title: 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.
abstract: 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.
  
  
  
  Four UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, UK.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Beaney
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, UK.
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK.
authors.forename: Stela
authors.initials: S
authors.lastname: McLachlan
authors.affiliation: UCL Department of Primary Care & Population Health, UCL Institute of Epidemiology, University College London, London, UK.
authors.forename: S Goya
authors.initials: SG
authors.lastname: Wannamethee
authors.affiliation: UCL Department of Primary Care & Population Health, UCL Institute of Epidemiology, University College London, London, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Jefferis
authors.affiliation: Population Health Research Institute, St George's University of London, Cranmer Terrace, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Whincup
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Price
authors.affiliation: Institute for Social and Economic Research, University of Essex, Colchester, UK.|Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.affiliation: MRC Unit for Lifelong Health and Ageing, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.affiliation: MRC Unit for Lifelong Health and Ageing, London, UK.|MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Ken
authors.initials: K
authors.lastname: Ong
authors.affiliation: MRC Unit for Lifelong Health and Ageing, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hardy
authors.affiliation: MRC Unit for Lifelong Health and Ageing, London, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuh
authors.affiliation: Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.affiliation: Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, UK. f.drenos@bristol.ac.uk.|MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK. f.drenos@bristol.ac.uk.
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000368:Aged; D000596:Amino Acids / Q000097:blood; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D002878:Chromosomes, Human, Pair 1; D003327:Coronary Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D021901:DNA, Intergenic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057166:High-Throughput Screening Assays; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D010316:Particle Size; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D008076:Cholesterol, HDL; D021901:DNA, Intergenic
keywords: Coronary heart disease; Genetic risk; HDL-cholesterol; Metabolomics