Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA1c.

ABSTRACT: Glycated haemoglobin (HbA1c) is widely used as a biomarker for the diagnosis of diabetes, for population-level screening, and for monitoring the glycaemic status during medical treatment. Although the heritability of HbA1c has been estimated at ~55-75%, a much smaller proportion of phenotypic variance is explained by the HbA1c-associated variants identified so far. To search for novel loci influencing the HbA1c levels, we conducted a genome-wide meta-analysis of 2 non-diabetic Japanese populations (n?=?7,704 subjects in total). We identified 2 novel loci that achieved genome-wide significance: TMC6-TMC8 (P?=?5.3?×?10-20) and SIX3-SIX2 (P?=?8.6?×?10-9). Data from the largest-scale European GWAS conducted for HbA1c supported an association between the novel TMC6-TMC8 locus and HbA1c (P?=?2.7?×?10-3). The association analysis with glycated albumin and glycation gap conducted using our Japanese population indicated that the TMC6-TMC8 and SIX3-SIX2 loci may influence the HbA1c level through non-glycaemic and glycaemic pathways, respectively. In addition, the pathway-based analysis suggested that the linoleic acid metabolic and 14-3-3-mediated signalling pathways were associated with HbA1c. These findings provide novel insights into the molecular mechanisms that modulate the HbA1c level in non-diabetic subjects.

SUBMITTER: Hachiya T 

PROVIDER: S-EPMC5701039 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature