Identification of a 1p21 independent functional variant for abdominal obesity View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-04-03

AUTHORS

Lu Liu, Yu-Fang Pei, Tao-Le Liu, Wen-Zhu Hu, Xiao-Lin Yang, Shan-Cheng Li, Rong Hai, Shu Ran, Lan Juan Zhao, Hui Shen, Qing Tian, Hong-Mei Xiao, Kun Zhang, Hong-Wen Deng, Lei Zhang

ABSTRACT

OBJECTIVES: Aiming to uncover the genetic basis of abdominal obesity, we performed a genome-wide association study (GWAS) meta-analysis of trunk fat mass adjusted by trunk lean mass (TFMadj) and followed by a series of functional investigations. SUBJECTS: A total of 11,569 subjects from six samples were included into the GWAS meta-analysis. METHODS: Meta-analysis was performed by a weighted fixed-effects model. In silico replication analysis was performed in the UK-Biobank (UKB) sample (N = 331,093) and in the GIANT study (N up to 110,204). Cis-expression QTL (cis-eQTL) analysis, dual-luciferase reporter assay and electrophoresis mobility shift assay (EMSA) were conducted to examine the functional relevance of the identified SNPs. At last, differential gene expression analysis (DGEA) was performed. RESULTS: We identified an independent SNP rs12409479 at 1p21 (MAF = 0.07, p = 7.26 × 10-10), whose association was replicated by the analysis of TFM in the UKB sample (one-sided p = 3.39 × 10-3), and was cross-validated by the analyses of BMI (one-sided p = 0.03) and WHRadj (one-sided p = 0.04) in the GIANT study. Cis-eQTL analysis demonstrated that allele A at rs12409479 was positively associated with PTBP2 expression level in subcutaneous adipose tissue (N = 385, p = 4.15 × 10-3). Dual-luciferase reporter assay showed that the region repressed PTBP2 gene expression by downregulating PTBP2 promoter activity (p < 0.001), and allele A at rs12409479 induced higher luciferase activity than allele G did (p = 4.15 × 10-3). EMSA experiment implied that allele A was more capable of binding to unknown transcription factors than allele G. Lastly, DGEA showed that the level of PTBP2 expression was higher in individuals with obesity than in individuals without obesity (N = 20 and 11, p = 0.04 and 9.22 × 10-3), suggesting a regulatory role in obesity development. CONCLUSIONS: Taken together, we hypothesize a regulating path from rs12409479 to trunk fat mass development through its allelic specific regulation of PTBP2 gene expression, thus providing some novel insight into the genetic basis of abdominal obesity. More... »

PAGES

1-11

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    http://scigraph.springernature.com/pub.10.1038/s41366-019-0350-z

    DOI

    http://dx.doi.org/10.1038/s41366-019-0350-z

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1113182226

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30944420


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