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Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia.

ABSTRACT: To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein.Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry.The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82-0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99).Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.

SUBMITTER: Spracklen CN

PROVIDER: S-EPMC5538572 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia.

Spracklen Cassandra N CN Smith Caitlin J CJ Saftlas Audrey F AF Triche Elizabeth W EW Bjonnes Andrew A Keating Brendan J BJ Saxena Richa R Breheny Patrick J PJ Dewan Andrew T AT Robinson Jennifer G JG Hoh Josephine J Ryckman Kelli K KK

Hypertension in pregnancy 20160922 1

<h4>Objective</h4>To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein.<h4>Methods</h4>Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk s ...[more]

PMID: 27657194

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Project description:CONTEXT: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. OBJECTIVE:To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS: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. MAIN OUTCOME MEASURE:Risk of coronary heart disease. RESULTS: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. CONCLUSION: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.

Project description:Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

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Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia.

Publications

Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia.

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