Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians

Ng, Maggie C. Y.; Park, Kyong Soo; Oh, Bermseok; Tam, Claudia H.T.; Cho, Young Min; Shin, Hyoung Doo; Lam, Vincent K.; Ma, Rong; So, Wing Yee; Cho, Yoon Shin; Kim, Hyung Lae; Lee, Hong Kyu; Chan, Juliana C.N.; Cho, Nam H.

doi:10.2337/db07-1583

Cited by 329 publications

(276 citation statements)

References 35 publications

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“…Genotypes were given codes of 0, 1 and 2, and the OR was expressed The SNP included from the European ancestry combined study was rs7756992 [47]. The SNPs included from DGI, WTCCC/UKT2D and FUSION, and Korean studies were rs7754840, rs10811661, rs8050136, rs111187, rs4402960, rs13266634, and rs7903146 [20,23,25]. The SNP included from Icelandic study was rs7923837 [ [25].…”

Section: Methodsmentioning

confidence: 99%

“…The SNPs included from DGI, WTCCC/UKT2D and FUSION, and Korean studies were rs7754840, rs10811661, rs8050136, rs111187, rs4402960, rs13266634, and rs7903146 [20,23,25]. The SNP included from Icelandic study was rs7923837 [ [25]. Insulin resistance was evaluated using the HOMA-IR, and insulin secretory function was assessed by determination of the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM.…”

Section: Methodsmentioning

confidence: 99%

“…the HHEX-IDE and CDKN2A-CDKN2B regions) [19][20][21][22][23]. We recently found that the diabetogenic genetic variants reported by the large-scale GWA studies in Europids [19][20][21][22][23] were also associated with the risk of type 2 diabetes in Asian populations, including Koreans [25].…”

Section: Introductionmentioning

confidence: 99%

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Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

et al. 2008

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Aims/hypothesis New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants and gestational diabetes mellitus (GDM). Methods The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A−CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls. Results Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34-1.79, p=4.17×10 −9 ) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29-1.72, p=1.05×10 −7 ) in the CDKN2A−CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09-1.49, p=0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01-1.38, p=0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07-1.43, p=0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03-2.43, p=0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A-CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM. Conclusions/interpretation Some of the type 2 diabetesassociated genetic variants that were discovered in the recent GWA studies are also associated with GDM in Koreans.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

et al. 2008

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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: 97%

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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“…Several studies have investigated the association of type 2 diabetes loci from GWAS with body fat and BMI. [20][21][22] However, there are few reports of the association between type 2 diabetes susceptibility SNPs and visceral fat accumulation. 21,23,24 Associations between type 2 diabetes susceptibility SNPs, except those exited in the FTO gene and visceral fat mass determined by using more precise method, such as CT and magnetic resonance imaging, have not been elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography

Hotta

Kitamoto

et al. 2012

J Hum Genet

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Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P¼0.00088 and P¼0.0010, respectively) and SFA (P¼0.00013 and P¼0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.

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Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians

Cited by 329 publications

References 35 publications

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

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

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography

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