CRP and FCGR2A genes have an epistatic effect on carotid artery intima‐media thickness: the Cardiovascular Risk in Young Finns Study

The role of the inflammatory mediator C‐reactive protein (CRP) in atherosclerosis is recognized although its specific functions are not entirely clear. CRP binds to the Fcγ receptor2A (FcγR2A) and its polymorphism, FCGR2A (Arg131His), strongly influences the binding. We wanted to evaluate the CRP‐mediated proatherogenic process on early atherosclerosis and investigated whether CRP and FCGR2A show an interactive effect on carotid intima‐media thickness (IMT). Polymorphisms of FCGR2A (Arg131His) and CRP (–717A > G, –286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped and their effects on IMT were analyzed in 2260 young adults participating in the Cardiovascular Risk in Young Finns Study. CRP haplotypes were constructed based on the CRP polymorphisms. The FCGR2A(Arg131His) polymorphism did not have an independent effect on IMT but a significant gene‐gene interaction, epistasis, between FCGR2A and CRP genetics on IMT was found. The epistatic effect was seen in men at haplotype and genotypic level; both CRP haplotype GCGCG (–717, –286, +1059, +1444 and +1846) and CRP–717A > G polymorphism interacted with FCGR2A(Arg131His) on IMT. After adjustment with classical risk factors the P‐values for interaction were P = 0.013 and P = 0.010, respectively. No associations were observed in women. In conclusion, this study showed that the effect of CRP genetics on early atherosclerotic changes is modulated by the FCGR2A genetics.     

Autoimmunity and atherosclerosis: functional polymorphism of PTPN22 is associated with phenotypes related to the risk of atherosclerosis. The Cardiovascular Risk in Young Finns Study

There is a growing body of evidence attesting the significance of inflammation in the pathogenesis of atherosclerosis. Protein tyrosine phosphate PTPN22 C/T single nucleotide polymorphism (SNP) at + 1858 has been identified recently as a susceptibility factor for various inflammatory autoimmune diseases. We hypothesized that data on the genetic polymorphism of the PTPN22 enzyme associated with an increased risk of autoimmunity could also provide insight into the possible role of autoimmunity in the pathogenesis of atherosclerosis. Therefore we analysed the PTPN22 + 1858 C/T polymorphism in a population of young Finnish adults (n = 2268) for whom data on carotid artery intima-media thickness (IMT), a presymptomatic predictor of atherosclerosis, and risk factors for atherosclerosis were available. In males carriage of the T allele of PTPN22 + 1858 was associated significantly with IMT in univariate and multivariate analyses, while in females it was associated with several risk factors for atherosclerosis (BMI, waist circumference, waist-to-hip ratio, serum concentrations of C-reactive protein and triglycerides) but not with IMT. Our results indicate that the genetic polymorphism of PTPN22 + 1858 known to predispose to autoimmunity also enhances the development of atherosclerosis and thereby links the genetics of autoimmunity and atherosclerosis.     

Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study

Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flow-mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24-39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P < 0·001) and systolic (P = 0·053) and diastolic (P = 0·002) blood pressure elevation, and associated inversely with flow-mediated dilation (P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0·029) and diastolic (P = 0·004) blood pressure elevation and flow-mediated dilation (P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age.     

Plasma IL‐6 concentration correlates with clinical disease activity and serum C‐reactive protein concentration in chronic urticaria patients

Background Our previous study was the first to demonstrate enhanced plasma IL‐6 concentrations in chronic urticaria (CU). It is known that C‐reactive protein (CRP) is a sensitive marker of an underlying systemic inflammation, triggered mainly as a response to IL‐6. Objective To evaluate plasma IL‐6 concentration in CU patients relating to the clinical disease activity and serum CRP concentration. Methods Serum CRP and plasma IL‐6 concentrations were measured in 58 CU patients and 30 healthy subjects. Ten CU patients were evaluated twice, during the active period as well as upon the spontaneous clinical remission of the disease. CU activity was assessed with the use of the symptom scores recommended by EAACI/GALEN/EDF guidelines. Results IL‐6 and CRP concentrations were significantly increased in CU patients as compared with the healthy subjects, whereas they decreased remarkably upon the spontaneous remission. IL‐6 concentration was associated with weekly urticaria activity scores and also significant differences were found between patients showing different degrees of urticarial activity. Significant correlation was observed between IL‐6 and CRP concentrations. Conclusions and Clinical Relevance This study reinforces evidence that, apart from a local cutaneous inflammation, CU is associated with a systemic inflammatory response. Such acute‐phase response is manifested by increased circulating IL‐6, which varies along with CRP changes and may be related to the urticarial activity. Cite this as: A. Kasperska‐Zajac, J. Sztylc, E. Machura and G. Jop, Clinical & Experimental Allergy, 2011 (41) 1386–1391.     

Role of gender disparity of circulating high‐sensitivity C‐reactive protein concentrations and obesity on asthma in Taiwan

Background Several studies have suggested that the association between obesity and asthma may be stronger in females than in males, but the reason is still unclear. Objective The aim of this study was to investigate whether differences in high‐sensitivity C‐reactive protein (hs‐CRP) levels explain why obesity is associated with asthma in females but not in males. Methods This study prospectively enrolled 754 subjects 18 years old from hospital‐based asthma patients and population‐based controls. We measured adiposity factors [body mass index (BMI), waist circumference and waist‐hip ratio], hs‐CRP and total IgE levels. Results After adjusting for potential confounding factors, we found a significant association between BMI and asthma in females with a significant interaction of gender and BMI on asthma (χ²=10.2, P=0.004). If hs‐CRP was added to the logistic model, the interaction was attenuated but still significant (χ²=7.02, P=0.03). After adjusting for BMI, we did not find that circulating hs‐CRP concentrations were significantly associated with asthma in males and females. Conclusion We found that BMI was associated with asthma in females, but our results do not support the suggestion that hs‐CRP levels contribute significantly to the link between obesity and asthma with respect to gender disparity. Cite this as: T.‐N. Wang, M.‐C. Lin, C.‐C. Wu, M.‐S. Huang, S. Y. Leung, C.‐C. Huang, P.‐S. Ho and Y.‐C. Ko, Clinical & Experimental Allergy, 2011 (41) 72–77.     

Overall sleep status and high sensitivity C‐reactive protein: a prospective study in Japanese factory workers

We investigated the relation between overall sleep status based on the modified Pittsburgh Sleep Quality Index (PSQI) global score and subsequent changes in serum high‐sensitivity C‐reactive protein (hsCRP) in a population of Japanese factory workers, who were predominantly female. A total of 991 Japanese with inflammation classified as low cardiovascular risk (baseline hsCRP < 1.0 mg L^?1) were grouped according to the presence or absence of unfavourable sleep, defined as a modified PSQI global score > 5.5 points. The subsequent changes in hsCRP after 3 years were then compared in the two groups. Analysis of covariance incorporating log‐transformed baseline hsCRP, age, sex, lifestyle and physical and biochemical profiles was used to compare the geometric means of hsCRP at year 3 in each sleep status group. A logistic regression model incorporating the same variables was used to calculate the odds ratios for development of inflammation with a medium‐to‐high cardiovascular risk (hsCRP at year 3 ≥ 1.0 mg L^?1) comparing the presence or absence of unfavourable sleep habits. The multivariate‐adjusted geometric mean of hsCRP at year 3 was significantly higher in subjects with unfavourable sleep habits compared with those with a normal pattern (0.275 versus 0.242 mg L^?1). The multivariate‐adjusted odds ratio for developing increased and potentially pathogenic levels of inflammation due to unfavourable sleep was 2.08 (95% confidence interval = 1.29–3.35). There was a significant linear trend for the development of increased inflammation across the modified PSQI global scores (P = 0.04). Unfavourable sleep is associated with activation of low‐grade systemic inflammation.     

Hepatic lipase promoter C-480T polymorphism is associated with serum lipids levels, but not subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study

The common C‐480T polymorphism (rs1800588) of the hepatic lipase gene (LIPC) has been associated with high‐density lipoprotein (HDL) cholesterol, atherosclerosis, and coronary artery disease. In this study, we examined whether the polymorphism is associated with serum lipid and lipoprotein concentrations, as well as with subclinical atherosclerosis in Young Finns. The participants comprised 2041 men and women (aged 24–39 years) enrolled in the Cardiovascular Risk in Young Finns Study with complete data concerning the rs1800588 polymorphism and serum lipids concentration. All participants underwent an ultrasound examination for brachial artery flow‐mediated vasodilatation (FMD) and carotid artery intima‐media thickness (IMT) measurement. The marker of arterial elasticity, carotid artery compliance (CAC), was also calculated by means of ultrasound and concomitant brachial blood pressure measurements. In all subjects, serum total cholesterol (p < 0.001), HDL cholesterol (p = 0.006), apolipoprotein AI (apoAI, p < 0.001), and triglyceride (p = 0.009) concentrations increased according to rs1800588 genotype in the order CC, CT, and TT. The same order applied only to apoAI after adjustment for age, body mass index, systolic and diastolic blood pressure, smoking, alcohol consumption, physical activity, diabetes, hypertension, contraceptive hormone use in women, and concentrations of glucose, insulin and C‐reactive protein in men and women separately (p = 0.007 and p = 0.003, respectively). The polymorphism was also associated with HDL cholesterol, total cholesterol, and triglyceride levels in women (adjusted p = 0.004, p = 0.007 and 0.02, respectively), but not in men (p was not significant for all). No significant association between the rs1800588 and brachial FMD, carotid IMT, or CAC was found among the entire study population or among women or men separately, with or without adjustment for the above‐mentioned factors. The rs1800588 is associated with serum lipid and apolipoprotein concentrations, especially in women, but does not seem to be a determinant of brachial artery FMD, carotid IMT, or CAC in young healthy adults.     

Glycosylphosphatidylinositol (GPI) anchored protein deficiency serves as a reliable reporter of Pig‐a gene Mutation: Support from an in vitro assay based on L5178Y/Tk+/− cells and the CD90.2 antigen

Lack of cell surface glycosylphosphatidylinositol (GPI)‐anchored protein(s) has been used as a reporter of Pig‐a gene mutation in several model systems. As an extension of this work, our laboratory initiated development of an in vitro mutation assay based on the flow cytometric assessment of CD90.2 expression on the cell surface of the mouse lymphoma cell line L5178Y/Tk^+/?. Cells were exposed to mutagenic and nonmutagenic compounds for 24 hr followed by washout and incubation for an additional 7 days. Following this mutant manifestation time, cells were labeled with fluorescent antibodies against CD90.2 and CD45 antigens. These reagents indicated the presence of GPI‐anchored proteins and general cell surface membrane receptor integrity, respectively. Instrument set‐up was aided by parallel processing of a GPI anchor‐deficient subclone. Results show that the mutagens reproducibly caused increased frequencies of mutant phenotype cells, while the nonmutagens did not. Further modifications to the method, including application of a viability dye and an isotype control for instrument set‐up, were investigated. As a means to verify that the GPI‐anchored protein‐negative phenotype reflects bona fide Pig‐a gene mutation, sequencing was performed on 38 CD90.2‐negative L5178Y/Tk^+/? clones derived from cultures treated with ethyl methanesulfonate. All clones were found to have mutation(s) within the Pig‐a gene. The continued investigation of L5178Y/Tk^+/? cells, CD90.2 labeling, and flow cytometric analysis as the basis of an in vitro mutation assay is clearly supported by this work. These data also provide evidence of the reliability of using GPI anchor‐deficiency as a valid reporter of Pig‐a gene mutation. Environ. Mol. Mutagen. 59:18–29, 2018. © 2017 Wiley Periodicals, Inc.