C-reactive Protein Single Nucleotide Polymorphisms Research Articles

THU0007 Investigation of CRP Gene Polymorphisms as Predictors of Cardiovascular Mortality in Inflammatory Polyarthritis – Results from the Norfolk Arthritis Register

BackgroundPatients with rheumatoid arthritis (RA) and inflammatory polyarthritis (IP) are at increased risk of premature death compared to the general population, with cardiovascular disease (CVD) forming the primary cause. C-reactive...

SAT0282 C-reactive protein (CRP) polymorphisms and haplotypes influence serum CRP levels independent of disease activity (BASDAI) in ankylosing spondylitis

BackgroundC-reactive protein (CRP) levels are used more frequently for determination of disease activity in patients with Ankylosing Spondylitis (AS), but these levels do not necessarily reflect disease activity in each...

Genetic Variants in the C-Reactive Protein Gene Are Associated with Microangiopathic Ischemic Stroke

Background and Purpose: C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and ischemic stroke. CRP serum levels are influenced by genetic variation in the CRP gene. Studies investigating the relationship between ischemic stroke and polymorphisms in the CRP gene produced equivocal results. Here we investigate single-nucleotide polymorphisms (SNPs) in the CRP gene in a large German ischemic stroke sample. Methods: In a case-control design, 1,669 patients with ischemic stroke due to large-artery atherosclerosis, cardioembolism or cerebral microangiopathy were genotyped for 4 haplotype tagging SNPs (rs3093075, rs1205, rs1130864 and rs1800947) in the CRP gene which have been shown to influence CRP serum concentrations. Geographically matched controls were drawn from 2 prospective population-based studies, the Dortmund Health Study and the Study of Health in Pomerania. The genetic association between the SNPs and stroke was assessed using SNP and haplotype approaches. Results were adjusted for covariates by logistic regression. Results: All 4 CRP SNPs reside in one linkage disequilibrium block. None of the SNPs or SNP haplotypes were associated with ischemic stroke as a whole. Three SNPs (rs3093075, rs1130864 and rs1800947) showed a significant association with microangiopathic stroke. A common 4-SNP haplotype was protective while 2 rarer haplotypes conferred susceptibility to microangiopathic stroke. All associations remained significant after adjustment for sex, age, hypertension, diabetes mellitus and hypercholesterolemia and after correction for multiple testing using the ‘false discovery rate’ method. Conclusion: Genetic variation in the CRP gene is associated with microangiopathic but not macroangiopathic or cardioembolic stroke in a large German stroke sample.

Response to Letter Regarding Article, “Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits”

HomeCirculationVol. 122, No. 4Response to Letter Regarding Article, “Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, “Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits” Tomonari Koike, Ying Yu, Jifeng Zhang and Jianglin Fan Yukio Ozaki Shuji Kitajima and Kazutoshi Nishijima Masatoshi Morimoto Teruo Watanabe Sucharit Bhakdi Yujiro Asada Y. Eugene Chen Tomonari KoikeTomonari Koike Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author , Ying YuYing Yu Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author , Jifeng ZhangJifeng Zhang Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author and Jianglin FanJianglin Fan Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author Yukio OzakiYukio Ozaki Department of Clinical and Laboratory Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author Shuji KitajimaShuji Kitajima Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan Search for more papers by this author and Kazutoshi NishijimaKazutoshi Nishijima Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan Search for more papers by this author Masatoshi MorimotoMasatoshi Morimoto Department of Rehabilitation, Kumamoto Health Science University, Kumamoto, Japan Search for more papers by this author Teruo WatanabeTeruo Watanabe Fukuoka Wajiro Hospital, Fukuoka, Japan Search for more papers by this author Sucharit BhakdiSucharit Bhakdi Institute of Medical Microbiology and Hygiene, Mainz, Germany Search for more papers by this author Yujiro AsadaYujiro Asada The First Department of Pathology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan Search for more papers by this author Y. Eugene ChenY. Eugene Chen Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich Search for more papers by this author Originally published27 Jul 2010https://doi.org/10.1161/CIRCULATIONAHA.110.951798Circulation. 2010;122:e407We appreciate the comments by Nakajima and Saito on our recent article published in Circulation.1 The major question they raised was why human C-reactive protein (CRP) transgenic rabbits failed to exhibit other metabolic disorders, because emerging data support that CRP levels are elevated in patients with metabolic syndrome.2 It is well documented that elevated plasma CRP levels are associated with many pathological states such as cardiovascular diseases and metabolic syndrome; however, these associations do not necessarily mean that high levels of CRP can cause these diseases. Indeed, population genetics studies have failed to link CRP single-nucleotide polymorphisms to the increased risk of cardiovascular diseases, although CRP single-nucleotide polymorphisms are associated with marked increases in CRP levels.3,4 Also, there is no evidence to date to show that elevation of plasma CRP alone can lead to metabolic syndrome both clinically and experimentally. It is apparent that further experiments with appropriate large-animal models are required to investigate CRP functions in metabolic syndrome. Because metabolic syndrome is composed of several metabolic disorders (eg, hypertension, dyslipidemia, and hyperglycemia), which are mediated by multiple genes and many environmental factors, it is unlikely that overexpression of a single CRP gene in animals can lead to all these abnormalities. In fact, we have recently transgenically expressed human CRP in hypertensive animals and found that in the setting of hypertension, CRP does exert certain detrimental effects on both lipid and glucose metabolism (unpublished data). Taken together, CRP functions in both physiology and pathophysiology remain to be further elucidated with genetically modified large animals, as we reported in the study.1DisclosuresNone. References 1 Koike T, Kitajima S, Yu Y, Nishijima K, Zhang J, Ozaki Y, Morimoto M, Watanabe T, Bhakdi S, Asada Y, Chen YE, Fan J. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation. 2009; 120: 2088–2094.LinkGoogle Scholar2 Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107: 391–397.LinkGoogle Scholar3 Wang Q, Hunt SC, Xu Q, Chen YE, Province MA, Eckfeldt JH, Pankow JS, Song Q. Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study. Am J Physiol Heart Circ Physiol. 2006; 291: H2752–H2757.CrossrefMedlineGoogle Scholar4 Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. 2008; 359: 1897–1908.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 27, 2010Vol 122, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.110.951798 Originally publishedJuly 27, 2010 PDF download Advertisement SubjectsAnimal Models of Human DiseaseEpidemiologyMechanismsPathophysiology

Abstract 2789: C-reactive protein and risk of lung cancer

Abstract Background: Chronic inflammation could act as a co-factor to tobacco smoke in increasing lung cancer risk, underscoring the potential for both lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP) and CRP single nucleotide polymorphisms (SNPs) with prospective risk of lung cancer. Methods: We conducted a nested case-control study of 592 lung cancers and 670 controls with available pre-diagnostic serum and 378 cases and 447 controls with available DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=77,464). Controls were matched to cases on age, sex, entry year, follow-up time, and smoking status (cumulative amount and time since quitting). We measured CRP levels in baseline serum samples and genotyped 5 common CRP SNPs. Results: Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR] for individuals in the fourth quartile (Q4, ≥5.6 mg/L) vs. those in Q1 (<1.0 mg/L)=1.98; 95% CI=1.35-2.89), with a trend for increasing risk across CRP quartiles (p-trend<0.001). This association was most apparent for squamous cell carcinomas (OR=2.92; 95% CI=1.30-6.54), in the 2-5 years before lung cancer diagnosis (OR=2.33; 95% CI=1.24-4.39), and among former (OR=2.48; 95% CI=1.53-4.03) and current smokers (OR=1.90; 95% CI=1.06-3.41). Although CRP SNPs and haplotypes were associated with significant differences in CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels, among both former (Q4=2.55% vs. Q1=1.39%) and current smokers (Q4=7.37% vs. Q1=4.03%). Conclusions: Elevated CRP levels are associated with subsequently increased lung cancer risk, in support of an etiologic role for chronic pulmonary inflammation in lung carcinogenesis. The separation in lung cancer absolute risks across circulating CRP levels among former and current smokers provides preliminary evidence for the utility of CRP measurements in lung cancer risk stratification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2789.

C-Reactive Protein and the Risk of Cancer: A Mendelian Randomization Study

Elevated plasma levels of C-reactive protein (CRP), a marker of inflammation, are associated with an increased risk of cancer, but it is unclear whether this association is causal. We examined whether four common single-nucleotide polymorphisms (SNPs) in the CRP gene that are associated with altered plasma CRP levels are causally associated with an increased risk of cancer. The study population included participants in a prospective study (n = 10 215) and a cross-sectional study (n = 36 403) of the adult general population in Denmark, all of whom were genotyped for the CRP SNPs. The association between plasma CRP levels measured by a high-sensitivity turbidimetry assay and the risk of cancer was examined for 8224 participants in the prospective study. The hazard ratio of cancer for a doubling of the plasma CRP level was 1.09 (95% confidence interval [CI] = 1.03 to 1.14). The nine most common genotype combinations of the four CRP SNPs were associated with up to a 72% increase (95% CI = 58% to 87%) in CRP levels but not with an increased risk of cancer. The estimated causal odds ratio for cancer associated with a genetically induced doubling in CRP level was 0.94 (95% CI = 0.81 to 1.08). This finding suggests that elevated CRP levels do not cause cancer.

CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans

Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymorphisms are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP polymorphisms are associated with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression. We genotyped 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK), selecting five tag polymorphisms: rs2808630, rs1205, rs3093066, rs1417938, and rs3093058. We compared the minor allele frequencies (MAF) of single nucleotide polymorphisms (SNPs) in AASK to MAFs of African Americans from NHANES III. Among AASK participants, we evaluated the association of SNPs with CRP levels and prospectively with a composite: halving the GFR, ESRD, or death. The MAF was higher for the rs2808630_G allele (P = 0.03) and lower for the rs1205_A allele (P = 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P < 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P = 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus beta blockers had increased risk of progression (P = 0.03). CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression.

Pleiotropy of C-Reactive Protein Gene Polymorphisms With C-Reactive Protein Levels and Heart Rate Variability in Healthy Male Twins

Reduced heart rate variability (HRV) and increased C-reactive protein (CRP) levels are both predictors of coronary artery disease and correlate with each other. We examined whether these 2 phenotypes share a common genetic substrate and investigated the relations of the CRP gene polymorphisms with both CRP levels and HRV indexes. We examined 236 male twins free of symptomatic coronary artery disease, with a mean age +/- SD of 54 +/- 2.9 years. The plasma CRP levels were measured and the frequency domain measures of HRV were assessed using a 24-hour electrocardiographic recording, including ultra-low-, very-low-, low-, and high-frequency power. Three single-nucleotide polymorphisms in the CRP gene were genotyped. Generalized estimating equations were used to examine the association between CRP and HRV, as well as the genotype-phenotype association. Bivariate structural equation modeling was performed to estimate the genetic and environmental correlations between CRP and HRV and the explanatory effect of CRP gene polymorphisms on the CRP-HRV association. Both CRP (h(2) = 0.76) and HRV indexes (h(2) = 0.56 to 0.64) showed high heritability. Greater CRP levels were significantly associated with lower HRV. A robust genetic correlation was found between CRP and ultra-low-frequency power (r(G) = -0.3, p = 0.001). One CRP single nucleotide polymorphism (rs1205) was significantly associated with both CRP (p = 0.003) and ultra-low-frequency power (p = 0.005) and explained 11% of the genetic covariance between them. In conclusion, reduced HRV correlates significantly with increased CRP plasma levels and this correlation is due, in large part, to common genetic influences. A polymorphism in the CRP gene contributes to both CRP levels and HRV.

Complement Factor H Y402H and C-Reactive Protein Polymorphism and Photodynamic Therapy Response in Age-Related Macular Degeneration

To investigate the association between complement factor H (CFH) and C-reactive protein (CRP) genotypes and response to photodynamic therapy (PDT) treatment for neovascular age-related macular degeneration (AMD). Retrospective cohort study. The study cohort consisted of 273 neovascular AMD patients treated with PDT. Genotypes were determined for the common T-->C single nucleotide polymorphism (SNP) in exon 9 of the CFH gene (rs1061170; Y402H), as well as 9 selected tagging SNPs across the CRP gene (rs2808635, rs1417938, rs1800947, rs1130864, rs1205, rs3093077, rs876538, rs876537, and rs1572970). Visual acuity outcome after PDT was retrospectively calculated and patients were classified as PDT-positive responders or PDT-negative responders. Logistic regression analysis was used to evaluate the association between individual SNPs and PDT treatment response while adjusting for relevant covariates. Response to PDT treatment defined by visual acuity; genotypes of CFH Y402H and CRP polymorphism. Of the 273 patients, 75 had a positive response after PDT treatment. The frequency of CC genotype of the CFH Y402H polymorphism in the PDT-positive response group was lower than in the negative PDT response group (26.4% vs 31.6%) but this difference failed to reach statistical significance. Two CRP SNPs (rs2808635 and rs876538) were significantly associated with PDT treatment response. Positive treatment response was seen in individuals homozygous for the minor allele of the rs2808635 (GG; odds ratio [OR], 3.92; 95% confidence interval [CI], 1.40-10.97; P = 0.048) and rs876538 (AA; OR, 6.49; 95% CI, 1.65-25.47; P = 0.048) variants after adjusting for relevant covariates. The remaining 7 CRP genetic variants did not reveal any significant association with treatment response. Our data did not show significant association between the CFH Y402H polymorphism and PDT treatment response for neovascular AMD; however, CRP genetic variants were associated with a positive response to PDT treatment for neovascular AMD.

C-Reactive protein gene variants are associated with postoperative C-reactive protein levels after coronary artery bypass surgery

BackgroundElevated baseline C-reactive protein (CRP) levels are associated with increased risk for developing cardiovascular disease. Several CRP gene variants have been associated with altered baseline CRP levels in ambulatory populations. However, the influence of CRP gene variants on CRP levels during inflammatory states, such as surgery, is largely unexplored. We describe the association between candidate CRP gene variants and postoperative plasma CRP levels in patients undergoing primary, elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB).MethodsUsing a multicenter candidate gene association study design, we examined the association between seventeen candidate CRP single nucleotide polymorphisms (SNPs) and inferred haplotypes, and altered postoperative CRP levels in 604 patients undergoing CABG surgery with CPB. Perioperative CRP levels were measured immediately prior to surgery, post-CPB and on postoperative days (POD) 1–4.ResultsCRP levels were significantly elevated at all postoperative time points when compared with preoperative levels (P < 0.0001). After adjusting for clinical covariates, the minor allele of the synonymous coding SNP, rs1800947 was associated with lower peak postoperative CRP levels (P = 2.4 × 10-4) and lower CRP levels across all postoperative time points (P = 4.8 × 10-5). rs1800947 remained highly significant after Bonferroni adjustment for multiple comparisons.ConclusionWe identified a CRP gene SNP associated with lower postoperative CRP levels in patients undergoing CABG surgery with CPB. Further investigation is needed to clarify the significance of this association between CRP gene variants and the acute-phase rise in postoperative CRP levels with regard to the risk of adverse postoperative outcomes.

Association between C-reactive protein gene haplotypes and C-reactive protein levels in Taiwanese: Interaction with obesity

Objective The level of C-reactive protein (CRP), an inflammatory marker that predicts future cardiovascular events, is a heritable trait. Our aim was to test the statistical associations between variations in the CRP gene and serum CRP levels in a Taiwanese population with interaction analysis. Methods A sample population of 617 Taiwanese subjects was enrolled. Five CRP single nucleotide polymorphisms (SNPs) previously reported to be associated with CRP level and with reasonable coverage of the CRP gene region were analyzed using polymerase chain reaction and restriction enzyme digestion or by TaqMan SNP Genotyping Assays. Results After adjusting for clinical covariates, minor alleles of 3 of the 5 SNPs were associated with change in CRP level: rs3091244 and rs1205 were associated with increased CRP level ( P = 0.001 and P < 0.001, respectively) and rs1800947 with decreased CRP level ( P = 0.003). Two haplotypes inferred from 5 SNPs (GCGCG and AAGCG) were associated with increased CRP level ( P = 0.017 and P < 0.0001, respectively). Interaction analysis revealed interaction of obesity with CRP genotypes associated with high CRP level (interaction P = 0.034 and 0.020 for SNPs rs2794521 and rs1800947, respectively). An effect of obesity on CRP level was also noted in haplotype interaction analysis with the association occurring predominantly in obese subjects ( P = 0.034). Conclusion CRP polymorphisms are independently associated with increased or decreased CRP level in Taiwanese. Further, CRP genotypes/haplotypes interact with obesity to set CRP level. These findings have implications for the prediction of atherosclerotic disease.

Genetics of C-reactive protein and complement factor H have an epistatic effect on carotid artery compliance: The Cardiovascular Risk in Young Finns Study

Atherosclerosis is characterized by a prominent inflammatory component and C-reactive protein (CRP) has been implicated to modulate the complement activity in atherosclerotic arteries via complement factor H (CFH) binding. In this study, we examined whether the gene-gene interactions between CRP haplotypes and CFH Tyr402His functional polymorphism exerted an effect on early atherosclerosis. Single nucleotide polymorphisms (SNPs) in CFH (Tyr402His) and CRP (-717A>G, -286C >T>A, +1059G>C, +1444C>T and +1846G>A) were genotyped in the participants of the Cardiovascular Risk in Young Finns Study (n=1698, aged 24-39 years). The CRP SNPs were further constructed into haplotypes and their interactive effects with the CFH Tyr402His polymorphism on the early atherogenic vascular changes [i.e. carotid artery compliance (CAC) and intima-media thickness (IMT)] were examined. After risk factor adjustment, a significant gene-gene interaction (P=0.007) on CAC was observed between CRP haplotype ATGTG and CFH Tyr402His polymorphism in males. Furthermore, logistic regression analysis verified the risk-modifying interactive effect on CAC between these loci (OR 3.70, 95% CI 1.37-10.02, P=0.010). No effects on CAC were observed in females and no effects on IMT were detected in either sex. We conclude that the combined presence of CRP haplotype ATGTG and CFH 402His allele may be disadvantageous to carotid artery elasticity in males.

Quantification of the Genetic Component of Basal C‐Reactive Protein Expression in SLE Nuclear Families

C-reactive protein (CRP) is a heritable acute-phase plasma protein also expressed at low, basal, levels in healthy individuals. Elevated basal CRP has been associated with increased cardiovascular risk, while CRP dysregulation may be a feature of systemic lupus erythematosus (SLE). In this cohort of 496 Caucasian SLE families we estimated basal CRP heritability, h(2)= 27.7%. We typed a dense map of CRP single nucleotide polymorphisms (SNPs) and found that seven were associated with basal CRP using both a regression approach and an orthogonal family-based test (P = 0.001-0.011), as were haplotypes carrying the minor allele of these SNPs. SNPs in the interleukin-1beta and interleukin-6 genes were associated with basal CRP. No association was seen between CRP genotype and SLE. Using a variance components approach we estimated that the CRP genotype accounted for only 15% of the total genetic component of basal CRP variation, perhaps explaining the limited evidence of association between CRP and disease. Most of the genetic determinants of basal CRP variation therefore remain unknown. Multiple genes may be involved and identifying them will provide an insight into pathways regulating CRP expression, highlight potential cardiovascular disease and SLE candidates and improve the ability of basal CRP to predict cardiovascular risk.

Fine-mapping the genetic basis of CRP regulation in African Americans: a Bayesian approach

Basal levels of C-reactive protein (CRP) have been associated with disease, particularly future cardiovascular events. Twin studies estimate 50% CRP heritability, so the identification of genetic variants influencing CRP expression is important. Existing studies in populations of European ancestry have identified numerous cis-acting variants but leave significant ambiguity over the identity of the key functional polymorphisms. We addressed this issue by typing a dense map of CRP single-nucleotide polymorphisms (SNPs), and quantifying serum CRP in 594 unrelated African Americans. We used Bayesian model choice analysis to select the combination of SNPs best explaining basal CRP and found strong support for triallelic rs3091244 alone, with the T allele acting in an additive manner (Bayes factor > 100 vs. null model), with additional support for a model incorporating both rs3091244 and rs12728740. Admixture analysis suggested SNP rs12728740 segregated with haplotypes predicted to be of recent European origin. Using a cladistic approach we confirmed the importance of rs3091244(T) by demonstrating a significant partition of haplotype effect based on the rs3091244(C/T) mutation (F = 8.91, P = 0.006). We argue that weaker linkage disequilibrium across the African American CRP locus compared with Europeans has allowed us to establish an unambiguous functional role for rs3091244(T), while also recognising the potential for additional functional mutations present in the European genome.

The modifying effect of C‐reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk

Obesity is a major risk factor for endometrial cancer. Obesity, particularly central obesity, is considered as a systemic inflammatory condition and is related strongly to insulin resistance. C-reactive protein (CRP) is the most recognized biologic marker of chronic systematic inflammation, and it is conceivable that the CRP gene may work together with obesity in the development of endometrial cancer. On the basis of a population-based case-control study in a Chinese population, the authors obtained obesity measurements and data on 6 CRP single-nucleotide polymorphisms (SNPs) from 1046 patients with newly diagnosed endometrial cancer (cases) and from 1035 age frequency-matched controls. The association of the CRP SNPs with endometrial cancer risk and their modification on the association between obesity and endometrial cancer risk were evaluated. Although CRP SNPs alone were not associated with endometrial cancer, the associations of endometrial cancer with central obesity, measured as the waist-to-hip ratio (WHR) and the waist circumference, seemed to be stronger in women who were homozygous for the major allele of reference SNP (rs)1130864 (cytidine [C]/C) than in women who had the C/thymidine (T) and T/T genotypes (interaction test: P = .013 for WHR; P = .083 for waist circumference). When the women were stratified further by menopausal status, the observed interactions persisted mainly in premenopausal women (interaction test: P < .001 for WHR; P = .002 for waist circumference). The current results suggested that, in the Chinese population that was studied, obesity-related insulin resistance and proinflammatory effects may play an important role in endometrial cancer risk, and these effects were modified significantly by the CRP SNP rs1130864.

Association of Common C-Reactive Protein (CRP) Gene Polymorphisms With Baseline Plasma CRP Levels and Fenofibrate Response

C-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. We 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. There 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). Our 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.

Single Nucleotide Polymorphisms in Inflammation-related Genes and Mortality in a Community-based Cohort in Washington County, Maryland

The purpose of this study was to examine the associations between single nucleotide polymorphisms (SNPs) in genes controlling inflammatory processes and mortality. Data were analyzed from 9,933 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland, in 1974 and 1989, designated "CLUE I" and "CLUE II," respectively. DNA from blood collected in 1989 was genotyped for 47 SNPs in 23 inflammation-related genes, including interferon-gamma (IFNgamma), lymphotoxin-alpha (LTalpha), tumor necrosis factor-alpha (TNFalpha), C-reactive protein (CRP), peroxisome proliferator-activated receptor (PPAR), and the human endothelial nitric oxide synthase (eNOS). All participants were followed from 1989 to the date of death or to June 20, 2005. The results showed no observable patterns of association for the SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations were observed between at least one mortality outcome and SNPs in eNOS (reference SNP (rs) 1799983), PPARG (rs4684847), CRP (rs2794521), IFNgamma (rs2069705), TNFalpha (rs1799964), and LTalpha (rs2229094). Additionally, three of the four examined CRP SNPs were strongly associated with CRP serum concentration among those with CRP measurements. The authors' findings from this community-based prospective cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although CRP genotypes may be associated with systemic inflammation.

Genetic determinants of basal C-reactive protein expression in Filipino systemic lupus erythematosus families

Basal C-reactive protein (CRP) is a heritable trait associated with long-term cardiovascular disease risk. Existing studies leave ambiguity over the key functional polymorphisms and fail to adjust for trans-acting effects. In a novel cohort of 285 Filipino systemic lupus erythematosus probands and their first-degree relatives, we quantified serum CRP and typed a dense map of CRP single-nucleotide polymorphisms (SNPs), along with SNPs in the interleukin-1 beta, interleukin-6 and apolipoprotein E genes. Ten CRP SNPs demonstrated association with basal CRP in a regression model (P=0.011-0.002). These delineated two haplotypes associated with high and low basal CRP expression (P=0.002). Differences in allele frequency were seen compared with Caucasian populations, enabling us to argue for an independent genetic effect from a phylogenetically distinct haplotype tagged by SNP rs1800947. We demonstrated an association between Apo epsilon 2 and higher basal CRP. Interleukin-6 genotype was associated with basal CRP, highlighting a role for acute-phase cytokines even in basal expression. Identifying these trans-acting variants may improve the use of basal CRP as a predictor cardiovascular risk, and increase our power to detect associations between CRP and disease.

Genome-wide association with select biomarker traits in the Framingham Heart Study.

BackgroundSystemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations.MethodsWe examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001.ResultsWith GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at .ConclusionThe Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.

Additive effect of interleukin-6 and C-reactive protein ( CRP) single nucleotide polymorphism on serum CRP concentration and other cardiovascular risk factors

Background Serum C-reactive protein (CRP) levels, closely associated with cardiovascular disease (CVD) risk are influenced by CRP or interleukin-6 ( IL-6) single nucleotide polymorphism (SNPs). However, it is still controversial. Therefore, we investigated the association of IL-6/CRP SNPs and serum CRP levels or other CVD risk factors in healthy adult Korean men. Methods In healthy adult men (age ≥ 20 years, n = 677), we genotyped IL-6−572C > G and CRP SNPs (− 717G > A, 1444C > T, 2147A > G) and measured anthropometric parameters, lipid profile, serum levels of CRP and IL-6 and insulin resistance. Results At IL-6−572C > G ( n = 677), subjects with G/G genotype ( n = 42) showed higher concentrations of CRP ( P = 0.027) and IL-6 ( P = 0.028) as compared with C allele carriers after age-adjustment (C/C: n = 371, C/G: n = 264). Fasting insulin and homeostatis model assessment insulin resistance (HOMA-IR) were also higher in G/G genotype. However, there were no significant differences in other metabolic biomarkers. Among 677 study subjects, 676 were genotyped at CRP−717G > A (G/G: n = 513, G/A: n = 150, A/A: n = 13), 672 at CRP+1444C > T (C/C: n = 580, C/T: n = 85, T/T: n = 7), and 668 at CRP+2147A > G (A/A: n = 273, A/G: n = 296, G/G: n = 99). There were no significant differences in CRP concentrations and other markers related to CVD risk according to each CRP SNP genotype. However, we could find the additive gene–gene interaction between IL-6−572C > G and CRP SNPs on CRP concentration; subjects with the ‘G/G’ at IL-6−572 showed the highest CRP levels when they have variant allele at CRP SNPs after adjusted for age, body mass index, cigarette smoking and alcohol drinking (− 717G > A: F = 7.806, P = 0.005; CRP + 1444C > T: F = 8.398, P = 0.004; and CRP + 2147A > G: F = 7.564, P = 0.006, respectively) Particularly, G allele carriers at CRP+2147A > G in subjects with IL-6−572G/G showed highest HOMA-IR ( F = 9.092, P = 0.003). Conclusion The present data showed that serum CRP levels and other CVD risk factors appeared more influenced by IL-6−572C > G rather than CRP SNPs (− 717G > A, 1444C > T, and 2147A > G), however CRP levels and insulin resistance may be additively affected by IL-6−572 and CRP SNP, particularly when subjects with G/G genotype at IL-6−572 have allele variant at CRP SNPs.