Yamada Yoshiji, Kato Kimihiko, Oguri Mitsutoshi, Horibe Hideki, Fujimaki Tetsuo, Yasukochi Yoshiki, Takeuchi Ichiro, Sakuma Jun
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.
CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
Biomed Rep. 2018 Jul;9(1):21-36. doi: 10.3892/br.2018.1105. Epub 2018 May 29.
Given that early-onset type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and hyperuricemia have been shown to have strong genetic components, the statistical power of a genetic association study may be increased by focusing on early-onset subjects with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with T2DM, MetS, and hyperuricemia, genetic variants that contribute to predisposition to these conditions in Japanese subjects remain to be identified definitively. We performed exome-wide association studies (EWASs) for early-onset T2DM, MetS, or hyperuricemia to identify genetic variants that confer susceptibility to these conditions. A total of 8,102 individuals aged ≤65 years were enrolled in the present study. The EWAS for T2DM was performed with 7,407 subjects (1,696 cases, 5,711 controls), that for MetS with 4,215 subjects (2,296 cases, 1,919 controls), and that for hyperuricemia with 7,919 subjects (1,365 cases, 6,554 controls). Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relationship of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed quality control for T2DM, MetS, or hyperuricemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with T2DM, MetS, or hyperuricemia, we applied Bonferroni's correction for statistical significance of association. The EWAS of allele frequencies revealed that four, six, or nine SNPs were significantly associated with T2DM (P<1.60×10), MetS (P<1.59×10), or hyperuricemia (P<1.61×10), respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that three, six, or nine SNPs were significantly related to T2DM (P<0.0031), MetS (P<0.0021), or hyperuricemia (P<0.0014). After examination of the association of identified SNPs to T2DM-, MetS-, or hyperuricemia-related traits, linkage disequilibrium of the SNPs, and results of previous genome-wide association studies, newly identified and were the susceptibility loci for T2DM, and for MetS, and for hyperuricemia. Given that was significantly associated with both T2DM and MetS, we newly identified four genes () that confer susceptibility to early-onset T2DM, MetS, or hyperuricemia. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for T2DM, MetS, or hyperuricemia.
鉴于早发型2型糖尿病（T2DM）、代谢综合征（MetS）和高尿酸血症已被证明具有很强的遗传成分，通过聚焦患有这些疾病的早发型受试者，基因关联研究的统计效能可能会提高。尽管全基因组关联研究已经确定了与T2DM、MetS和高尿酸血症显著相关的各种基因和位点，但在日本受试者中，导致这些疾病易感性的基因变异仍有待明确鉴定。我们对早发型T2DM、MetS或高尿酸血症进行了外显子组全关联研究（EWAS），以确定赋予这些疾病易感性的基因变异。本研究共纳入了8102名年龄≤65岁的个体。对T2DM的EWAS在7407名受试者（1696例病例，5711例对照）中进行，对MetS的EWAS在4215名受试者（2296例病例，1919例对照）中进行，对高尿酸血症的EWAS在7919名受试者（1365例病例，6554例对照）中进行。使用Illumina Human Exome - 12 DNA分析微珠芯片或Infinium Exome - 24微珠芯片阵列对单核苷酸多态性（SNP）进行基因分型。分别对通过T2DM、MetS或高尿酸血症质量控制的31210、31521或31142个SNP的等位基因频率关系进行Fisher精确检验。为了补偿与T2DM、MetS或高尿酸血症相关的基因型的多重比较，我们应用Bonferroni校正来确定关联的统计学显著性。等位基因频率的EWAS显示，分别有4个、6个或9个SNP与T2DM（P<1.60×10）、MetS（P<1.59×10）或高尿酸血症（P<1.61×10）显著相关。在对年龄和性别进行调整的多变量逻辑回归分析中，分别有3个、6个或9个SNP与T2DM（P<0.0031）、MetS（P<0.0021）或高尿酸血症（P<0.0014）显著相关。在检查已鉴定的SNP与T2DM、MetS或高尿酸血症相关性状的关联、SNP的连锁不平衡以及先前全基因组关联研究的结果后，新鉴定出 和 是T2DM的易感位点， 和 是MetS的易感位点， 是高尿酸血症的易感位点。鉴于 与T2DM和MetS均显著相关，我们新鉴定出4个基因（ ）赋予早发型T2DM、MetS或高尿酸血症易感性。确定这些基因中SNP的基因型可能对评估T2DM、MetS或高尿酸血症的遗传风险具有参考价值。
