Robertson Kirsty S, Hawe Emma, Miller George J, Talmud Philippa J, Humphries Steve E
Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St., London WC1E 6JF, UK.
Biochim Biophys Acta. 2003 Nov 20;1639(3):203-12. doi: 10.1016/j.bbadis.2003.09.008.
The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase (PON). Three distinct enzymes have been identified, encoded by PON1, PON2 and PON3, clustered on chromosome 7q21-q22. Two cSNPs in PON1 (L55M and Q192R) and one in PON2 (S311C) have been implicated as independent risk factors for coronary heart disease (CHD) in some, but not all, studies. A PON3 SNP (A99A) was identified and the effect of these four PON SNPs on HDL levels and CHD risk was examined in the prospective Northwick Park Heart Study II (NPHSII). Genotype frequencies did not differ between cases and controls but the CHD risk associated with smoking was significantly modified by PON1 L55M genotype. Compared to LL non-smokers, LL smokers had a hazard ratio (HR) of 1.30 (95% CI 0.81-2.06) while M-allele carriers had a HR of 1.76 (1.17-2.67). When genotypes were analysed in combination, men with the genotype PON1 55 LM/MM+PON2 311 CC, had HR of 3.54 (1.81-6.93) compared to PON1 LL+PON2 SS/SC men (interaction P=0.004). These effects were independent of classical risk factors. These data demonstrate the importance of stratifying by environmental factors and the use of multiple SNPs for genetic analysis.
高密度脂蛋白（HDL）的抗动脉粥样硬化作用部分归因于与HDL相关的对氧磷酶（PON）的作用。已鉴定出三种不同的酶，由PON1、PON2和PON3编码，聚集在7号染色体的q21-q22区域。在一些（但并非所有）研究中，PON1中的两个常见单核苷酸多态性（cSNP）（L55M和Q192R）以及PON2中的一个（S311C）被认为是冠心病（CHD）的独立危险因素。鉴定出一个PON3 SNP（A99A），并在前瞻性的诺斯威克公园心脏研究II（NPHSII）中研究了这四个PON SNP对HDL水平和CHD风险的影响。病例组和对照组的基因型频率没有差异，但PON1 L55M基因型显著改变了与吸烟相关的CHD风险。与LL非吸烟者相比，LL吸烟者的风险比（HR）为1.30（95%CI 0.81-2.06），而M等位基因携带者的HR为1.76（1.17-2.67）。当联合分析基因型时，与PON1 LL+PON2 SS/SC男性相比，基因型为PON1 55 LM/MM+PON2 311 CC的男性HR为3.54（1.81-6.93）（交互作用P=0.004）。这些影响独立于经典危险因素。这些数据证明了按环境因素分层以及使用多个SNP进行遗传分析的重要性。
