Research Article: Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream

Date Published: August 12, 2008

Publisher: Public Library of Science

Author(s): Eric J Brunner, Mika Kivimäki, Daniel R Witte, Debbie A Lawlor, George Davey Smith, Jackie A Cooper, Michelle Miller, Gordon D. O Lowe, Ann Rumley, Juan P Casas, Tina Shah, Steve E Humphries, Aroon D Hingorani, Michael G Marmot, Nicholas J Timpson, Meena Kumari, Bernard Keavney

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.

Partial Text: C-reactive protein (CRP) is a nonspecific marker of systemic inflammation that predicts incident type 2 diabetes. Chronic low-grade inflammation may induce insulin resistance and is a candidate pathway leading from obesity to diabetes [1–3]. Several population-based observational studies suggest an independent role for CRP in the development of insulin resistance and diabetes, but it is unclear whether this association is a causal one or the consequence of imperfect adjustment for adiposity and other confounding factors [4–10]. Preventing or delaying onset of diabetes and its complications is an important therapeutic aim, and there is interest in inflammatory effectors including CRP as drug targets [11,12]. It is therefore highly desirable to establish which mediators in the inflammatory cascade are causal for diabetes.

Participants were on average 60.9 y of age, the majority was men and from executive officer and senior administrative employment grades (Table 1). There were 354 (6.7%) cases of diabetes at follow-up. As expected, haplotypes were associated with circulating CRP levels (Table 2) but not with risk factors at baseline or follow-up (all p ≥ 0.07) except in one case at baseline: CGG-occupational status (p = 0.038). In contrast, all risk factors were associated with serum CRP, HbA1c, and HOMA-IR except physical activity level (CRP only) (Table 3).

This large study provides evidence that systemic CRP levels are not responsible for development of insulin resistance, hyperglycemia, or diabetes. The finding does not preclude the possibility that inflammatory signals contribute to causal processes leading to diabetes. We obtained a clear signal, using Mendelian randomization, that the association between systemic CRP and diabetes risk is not causal. However, the nature of the prospective relation between serum CRP and diabetes risk points to the potential effects of more proximal mediators in the inflammatory cascade.



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