Jansen Mona Dverdal, Knudsen Gun Peggy, Myhre Ronny, Høiseth Gudrun, Mørland Jørg, Næss Øyvind, Tambs Kristian, Magnus Per
Division of Epidemiology, Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway,
Mol Biol Rep. 2014 May;41(5):2733-43. doi: 10.1007/s11033-014-3096-7. Epub 2014 Apr 13.
Single nucleotide polymorphisms (SNPs) in loci 1p13 and 9p21 have previously been found to be associated with incident coronary heart disease (CHD). This study aimed to investigate whether these SNPs show associations with fatal CHD in a population-based cohort study after adjustment for socioeconomic- and lifestyle-related CHD risk factors not commonly included in genetic association studies. Using the population-based Cohort of Norway (CONOR), a nested case-cohort study was set up and DNA from 2,953 subjects (829 cases and 2,124 non-cases) were genotyped. The association with fatal CHD was estimated for four SNPs, three from locus 1p13 and one from locus 9p21. Multivariable Cox regression was used to estimate unstratified and gender-stratified hazard ratios while adjusting for major CHD risk factors. The associations between three SNPs from locus 1p13 and non-HDL cholesterol levels were also estimated. Men homozygous for the risk alleles on rs1333049 (9p21) and rs14000 (1p13) were found to have significantly increased hazard ratios in crude and adjusted models, and the hazard ratios remained statistically significant when both genders were analyzed together. Adjustment for additional socioeconomic- and lifestyle-related CHD risk factors influenced the association estimates only slightly. No significant associations were observed between the other two SNPs in loci 1p13 (rs599839 and rs646776) and CHD mortality in either gender. Both rs599839 and rs646776 showed significant, gradual increases in non-HDL cholesterol levels with increasing number of risk alleles. This study confirms the association between 9p21 (rs1333049) and fatal CHD in a Norwegian population-based cohort. The effect was not influenced by several socioeconomic- and lifestyle-related risk factors. Our results show that 1p13 (rs14000) may also be associated with fatal CHD. SNPs at 1p13 (rs599839 and rs646776) were associated with non-HDL cholesterol levels.
此前已发现，位于1p13和9p21位点的单核苷酸多态性（SNP）与冠心病（CHD）发病相关。本研究旨在通过一项基于人群的队列研究，在对遗传关联研究中通常未纳入的社会经济和生活方式相关的CHD危险因素进行校正后，调查这些SNP是否与致死性CHD相关。利用基于人群的挪威队列研究（CONOR），开展了一项巢式病例对照研究，并对2953名受试者（829例病例和2124例非病例）的DNA进行基因分型。对4个SNP进行致死性CHD关联估计，其中3个来自1p13位点，1个来自9p21位点。采用多变量Cox回归估计未分层和按性别分层的风险比，同时校正主要CHD危险因素。还估计了来自1p13位点的3个SNP与非高密度脂蛋白胆固醇水平之间的关联。发现rs1333049（9p21）和rs14000（1p13）风险等位基因纯合的男性在粗模型和校正模型中的风险比显著增加，在对男女进行合并分析时，风险比仍具有统计学意义。对其他社会经济和生活方式相关的CHD危险因素进行校正，仅对关联估计产生轻微影响。在1p13位点的其他两个SNP（rs599839和rs646776）与任何性别的CHD死亡率之间均未观察到显著关联。rs599839和rs646776均显示，随着风险等位基因数量增加，非高密度脂蛋白胆固醇水平显著逐渐升高。本研究证实了挪威基于人群的队列中9p21（rs1333049）与致死性CHD之间的关联。该效应不受多种社会经济和生活方式相关危险因素的影响。我们的结果表明，1p13（rs14000）也可能与致死性CHD相关。1p13（rs599839和rs646776）的SNP与非高密度脂蛋白胆固醇水平相关。
