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Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream

Brunner, EJ; Kivimaki, M; Witte, DR; Lawlor, DA; Smith, GD; Cooper, JA; Miller, M; ... Kumari, M; + view all (2008) Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream. PLOS MED , 5 (8) , Article e155. 10.1371/journal.pmed.0050155. Green open access

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Abstract

BackgroundRaised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.Methods and FindingsWe genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.ConclusionsObserved associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.

Type: Article
Title: Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pmed.0050155
Publisher version: http://dx.doi.org/10.1371/journal.pmed.0050155
Language: English
Additional information: © 2008 Brunner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: C-reactive protein, Middle-aged men, Systemic-lupus-erythematosus, Genome-wide association, Coronary-heart-disease, Metabolic syndrome, Gene polymorphisms, Whitehall-ii, Interindividual variability, Promoter polymorphisms
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Epidemiology and Public Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
URI: https://discovery.ucl.ac.uk/id/eprint/97462
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