Variant rs10911021 that associates with coronary heart disease in type 2 diabetes, is associated with lower concentrations of circulating HDL cholesterol and large HDL particles but not with amino acids.

Katherine E Beaney,Jackie A Cooper,Stela Mclachlan,Diana Kuh,Pasi Soininen,Steve E Humphries,Meena Kumari,Yoav Ben-Shlomo,Antti J Kangas,Andrew Wong,Rebecca Hardy,Fotios Drenos,Barbara J Jefferis,Peter H Whincup ,Sg Wannamethee ,Mika Ala‐Korpela ,Jackie F Price ,Ken K Ong ,Mika Kivimäki

doi:10.1186/s12933-016-0435-0

Abstract

AimsAn intergenic locus on chromosome 1 (lead SNP rs10911021) was previously associated with coronary heart disease (CHD) in type 2 diabetes (T2D). Using data from the UCLEB consortium we investigated the relationship between rs10911021 and CHD in T2D, whether rs10911021 was associated with levels of amino acids involved in the γ-glutamyl cycle or any conventional risk factors (CRFs) for CHD in the T2D participants.MethodsFour UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform.ResultsThe expected direction of effect between rs10911021 and CHD in T2D was observed (1377 no CHD/160 CHD; minor allele OR 0.80, 95 % CI 0.60–1.06) although this was not statistically significant (p = 0.13). No association between rs10911021 and CHD was seen in non-T2D participants (11218 no CHD/1274 CHD; minor allele OR 1.00 95 % CIs 0.92–1.10). In T2D participants, while no associations were observed between rs10911021 and the nine amino acids measured, rs10911021 was associated with HDL-cholesterol (p = 0.0005) but the minor “protective” allele was associated with lower levels (−0.034 mmol/l per allele). Focusing more closely on the HDL-cholesterol subclasses measured, we observed that rs10911021 was associated with six large HDL particle measures in T2D (all p < 0.001). No significant associations were seen in non-T2D subjects.ConclusionsOur findings are consistent with a true association between rs10911021 and CHD in T2D. The protective minor allele was associated with lower HDL-cholesterol and reductions in HDL particle traits. Our results indicate a complex relationship between rs10911021 and CHD in T2D.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0435-0) contains supplementary material, which is available to authorized users.

Highlights

Data from observational studies has long shown that those with type 2 diabetes (T2D) are at an increased risk of developing coronary heart disease (CHD) [1]
Both rs10911021 imputation and CHD outcome data were available for eight cohorts—British Regional Heart Study (BRHS), British Women’s Heart and Health Study (BWHHS), Caerphilly Prospective Study (CAPS), Edinburgh Artery Study (EAS), Edinburgh Type 2 Diabetes Study (ET2DS), English Longitudinal Study of Aging (ELSA), MRC National Survey of Health and Development (MRC1946) and Whitehall II (WHII)
Compared to the non-T2D study population, the diabetes study population had a higher BMI, higher triglycerides, higher blood pressure, fasting glucose, insulin and glycated haemoglobin

Summary

Introduction

Data from observational studies has long shown that those with type 2 diabetes (T2D) are at an increased risk of developing coronary heart disease (CHD) [1]. While the association of a number of genetic risk factors for CHD [4] and subclinical cardiovascular disease (CVD) [5] has been observed in diabetic populations, recently a risk locus not previously identified in the general population was found to be associated with CHD in T2D. This locus at chromosome 1q25, (lead SNP rs10911021), was found to be associated with CHD in diabetic individuals [6] (MAF = 0.29 in the CEU group of 1000 Genomes Phase 3). Intracellular glutathione is known to be lower in diabetic individuals [8]

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Conclusion