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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

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

Hachiya Tsuyoshi T Komaki Shohei S Hasegawa Yutaka Y Ohmomo Hideki H Tanno Kozo K Hozawa Atsushi A Tamiya Gen G Yamamoto Masayuki M Ogasawara Kuniaki K Nakamura Motoyuki M Hitomi Jiro J Ishigaki Yasushi Y Sasaki Makoto M Shimizu Atsushi A

Scientific reports 20171123 1

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-a ...[more]

PMID: 29170429

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Project description:Aims/hypothesisThe aim of the study was to evaluate longitudinal associations between HbA1c levels, diabetes status and subsequent cognitive decline over a 10 year follow-up period.MethodsData from wave 2 (2004-2005) to wave 7 (2014-2015) of the English Longitudinal Study of Ageing (ELSA) were analysed. Cognitive function was assessed at baseline (wave 2) and reassessed every 2 years at waves 3-7. Linear mixed models were used to evaluate longitudinal associations.ResultsThe study comprised 5189 participants (55.1% women, mean age 65.6 ± 9.4 years) with baseline HbA1c levels ranging from 15.9 to 126.3 mmol/mol (3.6-13.7%). The mean follow-up duration was 8.1 ± 2.8 years and the mean number of cognitive assessments was 4.9 ± 1.5. A 1 mmol/mol increment in HbA1c was significantly associated with an increased rate of decline in global cognitive z scores (-0.0009 SD/year, 95% CI -0.0014, -0.0003), memory z scores (-0.0005 SD/year, 95% CI -0.0009, -0.0001) and executive function z scores (-0.0008 SD/year, 95% CI -0.0013, -0.0004) after adjustment for baseline age, sex, total cholesterol, HDL-cholesterol, triacylglycerol, high-sensitivity C-reactive protein, BMI, education, marital status, depressive symptoms, current smoking, alcohol consumption, hypertension, CHD, stroke, chronic lung disease and cancer. Compared with participants with normoglycaemia, the multivariable-adjusted rate of global cognitive decline associated with prediabetes and diabetes was increased by -0.012 SD/year (95% CI -0.022, -0.002) and -0.031 SD/year (95% CI -0.046, -0.015), respectively (p for trend <0.001). Similarly, memory, executive function and orientation z scores showed an increased rate of cognitive decline with diabetes.Conclusions/interpretationSignificant longitudinal associations between HbA1c levels, diabetes status and long-term cognitive decline were observed in this study. Future studies are required to determine the effects of maintaining optimal glucose control on the rate of cognitive decline in people with diabetes.

Project description:BackgroundCombining HbA1c with glycated albumin (GA) may improve detection of dysglycaemia. As BMI correlates positively with HbA1c and negatively with GA, HbA1c may be more effective in obese and GA in nonobese individuals.MethodsTo relate these findings to Africans, we assessed in 1274 South Africans living in CapeTown (male 26%; age 48±16y; BMI 28.7 kg/m2 (range 15.6-73.8); obesity 39.9% and no prior diabetes history) the: (1) correlation of BMI with HbA1c and GA, (2) ability of HbA1c and GA separately and jointly, to detect OGTT-diagnosed dysglycaemia (diabetes plus prediabetes). Data collection took place between 2014 and 2016 in the City of Cape Town. Dysglycaemia was diagnosed by glucose criteria for the OGTT. Youden index was used to optimize diagnostic thresholds for HbA1c and GA.FindingsNormal glucose tolerance, prediabetes and diabetes occurred in 76%, 17% and 7%, respectively. BMI positively correlated with HbA1c [r = 0·34 [95%CI: 0·29,0·39)] and negatively with GA [-0·08 (0·13,0·03)]. For HbA1c the optimal threshold by Youden-index for dysglycaemia diagnosis was: 6·0% (95%CI: 5·8,6·2) and for GA: 13·44% (12·72,14·71). In the nonobese, obese and total cohort, HbA1c-alone detected: 51% (42-60), 72% (65,78), 63% (57,68), respectively; GA-alone detected 55% (52% (46,63), 52% (44, 59) and 53% (47,53), respectively; whereas: HbA1c+GA detected: 69% (60,76), 82% (75,87) and 76% (71, 81). Therefore, for the total cohort detection of dysglycaemia HbA1c-alone vs HbA1c+GA detected 63% (57,68) vs 76% (71,81).InterpretationThe opposite correlations of HbA1c and GA with BMI have now been demonstrated in an African-based population. Improving detection of dysglycaemia by combining HbA1c and GA has important implications for diabetes risk screening.FundingAES is supported by the intramural programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Minority Health and Health Disparities of the National Institutes of Health (NIH, Bethesda, Maryland, USA). DBS is supported by the intramural program of the Clinical Center of NIH. The South African Medical Research Council (SAMRC) funded the VMH study with funds from the National Treasury under its Economic Competitiveness and Support Package (MRC-RFA-UFSP-01-2013/VMH Study).

Dataset Information

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

Publications

Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA<sub>1c</sub>.

Similar Datasets

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