Association ofCDKAL1, IGF2BP2, CDKN2A/B, HHEX,SLC30A8,andKCNJ11With Susceptibility to Type 2 Diabetes in a Japanese Population

Abstract

OBJECTIVE—Recently, several genes have been shown to be associated with an increased risk of type 2 diabetes by genome-wide association studies in white populations. To further investigate the involvement of these polymorphisms in conferring susceptibility to type 2 diabetes, we examined the association of 14 single nucleotide polymorphisms (SNPs) within 11 candidate loci with type 2 diabetes in a Japanese population. RESEARCH DESIGN AND METHODS—We analyzed 14 SNPs (rs4402960 in IGF2BP2, rs10811661 in CDKN2A/B, rs1111875 and rs7923837 in HHEX, rs13266634 in SLC30A8, rs1113132 and rs11037909 in EXT2, rs9939609 and rs8050136 in FTO, rs7756992 in CDKAL1, rs1801282 in PPARG Pro12Ara, rs5219 in KCNJ11 Glu23Lys, rs7480010 in LOC387761, and rs9300039 in Ch11) in 1,630 Japanese subjects with type 2 diabetes and in 1,064 control subjects by using an invader assay or a TaqMan assay. RESULTS—Among the 11 loci examined, 6 were significantly associated with type 2 diabetes in our population by a logistic regression analysis, similar to previously reported results (rs4402960, P = 0.00009; rs10811661, P = 0.0024; rs5219, P = 0.0034; rs1111875, P = 0.0064; rs13266634, P = 0.0073; rs7756992, P = 0.0363). In this population, the remaining five loci were not significantly associated with type 2 diabetes. In addition, we identified significant association of the SNPs in FTO gene with BMI in the control subjects. CONCLUSIONS—We have identified 6 of the 11 loci that were identified by genome-wide association studies in white populations, and these loci are considered strong candidates for type 2 diabetes susceptibility across different ethnicities.

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

“…Especially, they were all located within CDKAL1 gene except for an intergenic variant of rs5015480 near HHEX gene. The association of the CDKAL1 gene concurred with the results from previous studies with American, 1 British, 5 French, 3 Danish, 4 Finnish, 2 Swedish, 1 Icelandic, 4 Korean, 9 Japanese, 10 and Chinese [11][12][13] populations. The significantly associated variants of the gene in the current study were specifically corresponding to those found in previous studies of Horikawa et al 14 and Wu et al 11 for rs7756992 and Zeggini et al 5 and Wu et al 11 for rs9465871 and rs10946398, respectively.…”

“…As an example, such deflation was suspected in a nominal effect resulted with a large ratio of males to females (1.5 for both patients and control subjects). 10 The genetic heterogeneity by gender might be attributed to sexual hormones which considerably influenced insulin sensitivity and secretion. 20,21 Especially, as estrogen could affect the susceptibility of T2DM 22 and regulate the activity of cdk5 in adult rat uterus, 23 it could serve as an important candidate resulting in the gender-specific effect of CDKAL1 on T2DM susceptibility.…”

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

“…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).…”

Engaging Hmong adults in genomic and pharmacogenomic research: Toward reducing health disparities in genomic knowledge using a community-based participatory research approach

“…Because of community members' concerns about dangers of warfarin and type 2 diabetes mellitus (T2DM), we selected relevant SNPs for the warfarin metabolizing gene CYP2C9 and the warfarin target gene VKORC1 and one SNP for the gene CDKN2A, which was reported to be associated with increased risk for T2DM (Saxena et al 2007;Scott et al 2007). Based on published guidelines , we specifically investigated allele frequencies for three validated SNPs associated with altered response to warfarin (CYP2C9*2, CYP2C9*3, and VKORC1) ) and one SNP (rs10811661 CDKN2A) associated with increased risk for T2DM (Omori et al 2008;Wu et al 2008). We selected these genes to serve as concrete examples of genetic based drug response or disease risk factors for our purpose of engaging Hmong community members in this study and did not provide actionable information of value for anyone involved in this study, regardless of their past or current exposure to warfarin, current T2DM or risk for T2DM.…”

“…Specific study results of the allele frequencies for the genetic variants and participants' biological characteristics are reported elsewhere (Straka 2010). For the genetic variant associated with increased risk of type 2 diabetes mellitus (CDKN2A, rs10811661), we informed participants that approximately 44% carried the single SNP associated with a 26-33% increased risk for developing T2DM and that this was not different than other populations made up of either a Han-Chinese (Wu et al 2008) or Japanese populations, respectively (Omori et al 2008). For the pharmacogenomic results associated with altered response to warfarin (based on analysis of CYP2C9*2, CYP2C9*3, and VKORC1), we informed participants that the Hmong displayed a prevalence of individuals who may have a lower dosage requirement for the drug warfarin compared to nonHmong.…”