kumar CK, Selvam S, Catherine S , Vijay V 2004 Temporal changes in prevalence of diabetes and impaired glucose tolerance associated with lifestyle transition occurring in the rural population in India Diabetologia, 47: 860865 Rema M, Saravanan G, Deepa R, Mohan V 2002 Familial clustering of diabetic retinopathy in South Indian Type 2 diabetic patients Diabet Med, 19: 910916 Sadikot SM, Nigam A, Das S, Bajaj S, Zargar AH, Prasannakumar KM, Sosale A, Munichoodappa C, Seshiah V, Singh SK, Jamal A, Sai K, Sadasivrao Y, Murthy SS, Hazra DK, Jain S, Mukherjee S, Bandyopadhay S, Sinha NK, Mishra R, Dora M, Jena B, Patra P, Goenka K on behalf of DiabetesIndia 2004 Comparing the ADA 1997 and the WHO 1999 criteria: Prevalence of Diabetes in India Study Diabetes
Research and Clinical Practice, 66: 309315 Sanghera DK, Bhatti JS, Bhatti GK, Ralhan SK, Wander GS, Singh JR, Bunker CH, Weeks DE, Kamboh MI, Ferrell RE 2005 The Khatri Sikh Diabetes Study SDS: Study design, methodology sample collection and initial results American Society of Human Genetics Annual Meeting; Abstract 2406 Snehalatha C, Ramchandran A, Kapur A, Vijay V 2003 Age-Specific Prevalence and Risk Associations for Impaired Glucose Tolerance in Urban Southern Indian Population JAPI, 51: 766-769 Stern MP 2002 The search for type 2 diabetes susceptibility genes using whole-genome scans: An epidemiologists perspective Diabetes Metab Res Rev, 18: 106-113 Tiwari AK 2005Wisdom of Ayurveda in perceiving diabetes: Enigma of therapeutic recognition Current Science, 88: 1043-1051 Venkatesan R, Vimaleswaran S, Babu HNS, Rao MRS, Mohan V 2003 Pro12Ala Polymorphism of PPAR2 and Gly482Ser Polymorphism of PGC-1genes: Association with Insulin Resistance and Type II Diabetes Mellitus in an Urban South Indian Population American Diabetes Association Annual Meeting: Abstract Number: 2230-PO Viswanathan V, Zhu Y, Bala K, Dunn S, Snehalatha C, Ramachandran A, Jayaraman M, Sharma K 2001 Association
between ACE gene polymorphism and diabetic nephropathy in South Indian patients JOP, 2: 83-7 Wild S, Roglic G, Green A, Sicree R, King H 2004 Global Prevalence of Diabetes Estimates for the year 2000 and projections for 2030 Diabetes Care, 27: 10471053
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