Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6–TMC8 and SIX3–SIX2 loci associated with HbA(1c)

Glycated haemoglobin (HbA(1c)) 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 HbA(1c) has been estimated at ~55–75%, a much smaller proportion of phenotypic variance is explained by the HbA(1c)-associated variants identified so far. To search for novel loci influencing the HbA(1c) 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 HbA(1c) supported an association between the novel TMC6–TMC8 locus and HbA(1c) (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 HbA(1c) 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 HbA(1c). These findings provide novel insights into the molecular mechanisms that modulate the HbA(1c) level in non-diabetic subjects.