A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

Yamauchi, Toshimasa; Hara, Kazuo; Maeda, Shiro; Yasuda, Kazuki; Takahashi, Atsushi; Horikoshi, Momoko; Nakamura, Masahiro; Fujita, Hayato; Grarup, Niels; Cauchi, Stéphane; Ng, Daniel P.K.; Ma, Rong; Tsunoda, Tatsuhiko; Kubo, Michiaki; Watada, Hirotaka; Maegawa, Hiroshi; Okada-Iwabu, Miki; Iwabu, Masato; Shojima, Nobuhiro; Shin, Hyoung Doo; Andersen, Gitte; Witte, Daniel R.; Jørgensen, Torben; Lauritzen, Torsten; Sandbæk, Annelli; Hansen, Torben; Ohshige, Toshihiko; Omori, Shintaro; Saito, Ikuo; Kaku, Kohei; Hara, Hiroshi; So, Wing Yee; Beury, Delphine; Chan, Juliana C.N.; Park, Kyong Soo; Tai, E. Shyong; Ito, Chikako; Tanaka, Yasushi; Kashiwagi, Atsunori; Kawamori, Ryuzo; Kasuga, Masato; Froguel, Philippe; Pedersen, Oluf; Kamatani, Naoyuki; Nakamura, Yusuke; Kadowaki, Takashi

doi:10.1038/ng.660

Cited by 242 publications

(220 citation statements)

References 36 publications

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“…Genome-wide association studies (GWASs) and subsequent meta-analyses have identified >56 susceptibility loci for type 2 DM (3)(4)(5)(6)(7)(8)(9)(10)(11). However, these susceptibility loci have been identified predominantly in Caucasian populations.…”

Section: Introductionmentioning

confidence: 99%

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

et al. 2014

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Abstract.Various loci and genes that confer susceptibility to coronary heart disease (CHD) have been identified in Caucasian populations by genome-wide association studies (GWASs). As type 2 diabetes mellitus (DM) is an important risk factor for CHD, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to CHD through affecting the susceptibility to type 2 DM. The purpose of the present study was to examine a possible association of type 2 DM in Japanese individuals with 29 polymorphisms identified as susceptibility loci for CHD by meta-analyses of the GWASs. The study subjects comprised of 3,757 individuals (1,444 subjects with type 2 DM and 2,313 controls). The polymorphism genotypes were determined by the multiplex bead-based Luminex assay, which combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. To compensate for multiple comparisons of genotypes, the criterion of a false discovery rate (FDR) ≤0.05 was adopted for testing the statistical significance of the association. The comparisons of allele frequencies by the χ 2 test revealed that the rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1) was significantly associated (P=0.0017; FDR=0.050) with type 2 DM. Multivariable logistic regression analysis with adjustment for age, gender and body mass index revealed that rs964184 of ZPR1 was significantly associated (P= 0.0012; odds ratio, 1.25; dominant model) with type 2 DM with the minor G allele representing a risk factor for this condition. Fasting plasma glucose levels (P=0.0076) and blood glycosylated hemoglobin contents (P=0.0132) significantly differed among ZPR1 genotypes with the G allele associated with increases in these parameters. ZPR1 may thus be a susceptibility locus for type 2 DM in Japanese individuals.

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Section: Introductionmentioning

confidence: 99%

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

et al. 2014

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“…The Thr-containing protein has a two-fold higher affinity for long-chain fatty acids than the Ala-containing protein (Wanby et al, 2005). The Ala54Thr polymorphism increases free fatty acid transport and triglyceride secretion in vitro (Yamauchi et al, 2010), which are associated with high levels of fasting insulin. Moreover, previous studies have found that FABP2 is a candidate gene possibly implicated in the pathogenesis of T2DM, MetS, and obesity in different ethnic groups (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Association of the FABP2 Ala54Thr polymorphism with type 2 diabetes, obesity, and metabolic syndrome: a population-based case-control study and a systematic meta-analysis

Liu¹,

Wu²,

Han³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Previous studies have reported associations between the functional FABP2 Ala54Thr (rs1799883) polymorphism and type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome in different populations with conflicting results. We investigated the association between the FABP2 Ala54Thr polymorphism and T2DM (235 cases, 431 controls), obesity (377 cases, 431 controls), and metabolic syndrome (315 cases, 323 controls) by logistic regression analysis in a Chinese study cohort recruited from Yichang, Hubei Province. We then comprehensively reviewed the association of the FABP2 Ala54Thr polymorphism with T2DM, obesity, and metabolic syndrome via meta-analysis. The strength of association was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). The FABP2 Ala54Thr polymorphism was significantly associated with obesity (AT vs AA:Y. Liu et al. 1156©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (1): 1155-1168 (2015) OR = 2.633, 95%CI = 1.065-6.663, P = 0.036; TT vs AA: OR = 4.160, 95%CI = 1.609-10.757, P = 0.003) and metabolic syndrome (TT vs AA: OR = 2.273, 95%CI = 1.242-4.156, P = 0.008) by logistic regression with adjustment for covariates. However, no significant association was found between T2DM and the FABP2 Ala54Thr polymorphism. We identified 24 studies on T2DM (4517 cases, 5224 controls), 9 studies on obesity (949 cases, 2002 controls), and 6 studies on metabolic syndrome (2194 cases, 3282 controls) by literature search. The metaanalyses revealed significant associations for metabolic syndrome (T allele: OR = 1.179, 95%CI = 1.015-1.362, P = 0.031) and T2DM (T allele: OR = 1.160, 95%CI = 1.08-1.24, P < 0.001), but no association for obesity (T allele: OR = 1.069, 95%CI = 0.925-1.235, P = 0.367).

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“…In the past decade, a number of genetic genome-wide association studies (GWAS) have revealed 40 loci consistently associated with susceptibility to T2D and have rapidly expanded our knowledge of the genetic architecture of this disease (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). However, the genes located in or near these loci do not fully elucidate the tissue-specific molecular mechanisms underlying the development of T2D.…”

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confidence: 99%

Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

Kodama

Horikoshi²,

Toda

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10 −20 ). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.bioinformatics | meta-analysis | integration | obesity | hyperglycemia

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A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

Cited by 242 publications

References 36 publications

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

Association of the FABP2 Ala54Thr polymorphism with type 2 diabetes, obesity, and metabolic syndrome: a population-based case-control study and a systematic meta-analysis

Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

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