1,The Role Of PRKCH Gene Variants In Coronary Artery Disease In A Chinese Population 2,Polymorphisms In The Genes Of MCP-1/CCR2,RANTES/CCR5 With Cronary Artery Disease: A Meta-analysis

Part 1:The role of PRKCH gene variants in coronary arterydisease in a Chinese populationPRKCH gene locating on chromosome 14q22-23, (spanning 229.1kb) consisted of14 exons. PKCη, which was encoded by PRKCH gene, was one isoform of PKC(protein kinase C, PKC). PKC as a Ca2+ depending protein kinase has several rolestransmembranely signal transduction. PKC modulated the metabolism, proliferationand differentiation of several cells. In addition, it was demonstrated that PKCηwasexpressed mainly in foamy macrophages that play an important role in absorbinglipoprotein, release of oxygen species in human atherosclerotic lesions. Therefore, itwas supposed that PKCηwas closedly associated with atherosclerosis. Recent studieshave shown that PRKCH gene variants were significantly associated withatherosclerosis (e.g. CAD and stroke) and blood lipid metabolism. The PCR-LDRsequencing method was used to detect the 1425G/A and ₁5 variants in the PRKCHgene.(1) Genotypes and allele frequencies of cases and controls and theirassociations with CADGenotype frequencies did not deviate from the Hardy-Weinberg equilibrium in thecontrols (P = 0.49 and 0.94, respectively). The frequencies of PRKCH gene variants(1425G/A and ₁5) were significantly higher among CAD group compared withcontrol group (19.5% and 23.4% in the cases vs 13.8% and 17.2% in the controls; P =0.001 for 1425G/A, P = 0.001 for ₁5). In a multiple logistic regression modeladjusted for age, sex, body mass index (BMI), etc, a markedly increased risk ofdeveloping CAD was found in subjects carrying GA or AA genotype (P = 0.005 andP = 0.018, respectively). There were significant differences of GA+AA genotype between the cases (1425G/A, 0.347; ₁5, 0.391) and controls (1425G/A, 0.253; ₁5,0.172). Subjects with the variant genotypes (GA+AA) had 54% (1425G/A) and 41%(₁5) increased risks of CAD relative to GG carriers (1425G/A, adjusted OR = 1.54,95% CI = 1.14-2.08; ₁5, adjusted OR = 1.41, 95% CI = 1.06-1.89).(2) Lipid profiles of cases and controls in the PRKCH genotypesWe noted that the alleles carriers (GA+AA) both had markedly high plasmaLDL-C (Low Density Lipoprotein Cholesterol) levels in relation to the wild-type GGcarriers in the cases (P = 0.001 for 1425G/A and P = 0.021 for ₁5, respectively),while not in the controls. Then we performed multiple testing using bonfferonicorrection with significant level of 0.025, consequently, we observed that theassociation of PRKCH gene variants with LDL-C levels remained significant.However, no noticeable differences were found between the PRKCH gene variantsand other lipid levels [TC (Total cholesterol), TG (Triglyceride) and HDL-C (HighDensity Lipoprotein Cholesterol)].(3) Frequencies of haplotypes based on the observed genotypes in twogroupsWe further performed a permutation test and comfirmed that the two variants werestill significantly correlated with the presence of CAD (P < 0.020). LD analysesshowed that ₁5 polymorphism was in LD with 1425G/A polymorphism (D' = 1.000,r2 = 0.785). Remarkable differences were found in haplotypes (AA, GG) frequenciesbetween CAD patients and control subjects. The haplotype AA was more frequent inCAD group than in control group (0.195 vs 0.138, P < 0.001), while the frequency ofhaplotype GG was 0.766 in CAD patients, significantly lower than that in controlsubjects (0.828, P < 0.001), indicating that the haplotype AA was significantlyassociated with an increased risk of CAD, while the haplotype GG with a decreased risk. No significant difference was observed in frequency of haplotype GA betweenCAD patients and control subjects (0.039 vs 0.033, P = 0.500). The global P valuewas 0.004 according to haplotype analysis, indicating that the variant haplotypes weresignificantly associated with the presence of CAD, compared to the haplotype withoutany variant locus. This significance yet persisted even after accomplishing apermutation test (the global P = 0.040).Part 2: Polymorphisms in the genes of MCP-1/CCR2,RANTES/CCR5 with coronary artery disease: a meta-analysisPolymorphisms, including G2518A, G190A, G403A, wt/Δ32, have been found tobe significantly associated with coronary artery disease (CAD) in several studies, inthe genes of monocyte chemotactic protein-1 (MCP-1), CC chemokine receptor 2(CCR2), regulated on activation normal T-cell expressed and secreted (RANTES),CC chemokine receptor 5 (CCR5), respectively. However, the results wereinconsistent. The objective of our study was to investigate the association of thesevariants with CAD, using a meta-analysis.(1) MCP-1 gene G2518A polymorphism and CADIn our meta-analysis, the MCP-1 mutant A allele led to an increased risk for CADin dominant model (OR = 1.13, 95% CI = 1.01-1.26, P = 0.040). The MCP-1 geneG2518A polymorphism was not significantly linked to CAD in recessive model (OR= 1.04, 95% CI = 0.85-1.29, P = 0.690) and in codominant model (OR = 1.09, 95%CI = 0.99-1.19, P = 0.070). In light of stratified analysis by race, we noted that theMCP-1 polymorphism was significantly associated with the presence of CAD in non-Asian in dominant model (OR = 1.15, 95% CI = 1.01-1.31, P = 0.040) andcodominant model (OR = 1.12, 95% CI = 1.00-1.24, P = 0.050), while not in Asian.(2) CCR2 gene G190A polymorphism and CADThe variant in the CCR2 gene G190A was significantly linked to increase the riskof CAD in recessive model (OR = 2.00, 95% CI = 1.24-3.20, P = 0.004), while not indominant model (OR = 1.40, 95% CI = 0.82-2.41, P = 0.220).(3) RANTES gene variants and CADIn our studies, no significant association was found between RANTES geneG403A variant and CAD in recessive model (OR = 0.85, 95% CI = 0.66-1.10, P =0.220), in dominant model (OR = 0.90, 95% CI = 0.62-1.31, P = 0.570), and incodominant model (OR = 0.91, 95% CI = 0.69-1.18, P = 0.460).(4) CCR5 gene wt/Δ32 polymorphisms and CADOur findings suggested that the CCR5 gene wt/Δ32 deletion did not increase therisk of CAD in recessive model (OR = 1.20, 95% CI = 0.69-2.09, P = 0.510), indominant model (OR = 1.59, 95% CI = 0.65-3.90, P = 0.310) and in codominantmodel (OR = 1.04, 95% CI = 0.86-1.27, P = 0.680), respectively.