Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Abstract

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.

Joint Effect of Carotid Plaque and C‐Reactive Protein on First‐Ever Ischemic Stroke and Myocardial Infarction?

“…Large population‐based cohort studies failed to demonstrate an independent association between CRP and early stages and progression of atherosclerosis measured by carotid IMT 45. These findings are supported by recent results of genomic,6, 46 epidemiological,7, 45 and experimental studies on CRP, which have not proved a causal role of CRP in the formation and progression of atherosclerosis 5, 47. In addition, some controversy about the prognostic value of CRP in CVD prediction still remains,48 and few studies have explored whether CRP's ability to predict CVD is dependent on the presence of atherosclerosis 12, 13.…”

C‐Reactive Protein Identifies Low‐Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer–Norfolk Prospective Population Study

“…Previous studies suggest that those with the MS or with elevated levels of CRP have an increased risk of CHD9, 21; however, 2 large recently published meta‐analyses assessing the associations of CRP concentration with risk of vascular outcomes did not include the MS in their subgroup analyses 2, 3. Our data indicate that metabolically unhealthy persons with elevated CRP levels have a significantly higher risk of future CHD compared with metabolically unhealthy persons with CRP levels <2 mg/dL.…”

“…Abdominal obesity, obese persons, and obesity were all defined as an elevated waist circumference ≥102 cm (≥40 in) in men and ≥89 cm (≥35 in) in women. Hypertension was defined as systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥85 mm Hg, or use of antihypertensive medication 2. Hypertriglyceridemia was defined as triglyceride levels ≥150 mg/dL (1.7 mmol/L), whereas low HDL‐C was defined as HDL‐C <40 mg/dL (1.03 mmol/L) in men or HDL‐C <50 mg/dL (1.30 mmol/L) in women.…”

“…The positive association between CRP levels and the risk of future coronary heart disease (CHD) has been studied extensively 2, 3. The metabolic syndrome (MS) represents a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which coexist more often than by chance alone.…”

“…Experimental and observational evidence suggests that inflammation may play a central role in the pathogenesis of cardiovascular disease 8. CRP is associated with all parameters of the MS9 and has been acknowledged to be an independent but not causal2, 10 risk factor for incident CHD and to add prognostic value for CHD risk on top of the MS criteria 3, 9, 11, 12, 13, 14…”