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。
