弗雷明汉心脏研究全基因组关联研究：肺功能测量结果
Framingham Heart Study genome-wide association: results for pulmonary function measures.
作者信息
Wilk Jemma B, Walter Robert E, Laramie Jason M, Gottlieb Daniel J, O'Connor George T
机构信息
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
出版信息
BMC Med Genet. 2007 Sep 19;8 Suppl 1(Suppl 1):S8. doi: 10.1186/1471-2350-8-S1-S8.
BACKGROUND
Pulmonary function measures obtained by spirometry are used to diagnose chronic obstructive pulmonary disease (COPD) and are highly heritable. We conducted genome-wide association (GWA) analyses (Affymetrix 100K SNP GeneChip) for measures of lung function in the Framingham Heart Study.
METHODS
Ten spirometry phenotypes including percent of predicted measures, mean spirometry measures over two examinations, and rates of change based on forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow from the 25th to 75th percentile (FEF25-75), the FEV1/FVC ratio, and the FEF25-75/FVC ratio were examined. Percent predicted phenotypes were created using each participant's latest exam with spirometry. Predicted lung function was estimated using models defined in the set of healthy never-smokers, and standardized residuals of percent predicted measures were created adjusting for smoking status, pack-years, and body mass index (BMI). All modeling was performed stratified by sex and cohort. Mean spirometry phenotypes were created using data from two examinations and adjusting for age, BMI, height, smoking and pack-years. Change in pulmonary function over time was studied using two to four examinations with spirometry to calculate slopes, which were then adjusted for age, height, smoking and pack-years.
RESULTS
Analyses were restricted to 70,987 autosomal SNPs with minor allele frequency > or = 10%, genotype call rate > or = 80%, and Hardy-Weinberg equilibrium p-value > or = 0.001. A SNP in the interleukin 6 receptor (IL6R) on chromosome 1 was among the best results for percent predicted FEF25-75. A non-synonymous coding SNP in glutathione S-transferase omega 2 (GSTO2) on chromosome 10 had top-ranked results studying the mean FEV1 and FVC measurements from two examinations. SNPs nearby the SOD3 and vitamin D binding protein genes, candidate genes for COPD, exhibited association to percent predicted phenotypes.
CONCLUSION
GSTO2 and IL6R are credible candidate genes for association to pulmonary function identified by GWA. These and other observed associations warrant replication studies. This resource of GWA results for pulmonary function measures is publicly available at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.
背景
通过肺活量测定法获得的肺功能指标用于诊断慢性阻塞性肺疾病（COPD），且具有高度遗传性。我们在弗雷明汉心脏研究中对肺功能指标进行了全基因组关联（GWA）分析（Affymetrix 100K SNP基因芯片）。
方法
检查了10种肺活量测定表型，包括预测指标的百分比、两次检查的平均肺活量测定指标，以及基于一秒用力呼气量（FEV1）、用力肺活量（FVC）、第25至75百分位数的用力呼气流量（FEF25 - 75）、FEV1/FVC比值和FEF25 - 75/FVC比值的变化率。使用每个参与者最新的肺活量测定检查创建预测百分比表型。使用健康从不吸烟者组中定义的模型估计预测肺功能，并针对吸烟状况、吸烟包年数和体重指数（BMI）调整预测指标百分比的标准化残差。所有建模按性别和队列分层进行。使用两次检查的数据并针对年龄、BMI、身高、吸烟和吸烟包年数进行调整来创建平均肺活量测定表型。使用两次至四次肺活量测定检查来计算斜率，研究肺功能随时间的变化，然后针对年龄、身高、吸烟和吸烟包年数进行调整。
结果
分析限于70,987个常染色体单核苷酸多态性（SNP），其次要等位基因频率≥10%，基因型检出率≥80%，哈迪 - 温伯格平衡p值≥0.001。1号染色体上白细胞介素6受体（IL6R）中的一个SNP在预测FEF25 - 75百分比的最佳结果中。10号染色体上谷胱甘肽S - 转移酶ω2（GSTO2）中的一个非同义编码SNP在研究两次检查的平均FEV1和FVC测量值时排名靠前。COPD候选基因超氧化物歧化酶3（SOD3）和维生素D结合蛋白基因附近的SNP与预测百分比表型相关。
结论
GSTO2和IL6R是通过GWA鉴定出的与肺功能相关的可信候选基因。这些以及其他观察到的关联值得进行复制研究。肺功能指标的GWA结果资源可在http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007网址公开获取。
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