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, S Goya Wannamethee, Barbara J Jefferis, Peter Whincup, Yoav Ben-Shlomo, Jacqueline F Price, Meena Kumari, Andrew Wong, Ken Ong, Rebecca Hardy, Diana Kuh, Mika Kivimaki, Antti J Kangas, Pasi Soininen, Mika Ala-Korpela, Fotios Drenos, Steve E Humphries, UCLEB Consortium

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Abstract

AIMS: An 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.

METHODS: Four UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform.

RESULTS: The 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.

CONCLUSIONS: Our 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.

Original languageEnglish
Article number115
Number of pages11
JournalCardiovascular Diabetology
Volume15
DOIs
Publication statusPublished - 22 Aug 2016

Keywords

  • Aged
  • Amino Acids
  • Biomarkers
  • Cholesterol, HDL
  • Chromosomes, Human, Pair 1
  • Coronary Disease
  • DNA, Intergenic
  • Diabetes Mellitus, Type 2
  • Down-Regulation
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • High-Throughput Screening Assays
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolomics
  • Middle Aged
  • Particle Size
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Protective Factors
  • Risk Assessment
  • Risk Factors
  • Journal Article
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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  • Projects

    MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.

    1/06/1331/03/18

    Project: Research

    MRC UoB UNITE Unit - Programme 5

    Lawlor, D. A. & Lawlor, D. A.

    1/06/1331/03/18

    Project: Research

    Cite this

    Beaney, K. E., Cooper, J. A., McLachlan, S., Wannamethee, S. G., Jefferis, B. J., Whincup, P., Ben-Shlomo, Y., Price, J. F., Kumari, M., Wong, A., Ong, K., Hardy, R., Kuh, D., Kivimaki, M., Kangas, A. J., Soininen, P., Ala-Korpela, M., Drenos, F., Humphries, S. E., & UCLEB Consortium (2016). 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. Cardiovascular Diabetology, 15, [115]. https://doi.org/10.1186/s12933-016-0435-0