C-reactive Protein Single Nucleotide Polymorphisms Research Articles

Mu-Opioid Receptor 1 and C-Reactive Protein Single Nucleotide Polymorphisms as Biomarkers of Pain Intensity and Opioid Consumption.

Children constitute a special group in pain therapy. Single nucleotide polymorphisms that are associated with differences in postoperative, inflammatory pain perception and opioid requirement are the A118G SNP in the mu-opioid receptor 1 (OPRM1) gene and the rs1205 CRP. This study aimed to determine connection between OPRM1 and rs1205 CRP SNPs in pediatric patients postoperatively and pain intensity, the opioid dose needed to control pain after scoliosis correction, and other clinical aspects. Genotypes of rs1205 CRP and OPRM1 polymorphisms in a sample of 31 patients were specified, and statistical analysis was performed in terms of age, genotype frequency, pain assessment, sufentanil flow, post-anesthesia care unit stay, and the use of coanalgesics. The frequency of A/A and A/G genotypes in the OPRM1 gene was in line with 1000Genomes data for the European population. Patients from the AG group of OPRM1 SNP more frequently required coanalgesics for adequate pain control; however, it was of weak statistical significance. Other parameters measured in the study were not statistically significant in relation to OPRM1 and CRP polymorphisms. The effect of SNPs on postoperative pain management and opioid therapy in children was not confirmed by this study. An expansion of the study sample and other opioid-related SNPs is required.

Single nucleotide polymorphisms in C-reactive protein (CRP) predict response to adjunctive celecoxib treatment of resistant bipolar depression

BackgroundAffective illness has been associated with a proinflammatory state, and it is generally accepted that the immune system plays a key role in the pathophysiology of mood disorders. Since inflammatory biomarkers are elevated in bipolar disorder, anti-inflammatory combination therapies may enhance response and reverse treatment resistance. PurposeIn the present study we investigated the possible impact of single nucleotide polymorphisms (SNPs) within the CRP gene on CRP blood levels, treatment response and level-of-stress perception in our cohort of treatment-resistant bipolar-depressed patients receiving escitalopram and celecoxib, or escitalopram and placebo, as previously reported (Halaris et al., 2020). MethodsStudy design, clinical findings, and CRP blood levels have been reported previously (Halaris et al., 2020; Edberg et al., 2018). In this follow-up study we extracted DNA from blood cells collected at baseline. Genome-wide genotyping was performed for all subjects using the Infinium Multi-Ethnic Global-8 v1.0 Kit. Based on reports in the literature indicating possible associations with psychiatric conditions, ten previously reported CRP gene polymorphisms were evaluated in a preliminary analysis. We focused on rs3093059 and rs3093077 were in complete LD. Carriers were defined as those possessing at least one C allele for rs3093059, or at least one G allele for rs3093077. Additionally, we determined blood levels of the medications administered. ResultsNon-carriers of rs3093059 and rs3093077 had significantly lower baseline CRP blood levels than carriers (p = 0.03). Increased rates of HAM-D17 response (p = 0.21) and remission (p = 0.13) and lower PSS-14 scores (p = 0.13) were observed in non-carriers among subjects receiving celecoxib but they did not reach statistical significance. When examining all subjects, nominally significant associations between carrier-status and remission (p = 0.04) and PSS-14 scores (p = 0.04) were observed after correcting for treatment arm. Non-carriers receiving celecoxib had the highest rates of response and remission, and the lowest stress scores. ConclusionsCarriers of the CRP SNPs may have higher baseline CRP levels, although non-carriers appear to benefit more from celecoxib co-therapy. Determination of the carrier status in conjunction with pretreatment blood CRP level measurement may contribute to personalized psychiatric practice, but replication of the present findings is needed.

Roles of C-reactive protein polymorphisms and life event changes on cognitive function in bipolar patients receiving valproate.

IntroductionPatients with bipolar disorder (BD) exhibit an inflamed condition that is associated with metabolic disturbance and cognitive impairment. Whether inflammation, represented by C-reactive protein (CRP), is causally associated with BD and influences treatment outcome has not been established.MethodsWe examined whether CRP is a causal factor for the risk of BD in drug-naïve, depressed BD patients and investigated whether polymorphisms in CRP and life event changes influence cognitive function in BD patients receiving valproate (VPA) treatment.ResultsOur results showed that BD patients had significantly higher CRP levels and worse cognitive function than the controls, while the frequencies of CRP single nucleotide polymorphisms in BD patients and in controls were not different. In addition, the life event scale score was higher for BD patients than for controls. Furthermore, the genotypes of CRP polymorphisms and the interactions between polymorphisms of CRP and life event scale score had a significant influence on cognitive performance in BD patients after 12 weeks of VPA treatment.ConclusionOur study demonstrated the clinical utility of the application of functional genetics in clarifying the interactions among CRP, life event stress, and BD and suggested the important roles of CRP gene–environment interactions in developing treatment strategies for BD.

Association of C-reactive protein polymorphisms with serum-CRP concentration and viral load among dengue-chikungunya mono/co-infected patients

India being endemic to Dengue (DENV) and chikungunya (CHIKV) infections faces high patient-mortality and morbidity with overlapping clinical features. C-reactive protein (CRP) acts as early defence system in response to these infections. This study investigated role of CRP single-nucleotide polymorphism (SNP) genotypes and protein levels towards DENV/CHIKV mono and co-infection among eastern Indian patients. 128 DENV-CHIKV co-infected, 206 DENV and 167 CHIKV mono-infected patients were subjected to genotyping of two CRP SNPs by PCR-RFLP along with 102 healthy individuals. CRP levels were determined by immunoturbidimetry. Statistical correlation of CRP genotypes with CRP concentration, DENV-CHIKV mono/co-infection and viral load was performed. Patients with rs3093059-CT and rs3091244-TT were more susceptible to DENV-CHIKV co-infection, whereas, rs3091244-CT might have imparted protection against CHIKV mono-infection. DENV-HVL was more prevalent within rs3093059-TT and rs3091244-CT co-infected patients, whereas, CHIKV-HVL among rs3091244-CC. Acute phase co-infected patients had significantly higher CRP level compared to mono-infections. Both mono and co-infected patients with aches/pain exhibited 2-3-fold higher CRP levels compared to those without. rs3093059-CT and rs3091244-CT co-infected patients had higher CRP concentration compared to rs3093059-TT and rs3091244-CC, respectively. Co-infected patients with WHO-defined warning signs had higher anti-dengue IgG/IgM ratio and serum CRP level compared to those without warning signs. Thus, patient's CRP genotype might play significant role in determining serum-CRP concentration, viral load and DENV-CHIKV mono/co-infection.

Association of CRP genetic variation with symptomatology, cognitive function, and circulating proinflammatory markers in civilian women with PTSD

Background: Posttraumatic stress disorder (PTSD) has been associated with increased inflammation. C-reactive protein (CRP) is a marker of systemic inflammation, and recently, single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with increased blood CRP protein levels and illness severity in PTSD patients. However, the mechanism by which the CRP SNPs are involved in PTSD remains unclear. Here we investigated the association of CRP genetic variation with blood proinflammatory protein levels, symptomatology, and cognitive function, and further explored the moderating effect of childhood maltreatment history, in adult patients with PTSD.Methods: Fifty-seven Japanese civilian women with PTSD and 73 healthy control women were enrolled. Three SNPs in the CRP gene, namely rs2794520, rs1130864, and rs3093059, were genotyped, and analyses focused on rs2794520 (T/C). Serum levels of high-sensitivity CRP (hsCRP), high-sensitivity tumor necrosis factor-α (hsTNF-α), and interleukin-6 were measured. PTSD symptoms were evaluated by the Posttraumatic Diagnostic Scale. Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status. Childhood maltreatment history was assessed by the Childhood Trauma Questionnaire.Results: Patients with the rs2794520 CC/CT genotype, compared to those with the TT genotype, showed significantly higher levels of hsCRP (p=0.009) and hsTNF-α (p=0.001), more severe PTSD symptoms (p=0.036), and poorer cognitive function (p=0.018). A two-way analysis of variance revealed a significant genotype-by-maltreatment interaction for more severe PTSD avoidance symptom (p=0.012).Limitations: The relatively small sample size limited our findings.Conclusions: These findings may provide an insight into the etiology of PTSD from the inflammatory perspective.

Meta-Analysis on the Association of C-Reactive Protein Polymorphisms with Metabolic Syndrome.

Polymorphisms in the C-reactive protein (CRP) genes might have crucial role in the development of metabolic syndrome (MetS). In the current comprehensive meta-analyses, we aim to provide a quantitative assessment of the association between CRP single-nucleotide polymorphisms (SNPs) and the risk of MetS. An electronic search was performed on several databases. After data extraction, random effect model was used to calculate the pooled odds ratio (OR) and 95% confidence intervals (CIs). Four independent studies including case–control, cohort, and cross-sectional methods were analyzed. Our meta-analysis indicated that CRP polymorphisms are not significantly associated with MetS (OR = 0.92, 95% CI = 0.77–1.10) with significant heterogeneity ( I 2 = 55.4%; p -value = 0.008). The subgroup analysis revealed that only GG has significant association with MetS (OR = 0.32, 95% CI = 0.13–0.80, p -value = 0.015) without significant heterogeneity ( I 2 = 0%, p -value > 0.05). In conclusion, this meta-analysis provides strong evidence that only some SNPs of CRP gene are associated with the risk for development of MetS; and this relationship does not exist in different ethnic populations.

Polymorphisms of C-reactive protein and growth arrest-specific gene 6 modulate ischemic stroke susceptibility through gene–gene interactions in Chinese Han population

This study explored whether inflammatory gene including C-reactive protein (CRP) and growth arrest-specific gene 6 (GAS6) are related to the etiology of ischemic stroke (IS), and to verify their potential interaction upon susceptibility to IS in Chinese population. A total of 236 patients with IS and 291 non-IS subjects were enrolled. Five single nucleotide polymorphisms (SNPs) in two candidate genes (CRP and GAS6) for IS were examined and determined by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and detected by DNA sequencing. We evaluated the association between SNPs and the risk of IS and evaluated their potential gene–gene interactions by using the generalized multifactor dimensionality reduction (GMDR), interaction dendrogram, entropy analysis and Interaction circle graph. A significant gene–gene interaction was then selected. We further tested the best model by logistic regression models. The results showed no significant difference between the IS (or its subtypes) group and the control group in the single-locus of all the analyzed variants. GMDR analysis indicated that the CRP SNPs rs3093059 and the GAS6 SNPs rs7400722 shared strong synergism in LAA analysis (Testing accuracy = 59.66%, CVC = 10, p = 0.0107). Dendrogram and circle graph analysis indicated a more-than-additive effect between the two loci. Furthermore, a recessive model of the two-locus interactions was confirmed by multivariate logistic regression model (OR = 1.940, 95% CI: 1.068–3.525, p = 0.030). The results indicate that CRP and GAS6 genes may fully participate in affecting the susceptibility to IS by gene–gene interaction, and may be conducive to provide a novel area for IS research.

C-reactive protein concentration in bipolar disorder: association with genetic variants

BackgroundSeveral recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene.Methods221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205).ResultsThere were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression.ConclusionsThese results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder.

C-Reactive Protein Gene Variants in Depressive Symptoms & Antidepressants Efficacy.

ObjectiveAlthough the pathogenesis of depression remains unclear, C-reactive protein (CRP) levels are commonly elevated in depressed patients. Thus, CRP single-nucleotide polymorphisms (SNPs) that influence CRP levels may be associated with depression. In the present study, we explored whether CRP SNPs are related to depressive symptoms and antidepressants efficacy in Han Chinese patients. MethodsWe analyzed data from 440 patients with first-episode depression. We obtained genome CRP SNPs, scores of the 17-item Hamilton Rating Scale for Depression 17 (HAMD17) and its four-factor at baseline and after 6 weeks. Quantitative trait analysis was performed using UNPHASED software and curative effects were analyzed using SPSS software. ResultsMale patients with SNP rs1800947G exhibited lower insomnia scores and rs2794521CC exhibited lower scores of anxiety/ physical symptoms, total HAMD17 score. Female patients with rs2794521TT exhibited higher scores of insomnia and lower antidepressants efficacy. ConclusionCRP SNPs rs1800947 and rs2794521 may be associated with depressive symptoms in patients with depression in a sex-specific fashion. Furthermore, rs2794521 may be a predictor of the efficacy of antidepressants in female patients.

CRP Genotypes Predict Increased Risk to Co-Present with Low Vitamin D and Elevated CRP in a Group of Healthy Black South African Women.

Low 25-hydroxyvitamin D (25(OH)D) and elevated C-reactive protein (CRP) concentrations are independently associated with adverse health outcomes, including cardiovascular disease (CVD). Although an inverse association between these factors has been described, the underlying mechanisms remain unknown. We postulate that environment–gene interactions, through which 25(OH)D interacts with single nucleotide polymorphisms (SNPs) within the CRP gene, modulate CRP; that certain CRP genotypes predispose individuals to a co-phenotype of low 25(OH)D and elevated CRP concentrations; and that this co-phenotype is associated with higher CVD risk. Twelve CRP SNPs were genotyped, and both 25(OH)D and CRP were quantified, in 505 black South African women. Alarmingly, 66% and 60% of the women presented with deficient/insufficient 25(OH)D and elevated CRP concentrations, respectively. CRP concentrations were higher in individuals with lower 25(OH)D concentrations. However, no 25(OH)D–CRP genotype interactions were evident. Several genotypes were associated with an altered risk of presenting with the co-phenotype, indicating a genetic predisposition. Women presenting with this co-phenotype had higher blood pressure and increased anthropometric measures, which may predispose them to develop CVD. We recommend increasing vitamin D fortification and supplementation efforts to reduce inflammation among black women with vitamin D deficiency, thereby possibly curbing diseases contingent on the co-phenotype described here.

Depression is Associated with CRP SNPs in Patients with Family History.

ObjectiveThe pathogenesis of depression is not fully understood, but studies have suggested that higher circulating levels of C reactive protein (CRP) might relate to depression occurrence. However, due to the highly variability of individual patients’ conditions, the results to date are inconsistent. Considering Single nucleotide polymorphisms (SNPs) of CRP gene have also been suggested to predict plasma CRP levels. In the present study, we hypothesize that inherited CRP allelic variations may co-vary with depressive symptomatology.MethodsWe recruited patients with a diagnosis of depression, with or without family depression history. We then detected serum CRP levels, as well as genome CRP SNPs from participants of this project.ResultsWe found a significantly higher circulating CRP levels in patients with a positive family history. Furthermore, we also identified certain inherited CRP SNPs (A allele in rs1417938 and C allele in rs1205) which could up-regulate serum CRP levels and thus be associated with depression occurrence.ConclusionOur findings raise new evidence for the relationship between circulating CRP level and depression occurrence.

Abstract 3445: C-reactive protein and lung cancer risk: a Mendelian randomization analysis

Abstract Background: Elevated levels of C-reactive protein (CRP) are associated with increased risk of lung cancer in observational studies. We investigated the causal relation between CRP and lung cancer using previously discovered single-nucleotide polymorphisms (SNPs) associated with CRP levels as genetic instruments. Methods: We analyzed four lung cancer case-control studies (EAGE, PLCO, ATBC, CPSII) with available GWAS data (total 5,713 cases and 5,736 controls). We identified 21 SNPs associated with CRP levels at P<10-7 in genome-wide association studies (GWAS) and constructed a weighted polygenic score (PGS) multiplying the number of CRP-increasing alleles in each locus by the GWAS-reported effect of the respective allele on CRP levels; this is the largest number of CRP SNPs used in a Mendelian randomization for lung cancer to date. We first examined whether the PGS is associated with smoking phenotypes (smoking status, cigarettes per day, pack-years, smoking duration). Subsequently, we used this PGS as an instrumental variable and estimated the odds ratio (OR) and 95% confidence interval (CI) of lung cancer per standard deviation change in the PGS using logistic regression and adjusting for age, gender, and smoking. We conducted subgroup analyses for different types of lung cancer histologies. Analyses were performed separately for each study and study-specific results were combined through random-effect meta-analysis. Results: The PGS was not significantly associated with the number of cigarettes smoked per day (P = 0.621), pack-years (P = 0.829), smoking status (0.739), or smoking duration (P = 0.743). Overall, there was no association between PGS and lung cancer risk in EAGLE (OR = 1.02, 95% CI 0.77-1.36; P = 0.876), PLCO (OR = 0.94, 95% CI 0.68-1.31; P = 0.722), ATBC (OR = 0.80, 95% CI 0.59-1.07; P = 0.132), or CPSII (OR = 0.61, 95% CI 0.37-1.02; P = 0.059) as well as after meta-analysis (OR = 0.88, 95% CI 0.73-1.05; P = 0.149; I2 = 17.3%]. Meta-analysis results were similar for adenocarcinoma (OR = 0.94, 95% CI 0.74-1.20; P = 0.630; I2 = 9.3%), squamous cell carcinoma (OR = 1.03, 95% CI 0.79-1.34; P = .844; I2 = 0%), small-cell lung cancer (OR = 0.97, 95% CI 0.62-1.50; P = 0.882; I2 = 34.9%), and other non-small cell lung cancer (OR = 0.93 (0.53-1.65), P = 0.815, I2 = 59.2%). Conclusions: Genetically elevated CRP levels are not associated with the risk lung cancer. Hence, our results provide no evidence of causality between CRP and lung cancer. Citation Format: Orestis A. Panagiotou, Neil E. Caporaso, Maria T. Landi, Nilanjan Chatterjee, NCI Lung Cancer GWAS Group. C-reactive protein and lung cancer risk: a Mendelian randomization analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3445.

Association of C-Reactive Protein (rs1205) Gene Polymorphism with Susceptibility to Psoriasis in South Indian Tamils.

Psoriasis is a multi-factorial heritable T-helper Th-1/Th-17 mediated inflammatory disease, affecting the skin. It is associated with co-morbidities such as Cardiovascular Disease (CVD). C-Reactive Protein (CRP) is a good inflammatory marker. CRP rs1205 polymorphism is associated with circulating plasma CRP levels. Although there is association between the rs1205 Single Nucleotide Polymorphism (SNP) and CVD, there are no prior reports regarding the association of CRP rs1205 SNP with psoriasis susceptibility. To study the association of the genetic variant rs1205 in the CRP gene with susceptibility to the disease and protein levels in South Indian Tamils with psoriasis. In this case-control genetic study, 300 cases of psoriasis and 300 age and gender matched controls were genotyped for CRP SNP rs1205 using Taq Man 5'allele discrimination assay at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India from February 2014 to January 2016. Plasma high sensitivity (hs)-CRP levels were estimated by ELISA. Disease severity was assessed by Psoriasis Area Severity Index (PASI). CRP genetic variation rs1205 was not associated with psoriasis risk in our South Indian Tamil population. However, the circulating levels of hs-CRP was significantly higher in patients with psoriasis, as compared with controls (p < 0.0001) and the protein levels were significantly associated with disease severity, as assessed by PASI scoring. No genotype was found significantly associated with PASI or CRP levels. Our results suggest that plasma CRP levels are higher in patients with psoriasis and correlate with disease severity, whilst CRP rs1205 is not associated with susceptibility to psoriasis in South Indian Tamils.

Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke.

To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke. The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed. We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p = 1.14 × 10(-9)) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p = 7.3 × 10(-8), approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP. Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation.

The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis.

This study investigates the association of CRP (C-reactive protein) single-nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25-75) disease duration of 1 (0.6-1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25-75) disease duration of 8.9 (3.5-17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19-0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P-value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg dl(-1) when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.

Child maltreatment, inflammation, and internalizing symptoms: Investigating the roles of C-reactive protein, gene variation, and neuroendocrine regulation.

Prior research has found inconsistent evidence regarding the association among childhood adversity, inflammation, and internalizing symptoms, perhaps because previous studies have yet to adequately integrate important factors such as the timing of the adversity, genetic variation, and other relevant processes such as neuroendocrine regulation. The aims of the present study were threefold: (a) to determine whether the effect of the timing of child maltreatment on C-reactive protein (CRP), an inflammatory marker, varies by CRP gene variation; (b) to explore whether links between salivary CRP and childhood internalizing symptoms depend on the presence and timing of maltreatment experiences; and (c) to investigate the role of CRP in the relations between child neuroendocrine regulation and internalizing symptoms and examine whether these associations are moderated by the presence and timing of child maltreatment. Participants included a sample of 267 maltreated and 222 nonmaltreated children (M age = 9.72, SD = 0.99; 52.4% male; 66% African American) who attended a summer day camp research program designed for school-aged low-income children. Department of Human Services records were examined to determine the onset and recency of maltreatment for children in the maltreated group. The results indicated that among children with recent onset maltreatment, those with at least one A allele from CRP single nucleotide polymorphism rs1417938 evidenced significantly higher CRP levels compared to recently maltreated children carrying the TT genotype. Moreover, higher levels of CRP were associated with higher levels of internalizing symptoms only for recently maltreated children. Finally, we did not find support for salivary CRP as a mechanism in the relation between neuroendocrine regulation and childhood internalizing symptoms. Our findings highlight the importance of the timing of child maltreatment and have important implications for characterizing variability in inflammation and internalizing symptoms among youth.

A novel haplotype within C-reactive protein gene influences CRP levels and coronary heart disease risk in Northwest Indians.

According to several epidemiological and clinical studies, the concentration of C-reactive protein (CRP) in blood is associated with the risk of coronary heart disease (CHD). However, these studies are limited in high incidence and prevalence area of North-West India. The present case control study investigated the contribution of three relevant CRP single nucleotide polymorphisms: -717A>G located in the promoter region (rs2794521), +1059G>C on exon2 (rs1800947) and +1444C>T in the 3' UTR (rs1130864) in 180 angiographically verified CHD cases and 175 control subjects. Minor allele frequencies (G, C and T) of rs2794521, rs1800947 and rs1130864 are observed to be 21.1, 11.7, 29.4 and 11.4, 10.0, 19.7 % in CHD cases and controls respectively. AA genotype of -717A>G and TT genotype of +1444C>T were significantly associated (P = 0.02 & 0.03 respectively) with the risk of CHD whereas, +1059G and +1444T were found to be strongly related (P = 0.023 & P = 0.008 respectively) with multivariable adjusted CRP levels. AGT Haplotype was significantly associated with the adjusted CRP levels (P < 0.05). Disease association analysis revealed that haplotype AGT influences CHD risk (OR 2.4, 95 % CI 1.23-4.84, P = 0.006) which exacerbates after correcting the confounding effects of risk variables (OR 2.5, 95 % CI 1.27-4.99, P = 0.004). With the global index of Akaike information criterion, it has been observed that the carrying each single unit of this susceptibility haplotype increases CHD risk by a value of 2.41 ± 0.439 (β ± SE) in the recessive mode.

Genetic variation across C-reactive protein and risk of prostate cancer.

Inflammation has been hypothesized to play an important etiological role in the initiation or progression of prostate cancer. Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk of prostate cancer. We investigated the role of genetic variation in CRP and prostate cancer, under the hypothesis that variants may alter risk of disease. We undertook a case-control study nested within the prospective Physicians' Health Study among 1,286 men with incident prostate cancer and 1,264 controls. Four single-nucleotide polymorphisms (SNPs) were selected to capture the common genetic variation across CRP (r(2) > 0.8). We used unconditional logistic regression to assess the association between each SNP and risk of prostate cancer. Linear regression models explored associations between each genotype and plasma CRP levels. None of the CRP SNPs were associated with prostate cancer overall. Individuals with one copy of the minor allele (C) in rs1800947 had an increased risk of high-grade prostate cancer (OR: 1.7; 95% CI: 1.1-2.8), and significantly lower mean CRP levels (P-value <0.001), however, we found no significant association with lethal disease. Mean CRP levels were significantly elevated in men with one or two copies of the minor allele in rs3093075 and rs1417939, but these were unrelated to prostate cancer risk. Our findings suggest that SNPs in the CRP gene are not associated with risk of overall or lethal prostate cancer. Polymorphisms in CRP rs1800947 may be associated with higher grade disease, but our results require replication in other cohorts.

Multiancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture Using Genomics and Epidemiology Study

C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP. We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)). We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study

Serum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Inflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high-sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort. At baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6 years). CRP was associated with a risk for any type of fracture [hazard ratio (HR) = 1.06; 95 % confidence interval (CI), 1.02-1.11], hip fractures (HR = 1.09; 1.02-1.17) and vertebral fractures [odds ratio (OR) = 1.34; 1.14-1.58]. An inverse relationship between CRP levels and section modulus (-0.011 cm(3); -0.020 to -0.003 cm(3)) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (p = 9 × 10(-56)), but not with fracture risk (HR = 1.00; 0.99-1.00; p = 0.23). Serum high-sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk.