Wootton Peter T E, Arora Nupur L, Drenos Fotios, Thompson Simon R, Cooper Jackie A, Stephens Jeffrey W, Hurel Steven J, Hurt-Camejo Eva, Wiklund Olov, Humphries Steve E, Talmud Philippa J
Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School,5 University Street, London WC1E 6JF, UK.
Hum Mol Genet. 2007 Jun 15;16(12):1437-44. doi: 10.1093/hmg/ddm094.
Animal and human studies suggest that both secretory PLA2 (sPLA2)-V and sPLA2-IIA (encoded, respectively, by the neighbouring PLA2G5 and PLA2G2A genes) contribute to atherogenesis. Elevated plasma sPLA2-IIA predicts coronary heart disease (CHD) risk, but no mass assay for sPLA2-V is available. We previously reported that tagging single nucleotide polymorphism (tSNP) haplotypes of PLA2G2A are strongly associated with sPLA2-IIA mass, but not lipid levels. Here, we use tSNPs of the sPLA2-V gene to investigate the association of PLA2G5 with CHD risk markers. Seven PLA2G5 tSNPs genotypes, explaining >92% of the locus genetic variability, were determined in 519 patients with Type II diabetes (in whom PLA2G2A tSNP data was available), and defined seven common haplotypes (frequencies >5%). PLA2G5 and PLA2G2A tSNPs showed linkage disequilibrium (LD). Compared to the common PLA2G5 haplotype, H1 (frequency 34.9%), haplotypes H2-7 were associated with overall higher plasma LDL (P < 0.00004) and total cholesterol (P < 0.00003) levels yet lower oxLDL/LDL (P = 0.006) and sPLA2-IIA mass (P = 0.04), probably reflecting LD with PLA2G2A. Intronic tSNP (rs11573248), unlikely itself to be functional, distinguished H1 from LDL-raising haplotypes and may mark a functional site. In conclusion, PLA2G5 tSNP haplotypes demonstrate an association with total and LDL cholesterol and oxLDL/LDL, not seen with PLA2G2A, thus confirming distinct functional roles for these two sPLA2s.
动物和人体研究表明,分泌型磷脂酶A2(sPLA2)-V和sPLA2-IIA(分别由相邻的PLA2G5和PLA2G2A基因编码)均参与动脉粥样硬化的形成。血浆sPLA2-IIA水平升高预示着冠心病(CHD)风险,但目前尚无针对sPLA2-V的批量检测方法。我们之前报道过,PLA2G2A的标签单核苷酸多态性(tSNP)单倍型与sPLA2-IIA水平密切相关,但与血脂水平无关。在此,我们利用sPLA2-V基因的tSNP来研究PLA2G5与CHD风险标志物之间的关联。在519例2型糖尿病患者(可获取PLA2G2A tSNP数据)中确定了7种PLA2G5 tSNP基因型,这些基因型解释了该基因座>92%的遗传变异性,并定义了7种常见单倍型(频率>5%)。PLA2G5和PLA2G2A的tSNP显示出连锁不平衡(LD)。与常见的PLA2G5单倍型H1(频率34.9%)相比,单倍型H2-7与总体较高的血浆低密度脂蛋白(LDL)(P<0.00004)和总胆固醇(P<0.00003)水平相关,但氧化型LDL/低密度脂蛋白(oxLDL/LDL)(P=0.006)和sPLA2-IIA水平(P=0.04)较低,这可能反映了与PLA2G2A的LD关系。内含子tSNP(rs11573248)本身不太可能具有功能,但它可将H1与升高LDL的单倍型区分开来,可能标记了一个功能位点。总之,PLA2G5 tSNP单倍型与总胆固醇、LDL胆固醇以及oxLDL/LDL存在关联,而PLA2G2A则无此关联,从而证实了这两种sPLA2具有不同的功能作用。