Association Study Of C-Reactive Protein Gene Variation With Low High-density Lipoprotein Cholesterol And Coronary Heart Disease

Background and objectivesHigh density lipoprotein cholesterol(HDL-C),which participates in the reverse transport of cholesterol,has an anti-atherosclerotic(AS)effect.The development of AS is accompanied by chronic inflammatory reaction and is an important risk factor for coronary heart disease(CHD)and severe stroke.As one of systemic inflammation reactive biological indicators,the increase of high sensitive C-reactive protein(hs-CRP)induced the thickening of endometrium and rupture of AS plaque.Previous studies have found that the variation of CRP gene is significantly associated with the increasing level of HDL-C.Whether CRP gene polymorphisms is associated with the decreased level of HDL-C has not been reported.Methods and subjectsAn cluster sampling method was use and the subjects were recruited in 2009 from Guanlin and Xushe towns of Yixing city,Jiangsu province,and 4156 individuals were included.Individuals who had previously been diagnosed as coronary heart disease and those who were taking blood lipid lowering drugs were excluded.Based on the method by combinating of linkage disequilibrium and bioinformatic functional prediction,4 tag single nucleotide polymorphisms(tag SNPs)rs1205,rs1073715,rs876537 and rs2808630 in CRP were selected for the minor allele frequency(MAF)>0.05 and r2>0.8 conditions,.Taq Man probe array was used for four CRP gene SNPs genotyping.Multiple logistic regression was applied to further evaluate association between the SNPs and low-HDL-C.ResultsThe level of hs-CRP was significantly different among rs1205 and rs876537 genotypes,P<0.001.The Logistic regression analysis showed that rs1205 and rs876537 were correlated with a low level of HDL-C significantly,and the recessive model was statistically significant,after adjustment age,sex,smoking and drinking,the odds ratios(ORs)and 95% confidence intervals(CIs)were 1.37(1.11-1.69)and1.32(1.07-1.63),with the P values of 0.003 and 0.009,respectively.In the hs-CRP elevated group(31.0mg/l),rs1205 and rs876537 were significantly associated the risk of decreased HDL-C,the ORs(95% CIs)for the recessive models were 1.47(1.1-1.98)and 1.40(1.04-1.88),P values were 0.01 and 0.03,respectively.In the normal hs-CRP group(<1.0mg/l),the variation of rs10737175 locus was related to the lower level of HDL-C,OR(95% CI)was 1.85(1.16-2.95),P value was 0.01.Female with rs1205,rs10737175,rs876537 TT genotype were more likely to suffer from low-HDL-C,the odds ratios(ORs)and 95% confidence intervals(CIs)were1.59(1.02-2.48),1.45(1.10-1.92)and 1.41(1.07-1.87),with the P values of 0.042,0.009 and 0.015 respectively Female with rs10737175 TT genotype had a lower HDL-C level than CC+TT carriers,P value was 0.035.ConclusionsCRP polymorphisms were associated with decreased low-HDL-C level and the results were significant particularly in female population.Background and objectives As a non-specific inflammatory factor,high-sensitivity C-reactive protein(hs-CRP)participants in the development of atherosclerosis(AS)and significantly associated with coronary heart disease(CHD).However,the results on the casual association between hs-CRP and CHD are inconsistent.Traditional epidemiological studies have some limitations on assessing the causal relationship,thus,through selecting the CRP polymorphisms as instrumental variable(IV),we aimed to evaluated the causal effect of hs-CRP with CHD using Mendelian Randomization(MR)analysis in Chinese Han population.Methods and subjects A total of 4,156 subjects were recruited by epidemiological cluster sampling.Individuals who had previously been diagnosed as CHD,chronic renal insufficiency,liver dysfunction,and those who had taken or were taking blood lipid lowering drugs were excluded.Based on the combination of linkage disequilibrium and functional site prediction,and under the minor allele frequency(MAF)>0.05 and r2>0.8conditions,4 tag single nucleotide polymorphisms(tag SNPs)rs1205,rs1073715,rs876537 and rs2808630 in CRP were selected.Linear regression was used to assess the relationship between CRP polymorphisms and CHD.Survival receiver operator characteristic curve(ROC)curve was used to identify the cutoff of hs-CRP with CHD.Cox regression model was applied to detect the association of hs-CRP with CHD by calculating the hazard ratio(HR)and 95% confidence interval(CI),multivariate Cox regression model was applied to adjust the covariates.The weighted linear regression model was used to analysis the casual effect of hs-CRP and CHD with Mendelian Randomization package in R 3.4.3.The results were displayed by calculation the Odds ratio(OR)and 95% CI.Results The level of hs-CRP was significantly increased among rs1205 and rs876537 genotypes,the standard regression coefficients were 0.064 and 0.066,P<0.001.No associations were found between CRP and CHD,even after stratified by the 55 years group,gender,smoking status and drinking status.Using ROC curve,the hs-CRP was divided into elevated group and normal group by a cutoff of 1.08 mg/L.The elevated hs-CRP was significantly associated with CHD,the HR(95% CI)was2.23(1.48-3.35),P<0.001;after adjusted age,gender,BMI,TC,TG,HDL-C,LDL-C,smoking status,drinking status,diabetes and hypertension,the HR(95% CI)was1.69(1.11-2.60)with a P value of 0.016.Thus,we select the CRP rs1205 and rs876537 as IV.When no covariate was adjusted,MR analysis showed that hs-CRP had no casual association with CHD,the OR(95% CI)was 1.04(0.67-1.62),P=0.855;After the covariates of-C,GLU,BMI,smoking,alcohol consumption,diabetes,and diabetes,MR analysis showed that hs-CRP still had no casual association with CHD,e OR(95% CI)was 1.07(0.69-2.18),P=0.777.Conclusions Hs-CRP level was affected by CRP rs1205 and rs876537,the association between hs-CRP and CHD is unlikely to be causal,suggesting that other inflammatory biomarker should be paid attention to rather than hs-CRP in the prevention and treatment of clinical CHD.