Department of Medical Biochemistry, University of Tampere Medical School, Tampere, Finland.
BMC Med Genet. 2012 Jul 2;13:32. doi: 10.1186/1471-2350-13-32.
The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults.
SNPs for association analysis were collected from the COX-2 gene and 5 kb up- and downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias.
Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p = 0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p = 0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p = 0.046) and maximal carotid intima-media thickness (p = 0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found.
Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood.
环氧化酶-2（COX-2）单核苷酸多态性的作用主要与晚期动脉粥样硬化有关，但对于其如何导致临床前疾病知之甚少。在本研究中，我们分析了 COX-2 基因变异是否与年轻健康白种人人群的早期亚临床动脉粥样硬化标志物，颈动脉内膜中层厚度和颈动脉扩张性独立相关。
从 COX-2 基因及其上下游 5kb 处收集用于关联分析的 SNP。共有 19 个 SNP 可用于分析，其中 4 个进行了基因分型，15 个进行了推断。心血管风险在年轻芬兰人中的研究。使用 MACH 1.0 和 HapMap II CEU（版本 22）样本作为参考进行基因型推断。使用线性回归的加性模型进行关联分析。PLINK 用于真实基因分型 SNP，ProbABEL 用于推断基因型剂量。使用虚假发现率考虑多重测试偏倚。
COX-2 中的两个变体（rs689470，rs689462）与扩张性呈正相关（p=0.005）线性回归加性模型。在调整性别，年龄，体重指数和吸烟状态后，这些 SNP 与扩张性之间的关联仍然具有统计学意义（p=0.031）。与主要等位基因纯合子相比，携带次要等位基因的受试者具有更高的颈动脉扩张性值。但是，在使用虚假发现率校正多重测试偏倚后校正 p 值时，关联丢失。另一个 COX-2 变体 rs4648261 与线性回归模型中的平均颈动脉内膜中层厚度（p=0.046）和最大颈动脉内膜中层厚度（p=0.048）相关。与主要等位基因纯合子相比，携带 rs4648261 次要等位基因的受试者的平均和最大颈动脉内膜中层厚度值较低。调整后，平均和最大颈动脉内膜中层厚度的关联均丢失。因此，没有发现研究的 COX-2 变体与颈动脉扩张性或颈动脉内膜中层厚度之间存在统计学意义的关联。
我们的结果表明，在芬兰人群中，COX-2 变体与年轻成年期的早期动脉粥样硬化变化之间没有明显关联。
