Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease

Faculty of Medicine, Imperial College London, London, United Kingdom.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 08/2009; 302(1):37-48. DOI: 10.1001/jama.2009.954
Source: PubMed


Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.
To investigate association of genetic loci with CRP levels and risk of coronary heart disease.
We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.
Risk of coronary heart disease.
Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.
The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

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    • "A total of 41 studies were selected initially. After reading the full text of these articles, 9 eligible studies were harvested for the current meta-analysis of the association of rs7529229 with CHD [7, 22, 23]. Details of articles in the meta-analysis are shown in Figure 2. Our meta-analysis comprised 11,678 CHD cases and 12,861 controls from two ethnic populations (Europeans and Asians). "
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    ABSTRACT: The goal of our study is to test the association of IL6R rs7529229 polymorphism with CHD through a case-control study in Han Chinese population and a meta-analysis. Our result showed there is a lack of association between IL6R rs7529229 polymorphism and CHD on both genotype and allele levels in Han Chinese (P > 0.05). However, a meta-analysis among 11678 cases and 12861 controls showed that rs7529229-C allele was significantly associated with a decreased risk of CHD, especially in Europeans (P < 0.0001, odds ratio = 0.93, 95% confidential interval = 0.89-0.96). Since there is significant difference among different populations, further studies are warranted to test the contribution of rs7529229 to CHD in other ethnic populations.
    BioMed Research International 05/2014; 2014:504727. DOI:10.1155/2014/504727 · 2.71 Impact Factor
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    • "Serum CRP has a long half-life with low circadian variation, and can be easily measured using standardized methods [8,9]. CRP level is heritable [10] and is associated with common genetic variants [6,11,12]. CRP-associated genetic loci have been identified through the genome-wide association study (GWAS) in large sample size in multiple ethnic groups [13,14]. CRP level is also associated with age, sex and environmental factors such as secondhand smoke exposure, air pollution and diet [15]. "
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    ABSTRACT: A more thorough understanding of the differences in DNA methylation (DNAm) profiles in populations may hold promise for identifying molecular mechanisms through which genetic and environmental factors jointly contribute to human diseases. Inflammation is a key molecular mechanism underlying several chronic diseases including cardiovascular disease, and it affects DNAm profile on both global and locus-specific levels. To understand the impact of inflammation on the DNAm of the human genome, we investigated DNAm profiles of peripheral blood leukocytes from 966 African American participants in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. By testing the association of DNAm sites on CpG islands of over 14,000 genes with C-reactive protein (CRP), an inflammatory biomarker of cardiovascular disease, we identified 257 DNAm sites in 240 genes significantly associated with serum levels of CRP adjusted for age, sex, body mass index and smoking status, and corrected for multiple testing. Of the significantly associated DNAm sites, 80.5% were hypomethylated with higher CRP levels. The most significant Gene Ontology terms enriched in the genes associated with the CRP levels were immune system process, immune response, defense response, response to stimulus, and response to stress, which are all linked to the functions of leukocytes. While the CRP-associated DNAm may be cell-type specific, understanding the DNAm association with CRP in peripheral blood leukocytes of multi-ethnic populations can assist in unveiling the molecular mechanism of how the process of inflammation affects the risks of developing common disease through epigenetic modifications.
    PLoS ONE 08/2013; 8(8):e73480. DOI:10.1371/journal.pone.0073480 · 3.23 Impact Factor
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    • "While established as an indicator of systemic inflammation, some have suggested that CRP may have a mechanistic role in heart and lung disease. Recent studies focusing on genetic variation in CRP production in coronary artery disease and COPD suggest that CRP is not causal but rather a reflection of the role of inflammation in the disease process [17] [36] [37]. A variety of studies of patients with pulmonary hypertension have shown that elevated CRP levels are linked to adverse outcomes. "
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    ABSTRACT: Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited. The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses. Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of clinical cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
    International journal of cardiology 08/2013; 168(4). DOI:10.1016/j.ijcard.2013.06.028 · 4.04 Impact Factor
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