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Biomolecules. 2019 Jul 30;9(8). pii: E321. doi: 10.3390/biom9080321.

Genome-Wide Association Study of Metabolic Syndrome Reveals Primary Genetic Variants at CETP Locus in Indians.

Author information

1
Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India.
2
Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi 110020, India.
3
Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
4
Department of Endocrinology, S.M.S. Medical College, Jaipur, Rajasthan 302004, India.
5
Division of Endocrinology, University College of Medical Sciences, New Delhi 110095, India.
6
Department of Endocrinology, All India Institute of Medical Sciences, New Delhi 110029, India.
7
Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India.
8
Department of Endocrinology, International Life Sciences Institute, New Delhi 110024, India.
9
National Institute of Bio Medical Genomics, Netaji Subhas Sanatorium (Tuberculosis Hospital), Kalyani 741251, West Bengal, India.
10
Department of Endocrinology, All India Institute of Medical Sciences, New Delhi 110029, India. nikhil_tandon@hotmail.com.
11
Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi 110020, India. db@jnu.ac.in.
12
Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. db@jnu.ac.in.

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 (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 (N = 2,158) and replication phase (N = 7,935). 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.

KEYWORDS:

gene regulation; genetic variants; genome wide association study; metabolic syndrome

PMID:
31366177
DOI:
10.3390/biom9080321
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