Dutta Ambarish, Henley William, Lang Iain A, Murray Anna, Guralnik Jack, Wallace Robert B, Melzer David
Epidemiology and Public Health Group, Peninsula Medical School, University of Exeter, Exeter, UK.
Circ Cardiovasc Genet. 2011 Oct;4(5):542-8. doi: 10.1161/CIRCGENETICS.111.960146. Epub 2011 Aug 18.
Common variation at chromosome 9p21 (marked by rs10757278 or rs1333049) is associated with coronary artery disease (CAD) and peripheral vascular disease. A decreasing effect at older age was suggested, and effects on long-term mortality are unclear. We estimated 9p21 associations with CAD and all-cause mortality in a CAD diagnosis-free older population. We also estimated classification gains on adding the variant to the Framingham Risk Score (FRS) for CAD.
DNA was from an Established Populations for Epidemiological Study of the Elderly-Iowa cohort from 1988 (participants >71 years), with death certificates obtained to 2008 for 92% of participants. Cox regression models were adjusted for confounders and CAD risk factors. Of 1095 CAD diagnosis-free participants, 52% were heterozygous (CG) and 22% were homozygous (CC) for the risk C allele rs1333049. Unadjusted CAD-attributed death rates in the CC group were 30 vs 22 per 1000 person-years for the GG group. The C allele was associated with all-cause (hazard ratio, 1.19; 95% CI, 1.08-1.30) and CAD (hazard ratio, 1.29; 95% CI, 1.08-1.56) mortality, independent of CAD risk factors. There was no association with stroke deaths. Variant associations with CAD mortality were attenuated after the age of 80 years (age-interaction term P=0.05). In age group 71 to 80 years, FRS classified as high risk 21% of respondents who died of CAD within 10 years; adding 9p21 identified 27% of respondents.
In 71- to 80-year-old subjects free of CAD diagnoses, 9p21 is associated with excess mortality, mainly attributed to CAD mortality. Adding 9p21 to the FRS may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation.
9号染色体p21区域的常见变异（由rs10757278或rs1333049标记）与冠状动脉疾病（CAD）和外周血管疾病相关。有研究提示该变异在老年人中的影响逐渐减弱，且其对长期死亡率的影响尚不清楚。我们评估了在无CAD诊断的老年人群中9p21变异与CAD及全因死亡率的关联。我们还评估了将该变异添加到CAD的弗雷明汉姆风险评分（FRS）中的分类增益。
DNA来自1988年爱荷华州老年流行病学研究既定人群队列（参与者年龄>71岁），92%的参与者可获取截至2008年的死亡证明。Cox回归模型对混杂因素和CAD危险因素进行了校正。在1095名无CAD诊断的参与者中，52%为rs1333049风险C等位基因的杂合子（CG），22%为纯合子（CC）。CC组未经调整的CAD归因死亡率为每1000人年30例，而GG组为22例。C等位基因与全因死亡率（风险比，1.19；95%可信区间，1.08 - 1.30）和CAD死亡率（风险比，1.29；95%可信区间，1.08 - 1.56）相关，独立于CAD危险因素。与中风死亡无关联。80岁以后，该变异与CAD死亡率的关联减弱（年龄交互项P = 0.05）。在71至80岁年龄组中，FRS将10年内死于CAD的受访者中的21%分类为高危；添加9p21变异后可识别出27%的受访者。
在71至80岁无CAD诊断的受试者中，9p21与超额死亡率相关，主要归因于CAD死亡率。将9p21添加到FRS中可能会改善老年人CAD预防的针对性，但需要在独立样本中进行验证以确认。
