Elevated levels of inflammatory markers, particularly C-reactive protein, indicate an increased risk of coronary heart disease. Although plasma lipid levels were more strongly associated with an increased risk than were inflammatory markers, the level of C-reactive protein remained a significant contributor to the prediction of coronary heart disease.

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Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10 −34) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.

Context Previous studies have examined the associations of individual clinical risk factors with risk of peripheral artery disease (PAD), but the combined effects of these risk factors are largely unknown. Objective To estimate the degree to which four conventional cardiovascular risk factors, smoking, hypertension, hypercholesterolemia and type 2 diabetes, are associated with the risk of PAD among men. Design, settings and participants We prospectively followed 44,985 men from the Health Professionals Follow-up Study without a history of cardiovascular disease at baseline for 25 years (1986-2011). The presence of risk factors was updated biennially during follow-up. Main outcome measure Clinically significant PAD (defined as limb amputation/revascularization, angiogram reporting vascular obstruction of ≥50%, ankle-brachial index<0.90 or physician-diagnosed PAD). Results During a median follow-up of 24.2 years (interquartile range 20.8-24.7 years), 537 PAD cases occurred. Each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other three risk factors and confounders. The age-adjusted incidence rates per 100,000 person years were 6 cases for 0 risk factors, 18 cases for 1 risk factor, 39 cases for 2 risk factors, 76 cases for 3 risk factors and 139 cases for 4 risk factors. The multivariable-adjusted hazard ratio (HR) for each additional risk factor compared was 2.06 (95% confidence interval [95% CI], 1.92-2.32). Men without any of the four risk factors had a HR of PAD of 0.23 (95% CI, 0.14-0.36) compared with all other men in the cohort. In 96% (95% CI, 94-98%) of PAD cases, at least one of the four risk factors was present at the time of PAD diagnosis. The population-attributable risk associated with these four risk factors was 75% (95% CI, 64-87%). The incidence of PAD among men with all four risk factors was 1.4/1,000. Conclusion Among men in this cohort, smoking, hypertension, hypercholesterolemia and type 2 diabetes account for most of the risk associated with development of clinically significant PAD.