Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population

Chandak, Giriraj Ratan; Janipalli, C. S.; Bhaskar, Suryanarayanan; Kulkarni, S. R.; Mohankrishna, P; Hattersley, Andrew T.; Frayling, Timothy M.; Yajnik, C.S.

doi:10.1007/s00125-006-0502-2

Cited by 243 publications

(223 citation statements)

References 14 publications

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“…It is noteworthy that the association between the SNP in TCF7L2 and type 2 diabetes has consistently been observed in different ethnic groups [14,15], which supports the reliability of both previous studies as well as our present study. The mechanism of action of TCF7L2 in glucose metabolism and the pathogenesis of type 2 diabetes has yet to be elucidated, but it is possible that TCF7L2 has a role in regulating glucose-sensitive insulin secretion from beta cells.…”

Section: Discussionsupporting

confidence: 93%

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population

Horikoshi

Hara

Ito³

et al. 2007

Diabetologia

137

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Aims/hypothesis It has been suggested that transcription factor 7-like 2 protein (TCF7L2) plays an important role in glucose metabolism by regulating the production level of glucagon-like peptide-1, a hormone which modifies glucosedependent insulin secretion. Recently, variants of TCF7L2 gene were reported to confer an increased risk of type 2 diabetes in three different samples from European and European-origin populations. We studied whether the single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in samples from a Japanese population. Methods Five SNPs were genotyped in three different sample sets. Association with type 2 diabetes was investigated in each, as well as in combined sample sets. Results The SNP rs7903146 was nominally associated with type 2 diabetes in the initial (p=0.08) and two replication sample sets (p=0.05 and 0.06). For the combined sample set, in which we successfully genotyped 1,174 type 2 diabetes patients and 823 control subjects, rs7903146 showed a significant association with type 2 diabetes (odds ratio=1.69 [95% CI 1.21-2.36], p=0.002) with the same direction as the previous reports in samples from European and European-origin populations. SNPs rs7903146 and rs7901695 were in complete linkage disequilibrium. The rest of the five SNPs (rs7895340, rs11196205 and rs12255372) did not show any significant associations with type 2 diabetes. Conclusions/interpretation The consistent association between rs7903146 in TCF7L2 and type 2 diabetes in different ethnic groups, including the Japanese population, suggests that TCF7L2 is a common susceptibility gene for type 2 diabetes.

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Section: Discussionsupporting

confidence: 93%

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population

Horikoshi

Hara

Ito³

et al. 2007

Diabetologia

137

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“…35) and has been replicated in subsequent studies in many different ethnicities. [8][9][10][11][12][13][14][15][16] The association of other newly emerged GWAS loci, such as IGF2BP2, CDKAL1, CDKN2A/B, HHEX, SLC30A8 and KCNJ11, was replicated in Japanese; 17,18 IGF2BP2, SLC30A8, HHEX, CDKAL1, CDKN2A/B and FTO in Asians from Hong Kong and Korea; 19 IGF2BP2, CDKAL1, CDKN2A/B, HHEX and SLC30A8 in Han Chinese; 20 and IGF2BP2, PPARG2 and FTO in Indian Sikhs. 21 More recently, a meta-analysis of three large GWA studies by the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium identified six additional T2D loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) to be strongly associated with increased susceptibility to T2D with modest ORs (1.15À1.3).…”

Section: Introductionmentioning

confidence: 96%

Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs

et al. 2009

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A recent meta-analysis on three genome-wide association (GWA) scans identified six loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) highly associated with type II diabetes (T2D) in Caucasians. This investigation seeks to confirm this association with diabetes and related metabolic traits in Khatri Sikh diabetics of North India. We genotyped highly significant variants from each locus in a case-control cohort consisting of 680 T2D cases and 637 normoglycemic (NG) controls. Only CDC123/CAMKID (rs12779790) replicated earlier evidence of association with T2D under a dominant model (odds ratio (OR): 1.27; 95% confidence interval (CI): 1.02-1.57; P¼0.031) during initial testing. However, we could not confirm this association using multiple testing corrections. In a multiple linear-regression analysis, the same variant in the CDC123/CAMKID revealed a marked decrease in fasting insulin levels among 'G' (risk) allele carriers independently in NG controls (P¼0.030) and in T2D cases (P¼0.009), as well as in the combined sample (P¼0.003) after adjusting for covariates. Evidence of impaired b-cell function was also observed among 'G' (risk) allele carriers in T2D cases (P¼0.008) and in a combined cohort (P¼0.026). Our data could not confirm the role of the remaining variants with risk either for T2D or quantitative phenotypes measuring insulin secretion or insulin resistance. These findings suggest that CDC123/CAMKID could be a major risk factor for the development of T2D in Sikhs by affecting b-cell function. To our knowledge, this is the first study reporting the role of recently emerging loci in this high-risk population from the South Asian subcontinent.

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“…Grant et al suggested that two SNPs (rs12255372 and rs7903146) [3] be analysed for replication of their finding in other populations. Since the original publication, a number of studies have confirmed the association between TCF7L2 and type 2 diabetes mellitus in European, Asian and American cohorts [4][5][6][7][8][9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 98%

Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men

et al. 2007

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Aims/hypothesis In a population-based cohort of elderly men with well-defined phenotypes and biochemical markers related to type 2 diabetes mellitus, we analysed two single nucleotide polymorphisms (SNPs), rs7903146 and rs12255372, in the transcription factor 7-like 2 gene (TCF7L2), which are associated with an increased risk of type 2 diabetes mellitus. Materials and methods The 1,142 subjects were from the population-based Uppsala Longitudinal Study of Adult Men cohort study (see http://www.pubcare.uu.se/ULSAM/, last accessed in May 2007). Insulin sensitivity was assessed using a euglycaemic-hyperinsulinaemic clamp; fasting intact and 32-33 split proinsulin, immunoreactive insulin and specific insulin were measured in plasma samples. The SNPs rs7903146 and rs12255372 were genotyped using a fluorescent homogeneous single base extension assay. The SNP genotypes were analysed against diabetes prevalence at age 70 using logistic regression and against quantitative biochemical measures using linear regression analysis. Results We replicated the association with type 2 diabetes mellitus for both SNPs in this cohort of elderly males. The highest significant odds ratio (2.15, 95% CI 1.20-3.85) was found for SNP rs7903146. The odds ratio for SNP rs12255372 was 1.69 (95% CI 1.20-2.39). Both TCF7L2 SNPs were found to be significantly associated with plasma proinsulin when adjusting for insulin sensitivity, both in the whole cohort and when the diabetic subjects were excluded. Analysis for fasting plasma insulin or insulin sensitivity did not give significant results. Conclusions/interpretation The association between the risk alleles of the two SNPs studied and levels of proinsulin in plasma, identified when adjusting for insulin sensitivity using euglycaemic-hyperinsulinaemic clamp measurements in this study, is an important novel finding.

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Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population

Abstract: Aims and hypothesis India has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood.

Cited by 243 publications

References 14 publications

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population

Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs

Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men

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