Polymorphisms within the C-Reactive Protein (CRP) Promoter Region Are Associated with Plasma CRP Levels
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PROVIDER: S-EPMC2253965 | biostudies-literature | 2008 Jan
REPOSITORIES: biostudies-literature
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Project description:Elevated plasma levels of C-reactive protein (CRP), an inflammation-sensitive marker, have emerged as an important predictor of future cardiovascular disease and metabolic abnormalities in apparently healthy men and women. Here, we performed a systematic survey of common nucleotide variation across the genomic region encompassing the CRP gene locus. Of the common single-nucleotide polymorphisms (SNPs) identified, several in the CRP promoter region are strongly associated with CRP levels in a large cohort study of cardiovascular risk in European American and African American young adults. We also demonstrate the functional importance of these SNPs in vitro.
| S-EPMC1226195 | biostudies-literature
Project description:C-reactive protein (CRP) is an acute phase reactant protein produced primarily by the liver. Circulating CRP levels are influenced by genetic and non-genetic factors, including infection and obesity. Genome-wide association studies (GWAS) provide an unbiased approach towards identifying loci influencing CRP levels. None of the six GWAS for CRP levels has been conducted in an African ancestry population. The present study aims to: (i) identify genetic variants that influence serum CRP in African Americans (AA) using a genome-wide association approach and replicate these findings in West Africans (WA), (ii) assess transferability of major signals for CRP reported in European ancestry populations (EA) to AA and (iii) use the weak linkage disequilibrium (LD) structure characteristic of African ancestry populations to fine-map the previously reported CRP locus. The discovery cohort comprised 837 unrelated AA, with the replication of significant single-nucleotide polymorphisms (SNPs) assessed in 486 WA. The association analysis was conducted with 2 366 856 genotyped and imputed SNPs under an additive genetic model with adjustment for appropriate covariates. Genome-wide and replication significances were set at P < 5 × 10(-8) and P < 0.05, respectively. Ten SNPs in (CRP pseudogene-1) CRPP1 and CRP genes were associated with serum CRP (P = 2.4 × 10(-09) to 4.3 × 10(-11)). All but one of the top-scoring SNPs associated with CRP in AA were successfully replicated in WA. CRP signals previously identified in EA samples were transferable to AAs, and we were able to fine-map this signal, reducing the region of interest from the 25 kb of LD around the locus in the HapMap CEU sample to only 8 kb in our AA sample.
| S-EPMC3373247 | biostudies-literature
Project description:ObjectiveC-reactive protein (CRP) is an inflammatory marker that contributes to the prediction of cardiovascular disease. We investigated the influences of CRP polymorphisms on baseline CRP levels and fenofibrate-induced CRP changes in subjects with the metabolic syndrome.Research design and methodsWe examined the association of CRP single nucleotide polymorphisms (SNPs) (m772A>G, m301G>A >T, i178T>A, 3u1273C>T, and 3u2131C>T) with baseline plasma CRP levels among 1,123 white U.S. participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the modulating effect of these SNPs on CRP response to a 3-week fenofibrate treatment among 290 participants with the metabolic syndrome.ResultsThere were strong associations of m301G>A>T (rs3091244; P = 0.003), i178T>A (rs1417938; P = 0.001), 3u1273C>T (rs1130864; P = 0.001), and 3u2131C>T (rs1205; P < 0.001) with baseline CRP levels. Moreover, among subjects with the metabolic syndrome, fenofibrate induced the greatest reduction in CRP levels for TT subjects of the i178T>A compared with TA and AA subjects (-30 for TT, -19 for TA, and -11% for AA; P = 0.004). Similarly, for the m301G>A>T, major allele carriers displayed maximal reduction of CRP over noncarriers (-20 for GG, -15 for GA and GT, and -0.3% for TA and AA; P = 0.020).ConclusionsOur results demonstrate that common genetic variants within the CRP gene affect baseline CRP levels and further modulate CRP response in subjects with the metabolic syndrome treated with fenofibrate. This knowledge could contribute to a better prediction of therapeutic success.
| S-EPMC4615595 | biostudies-literature
Project description:C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD).We conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses' Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A>T and 4741G>C, but associated with lower CRP levels for SNPs 2667G>C and 3872C>T. SNP 2667G>C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01-2.44); p = 0.047] and men [1.93 (95% CI 1.30-2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations.Common variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene.
| S-EPMC2148071 | biostudies-literature
Project description:C-reactive protein (CRP) is an acute-phase plasma protein that can be used as a biomarker for activation of the immune system. A spectral analysis of CRP level over time for patients with gynaecological tumours has been reported by Madondo et al., using a periodogram method, suggesting that there is no significant periodicity in the data. In our study, we investigate the impact of low sample number on periodogram analysis, for non-uniform sampling intervals-we conclude that data of Madondo et al. cannot rule out periodic behaviour. The search for patterns (periodic or otherwise) in the CRP time-series is of interest for providing a cue for the optimal times at which cancer therapies are best administered. In this paper we show (i) there is no evidence to rule out periodicity in CRP levels, and (ii) we provide a prescription for the minimum data sample rate required in future experiments for improved testing of a periodic CRP signal hypothesis. The analysis we provide may be used for establishing periodicity in any short time-series signal that is observed without a priori information.
| S-EPMC6086826 | biostudies-literature
Project description:Although many studies have found psychological depression associated with higher circulating levels of C-reactive protein (CRP), not all findings are consistent. Since DNA sequence variation in the CRP gene has also been shown to predict plasma CRP levels, we hypothesized that plasma CRP may covary with depressive symptomatology as a function of allelic variation in the CRP gene. We tested this hypothesis in 868 healthy community volunteers of European ancestry. Depressive symptomatology was measured using the Center for Epidemiological Studies-Depression (CESD) scale, and plasma CRP was assayed from whole blood. Three polymorphisms [rs1417938 (A/T), rs1800947 (C/G) and rs1205 (C/T)] were genotyped and three-locus haplotypes were generated. Regression models adjusting for demographic and lifestyle-related covariates showed no direct association of CESD depression scores with CRP. In regression models adjusting for age, gender, education, smoking status and statin use, one CRP haplotype (T-G-C) was associated with CRP level (p=0.014) and a second haplotype (A-G-T) showed marginal association (p=0.064, respectively). Neither haplotype was related to depressive symptoms. However, plasma CRP was predicted by the interaction of A-G-T haplotype with depressive symptomatology (p=0.009). Higher CESD scores were associated positively with CRP levels among individuals with the A-G-T haplotype (p=0.004). In secondary analyses, body mass index was found to partially account for the moderating effects of the A-G-T haplotype on the association of depression with circulating CRP. In conclusion, we found that haplotypic variation in the CRP locus moderates an association of depressive symptoms with circulating CRP, which is partially mediated by BMI.
| S-EPMC3074460 | biostudies-literature
Project description:BackgroundRecent evidence suggests that higher CRP (C-reactive protein) levels are associated with lower risk of Alzheimer disease, speculating that CRP might be involved in Aβ clearance mechanisms. Testing this hypothesis, we explored whether genetically proxied CRP levels are also associated with lobar intracerebral hemorrhage (ICH), commonly caused by cerebral amyloid angiopathy.MethodsWe used 4 genetic variants within the CRP gene that explain up to 64% of the variance of circulating CRP levels and explored in 2-sample Mendelian randomization analyses associations with risk of any, lobar, and deep ICH (1545 cases and 1481 controls).ResultsHigher genetically proxied CRP levels were associated with lower odds of lobar ICH (odds ratio per SD increment in CRP, 0.45 [95% CI, 0.25-0.73]) but not deep ICH (odds ratio, 0.72 [95% CI, 0.45-1.14]). There was evidence of colocalization (posterior probability of association, 72.4%) in the signals for CRP and lobar ICH.ConclusionsOur results provide supportive evidence that high CRP levels may have a protective role in amyloid-related pathology.
| S-EPMC10085000 | biostudies-literature
Project description:To test the statistical association of the CRP and SAA1 locus variants with their corresponding circulating levels and metabolic and inflammatory biomarker levels by using mediation analysis, a sample population of 599 Taiwanese subjects was enrolled and five CRP and four SAA1 variants were genotyped. Correlation analysis revealed that C-reactive protein (CRP) and serum amyloid A (SAA) levels were significantly associated with multiple metabolic phenotypes and inflammatory marker levels. Our data further revealed a significant association of CRP and SAA1 variants with both CRP and SAA levels. Mediation analysis revealed that SAA levels suppressed the association between SAA1 genotypes/haplotypes and CRP levels and that CRP levels suppressed the association between CRP haplotypes and SAA levels. In conclusion, genetic variants at the CRP and SAA1 loci independently affect both CRP and SAA levels, and their respective circulating levels act as suppressors. These results provided further evidence of the role of the suppression effect in biological science and may partially explain the missing heritability in genetic association studies.
| S-EPMC4897670 | biostudies-literature
Project description:BackgroundWhile the risk of TB is elevated in HIV-positive subjects with low CD4 cell counts, TB may in itself be associated with CD4 lymphocytopenia. We investigated markers of immune activation (neopterin) and inflammation (CRP) in TB patients with and without HIV coinfection and their association with CD4 cell levels, and determined their predictive capacity as alternative markers of advanced immunosuppression.MethodsParticipants selected from a cohort of adults with TB at Ethiopian health centers (195 HIV+/TB+, 170 HIV-/TB+) and 31 controls were tested for plasma levels of neopterin and CRP. Baseline levels of neopterin and CRP were correlated to CD4 cell count before and after anti-TB treatment (ATT). The performance to predict CD4 cell strata for both markers were investigated using receiver operating curves.ResultsLevels of both biomarkers were elevated in TB patients (neopterin: HIV+/TB+ 54 nmol/l, HIV-/TB+ 23 nmol/l, controls 3.8 nmol/l; CRP: HIV+/TB+ 36 μg/ml, HIV-/TB+ 33 μg/ml, controls 0.5 μg/ml). Neopterin levels were inversely correlated (-0.53, p<0.001) to CD4 cell count, whereas this correlation was weaker for CRP (-0.25, p<0.001). Neither of the markers had adequate predictive value for identification of subjects with CD4 cell count <100 cells/mm3 (area under the curve [AUC] 0.64 for neopterin, AUC 0.59 for CRP).ConclusionNeopterin levels were high in adults with TB, both with and without HIV coinfection, with inverse correlation to CD4 cell count. This suggests that immune activation may be involved in TB-related CD4 lymphocytopenia. However, neither neopterin nor CRP showed promise as alternative tests for immunosuppression in patients coinfected with HIV and TB.
| S-EPMC4668010 | biostudies-literature
Project description:BackgroundHigh sensitivity C-reactive protein (hsCRP) levels are shown to be influenced by genetic variants in Europeans; however, little is explored in Indian population.MethodsHerein, we comprehensively evaluated association of all previously reported genetic determinants of hsCRP levels, including 18 cis (proximal to CRP gene) and 73 trans-acting (distal to CRP gene) variants in 4,200 North Indians of Indo-European ethnicity. First, we evaluated association of 91 variants from 12 candidate loci with hsCRP levels in 2,115 North Indians (1,042 non-diabetic subjects and 1,073 patients with type 2 diabetes). Then, cis and trans-acting variants contributing maximally to hsCRP level variation were further replicated in an independent 2,085 North Indians (1,047 patients with type 2 diabetes and 1,038 non-diabetic subjects).ResultsWe found association of 12 variants from CRP, LEPR, IL1A, IL6, and IL6R with hsCRP levels in non-diabetic subjects. However, only rs3093059-CRP [β = 0.33, P = 9.6×10⁻⁵] and the haplotype harboring rs3093059 risk allele [β = 0.32 µg/mL, P = 1.4×10⁻⁴/P(perm) = 9.0×10⁻⁴] retained significance after correcting for multiple testing. The cis-acting variant rs3093059-CRP had maximum contribution to the variance in hsCRP levels (1.14%). Among, trans-acting variants, rs1892534-LEPR was observed to contribute maximally to hsCRP level variance (0.59%). Associations of rs3093059-CRP and rs1892534-LEPR were confirmed by replication and attained higher significance after meta-analysis [β(meta) = 0.26/0.22; P(meta) = 4.3×10⁻⁷/7.4×10⁻³ and β(meta) = -0.15/-0.12; P(meta) = 2.0×10⁻⁶/1.6×10⁻⁶ for rs3093059 and rs1892534, respectively in non-diabetic subjects and all subjects taken together].ConclusionIn conclusion, we identified rs3093059 in CRP and rs1892534 in LEPR as major cis and trans-acting contributor respectively, to the variance in hsCRP levels in North Indian population.
| S-EPMC3169613 | biostudies-literature