Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie , Japan.
CREST, Japan Science and Technology Agency, Kawaguchi, Saitama , Japan.
Physiol Genomics. 2018 Mar 1;50(3):179-189. doi: 10.1152/physiolgenomics.00117.2017. Epub 2018 Jan 12.
Recent genome-wide association studies have identified various obesity or metabolic syndrome (MetS) susceptibility loci. However, most studies were conducted in a cross-sectional manner. To address this gap, we performed a longitudinal exome-wide association study to identify susceptibility loci for obesity and MetS in a Japanese population. We traced clinical data of 6,022 Japanese subjects who had annual health check-ups for several years (mean follow-up period, 5 yr) and genotyped ~244,000 genetic variants. The association of single nucleotide polymorphisms (SNPs) with body mass index (BMI) or the prevalence of obesity and MetS was examined in a generalized estimating equation model. Our longitudinal exome-wide association studies detected 21 BMI- and five MetS-associated SNPs (false discovery rate, FDR <0.01). Among these SNPs, 16 have not been previously implicated as determinants of BMI or MetS. Cross-sectional data for obesity- and MetS-related phenotypes in 7,285 Japanese subjects were examined in a replication study. Among the 16 SNPs, three ( rs9491140 , rs145848316 , and rs7863248 ) were related to BMI in the replication cohort ( P < 0.05). In conclusion, three SNPs [ rs9491140 of NKAIN2 (FDR = 0.003, P = 1.9 × 10), rs145848316 of KMT2C (FDR = 0.007, P = 4.5 × 10), and rs7863248 of AGTPBP1 (FDR = 0.006, P = 4.2 × 10)] were newly identified as susceptibility loci for BMI.
最近的全基因组关联研究已经确定了各种肥胖或代谢综合征（MetS）易感性基因座。然而，大多数研究都是采用横断面方式进行的。为了解决这一差距，我们对日本人群进行了一项纵向外显子组全基因组关联研究，以确定肥胖和 MetS 的易感基因座。我们追踪了 6022 名日本受试者的临床数据，这些受试者在几年内进行了年度健康检查（平均随访时间为 5 年），并对约 244000 个遗传变异进行了基因分型。采用广义估计方程模型，对单核苷酸多态性（SNP）与体重指数（BMI）或肥胖和 MetS 的患病率之间的关联进行了检验。我们的纵向外显子组全基因组关联研究检测到 21 个 BMI 和 5 个 MetS 相关 SNP（错误发现率，FDR <0.01）。在这些 SNP 中，有 16 个以前没有被认为是 BMI 或 MetS 的决定因素。在 7285 名日本受试者的肥胖和 MetS 相关表型的横断面数据中进行了重复研究。在 16 个 SNP 中，有 3 个（rs9491140、rs145848316 和 rs7863248）在复制队列中与 BMI 相关（P <0.05）。综上所述，三个 SNP[NKAIN2 的 rs9491140（FDR = 0.003，P = 1.9×10）、KMT2C 的 rs145848316（FDR = 0.007，P = 4.5×10）和 AGTPBP1 的 rs7863248（FDR = 0.006，P = 4.2×10）]被新确定为 BMI 的易感基因座。
