Abstract
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 (6617 MetS and 3476 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 (N = 2158) and replication phase (N = 7935). We discovered two variants within/near the CETP gene—rs1800775 and rs3816117—associated with MetS at genome-wide significance level during replication phase in Indians. Additional CETP 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 CETP locus constituting all seven CETP signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus—rs16890462 in the vicinity of SFRP1 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.
Highlights
Metabolic syndrome (MetS) refers to a complex pathophysiological state attained by conjugation of a set of cardiometabolic risk components in an individual that include—central obesity, dyslipidemia, elevated blood pressure, and fasting plasma glucose [1]
The present study was the first genome-wide association study that identifies a common genetic basis of compound metabolic syndrome (MetS) phenotype in Indians of Indo-European origin living in India
Haplotype analysis revealed a stronger haplotype within CETP locus (OR = 1.26, p = 7.97 × 10−8 for GCCCAGC haplotype) harboring risk alleles of single nucleotide polymorphism (SNP) rs173539, rs247617, rs3764261, rs1800775, rs3816117, rs7205804, and rs1532624 respectively for association with MetS in Indians
Summary
Metabolic syndrome (MetS) refers to a complex pathophysiological state attained by conjugation of a set of cardiometabolic risk components in an individual that include—central obesity, dyslipidemia, elevated blood pressure, and fasting plasma glucose [1]. Genetic loci in BUD13, ZNF259, APOA5, LPL, and CETP in Europeans [18], TCF7L2, APOA5, LPL, CETP, APOE, and APOC1 in African Americans [19], CA10 and CTNNA3 in Africans [20], APOA1/C3/A4/A5 gene cluster region in Finnish [21], APOA5, BUD13, and ALDH2 in Han Chinese [22], LPL, MYL2, CCDC63, and CETP in Koreans [23], and APOA and COLEC12 in Taiwanese [24] have been attributed for strong association with MetS These studies highlight multiple shared lipid metabolism pathway genes across diverse populations as well as novel population-specific genes, which require the need for additional population-wide genetic studies to delineate remaining genetic heritability of MetS across varied ethnicities [25]. Indians have an increased body fat mass, a greater truncal, intra-abdominal subcutaneous adipose tissue with ectopic fat buildup compared to Caucasians, resulting in an enhanced risk for metabolic syndrome and CVD [28,30] These reasons underscore the possibility of population-specific genetic risk towards MetS phenotype in India.
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