Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India.
Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi 110020, India.
Biomolecules. 2019 Jul 30;9(8):321. doi: 10.3390/biom9080321.
Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6,617 MetS and 3,476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages-discovery phase ( = 2,158) and replication phase ( = 7,935). We discovered two variants within/near the gene-rs1800775 and rs3816117-associated with MetS at genome-wide significance level during replication phase in Indians. Additional loci rs7205804, rs1532624, rs3764261, rs247617, and rs173539 also cropped up as modest signals in Indians. Haplotype association analysis revealed GCCCAGC as the strongest haplotype within the locus constituting all seven signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus-rs16890462 in the vicinity of gene. Overlaying gene regulatory data from ENCODE database revealed that single nucleotide polymorphism (SNP) rs16890462 resides in repressive chromatin in human subcutaneous adipose tissue as characterized by the enrichment of H3K27me3 and CTCF marks (repressive gene marks) and diminished H3K36me3 marks (activation gene marks). The variant displayed active DNA methylation marks in adipose tissue, suggesting its likely regulatory activity. Further, the variant also disrupts a potential binding site of a key transcription factor, NRF2, which is known for involvement in obesity and metabolic syndrome.
印度人是一个人口增长迅速的族群，其遗传异质性与西方人群相比非常巨大。然而，在过去几十年中，由于快速的城市化进程导致代谢综合征（MetS）的患病率显著增加，他们已经成为了一个定居人口。我们对来自印度糖尿病联盟（INDICO）生物样本库的 10093 名具有欧印血统的印度个体（6617 名 MetS 患者和 3476 名对照者）进行了一项代谢综合征的全基因组关联研究（GWAS）。该研究分两个阶段进行——发现阶段（n=2158）和复制阶段（n=7935）。在复制阶段，我们在印度人群中发现了两个位于/附近的基因-rs1800775 和 rs3816117 与 MetS 相关的变体，达到了全基因组显著水平。在印度人群中，还出现了其他几个较弱的信号，包括 rs7205804、rs1532624、rs3764261、rs247617 和 rs173539。单体型关联分析显示，在 基因内，GC C CAGC 是最强的单体型，构成了所有七个信号。在联合分析中，我们在 基因附近发现了一个新的、具有功能相关性的亚全基因组显著位点-rs16890462。覆盖 ENCODE 数据库的基因调控数据显示，单核苷酸多态性（SNP）rs16890462 位于人类皮下脂肪组织的抑制性染色质中，其特征是富含 H3K27me3 和 CTCF 标记（抑制基因标记），而 H3K36me3 标记减少（激活基因标记）。该变体在脂肪组织中显示出活跃的 DNA 甲基化标记，表明其可能具有调节活性。此外，该变体还破坏了一个关键转录因子 NRF2 的潜在结合位点，NRF2 已知与肥胖和代谢综合征有关。
