| Objective?We aim to explore the association of susceptibility polymorphisms and CHD by meta-analyses andgenotyping. DNA methylation sequencing of canadiate genes are also analyzed to investigate the associationbetween DNA methylation and CHD.Methods?Meta-analyses for HFE and APOA5genes were done using the Review Manager (version5.0, TheCochrane Collaboration). Using the standardized coronary angiography method, we collected290CHD cases?198non-CHD controls and331unrelated healthy volunteers. MassARRAY MALDI-TOF mass spectrometry wasused for genotyping of the20canadiate polymorphisms. We selected36CHD cases and36controls (18male and18female, respectively) matched with age, gender and clinical index. The DNA methylation levels of the CpGisland region on the PLA2G7?CDKN2B?and GCK genes were measured through the sodium bisulfite DNAconversion and pyrosequencing technology.Results:(1) Meta-analyses: Allele rs662799-G can increase the risk for CHD in Europeans by77%(P <0.00001,OR=1.77,95%CI=1.42-2.20), while the risk in Asians can increase by38%(P <0.00001, OR=1.38,95%CI=1.25-1.52). Rs1799945-G was also risky for CHD in Caucasians (P=0.02, OR=1.06,95%CI=1.01-1.11)while not a risky for Chinese (P=0.77, OR=0.91,95%CI=0.50-1.68).(2) Case-control study?Allele rs7756935-C of PLA2G7gene was shown as a protective factor of CHD (P=0.03, OR (95%CI)=0.68(0.48-0.97)). Allele rs964184-G of ZNF259(P=0.04, OR (95%CI)=1.40(1.01-1.93))and rs662799-G of APOA5genes (P=0.03, OR (95%CI)=1.42(1.04-1.95)) were shown as risk factors of CHD.Rs7528419variation of CELSR2gene was shown to protect the risk of CHD in males. Rs964184(ZNF259) andrs662799(APOA5) variations were risky for CHD. Variations of two other SNPs (rs7756935and rs1805017) ofPLA2G7gene acted as a protective factor of CHD in females.(3) There was no significant difference between the distribution of genotype or allele of rs17321515andCHD. Patients that carried AA genotype had a lower triglyceride (TG) level (1.76±1.04) than patients carried AGgenotype (2.09±1.07)(P <0.05) in CHD group. And the low density lipoprotein (LDL) level (2.52±1.48) washigher than AG genotype carriers (2.14±1.08)(P <0.05). While in non-CHD control group, the TG value of AAcarriers (2.22±1.14)?AG carriers (2.03±1.09) were higher than the GG carriers (1.68±1.03)(P <0.05).(4) There was no association between rs4299376polymorphism of ABCG5/ABCG8gene and CHD risk. Infemale group, the triglyceride (TG) and total cholesterol (TC) were higher in CHD patients than non-CHDcontrols (TG: CHD:2.23±1.05, non-CHD:1.84±1.03, P=0.01; TC: CHD:4.79±1.17, non-CHD:4.36±1.03,P=0.01). Separate the groups by age, the CHD cases had a lower high density lipoprotein (HDL) level in groupover60years old (CHD:1.09±0.23, non-CHD:1.16±0.25, P=0.03). (5) There was a significant association between PLA2G7gene promoter DNA methylation and the risk ofCHD (6.41±2.62vs4.98±3.06?P=0.026). CHD cases had a hypermehylation level of CDKN2B than controls(7.66±3.02vs6.43±2.23?P=0.043). CDKN2B methylation level was higher in male than in female (8.07±2.76vs6.02±2.26?P=0.007). For gene-body methylation, GCK methylation level in CHD cases was lower than incontrols. A breakdown analysis by gender showed that PLA2G7and CDKN2B promoter methylation levels weresignificantly associated with the risk of CHD in females (P=0.003,0.009). The CHD patients had a highermethylation level than controls in females while no significant difference was found in males.(6) Significant gender-specific correlation patterns were observed between age and PLA2G7and CDKN2Bpromoter methylation. A negative correlation was presented in male (PLA2G7: r=-0.365, P=0.037; CDKN2B: r=-0.370, P=0.034) and a positive correlation in female (PLA2G7: r=0.373, P=0.035; CDKN2B: r=0.406, P=0.021). There was no significant correlation between GCK gene-body methylation and age. Separate the group byage60, we found that there was no significant difference between age and methylation younger than60years bothin male and female. The most significant difference was found in females aged60years and older (PLA2G7?r=0.437, P=0.033; CDKN2B?r=0.579, P=0.007). Association of methylation level of PLA2G7and age was alsofound in male aged60years and older (PLA2G7?r=-0.509, P=0.013).Conclusion:(1) meta-analyses?Rs662799(APOA5) variation is the susceptibility locus for CHD. rs1799945(HFE) is risky for CHD in Caucasians but not in Chinese. The meta-analyses about association betweenpolymorphisms and CHD have been reported in Molecular Medicine Reports (IF=1.17) and Gene (IF=2.2).(2) We identified four Lp-PLA2-associated SNPs significantly associated with CHD in Han Chinese.Specifically, rs7528419was a risk factor for CHD in males, while two SNPs (rs7756935and rs1805017) wereprotective factors for CHD in females. Rs964184was a risk factor for CHD. The results of the case-control studyhave been published in Experimental and therapeutic medicine (IF=0.34).(3) The TRIB1gene polymorphism rs17321515and ABCG5/ABCG8polymorphism rs4299376had nosignificant association with CHD risk. For rs17321515, the patients carried AA genotype had a lower TG leveland a higher LDL level, while non-CHD controls carried A allele had a higher TG level. For rs4299376, femalewith CHD had a high level of TG and TC, and the elder persons with CHD had a lower HDL level than non-CHDcontrols. One of the researches about polymorphisms and lipid levels has been published in Highlights ofSciencepaper Online. And another research has been accepted by Academic journal of second military medicaluniversity.(4) Hypomethylation of PLA2G7and CDKN2B genes promoters can increase the risk of CHD. CDKN2Bmethylation level was higher in male than in female. For gene-body methylation, GCK methylation level in CHDcases was lower than in controls. PLA2G7and CDKN2B promoter methylation was significantly associated withthe risk of CHD in females.(5) Significant gender-specific correlation patterns were observed between age and PLA2G7and CDKN2Bpromoter methylation. The most significant difference was found in females aged60years and older. Associationof methylation level of PLA2G7and age was also found in male aged60years and older. The association betweenDNA methylation and CHD has been reported in Plos One (IF=3.73) and BioMed Research International (journalof biomedicine and biotechnology, IF=2.88). Another paper is preparing for submitting.. |
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