A Variant In The Vitamin D Receptor Gene (VDR) Is Associated With Time To Onset Of Chronic Obstructive Pulmonary Disease (COPD) In Men

Abstract

RATIONALE: Funding: NIH/NIA AG027014 We hypothesized that variants of genes in the vitamin D pathway are associated with time to onset of COPD. We conducted a survival analysis study to investigate whether single nucleotide polymorphisms (SNPs) in the vitamin D receptor gene (VDR) and the vitamin D binding protein gene (GC) are associated with time to onset of COPD in a population sample of men. METHODS: We investigated 36 SNPs in VDR and GC in the VA Normative Aging Study, a longitudinal study of aging. A total of 1215 men with repeated lung function measures over 40 years and DNA samples for genotyping were analyzed. Subjects were enrolled in the study after an initial health screening determined that they were free of known chronic medical conditions such as coronary heart disease, hypertension, chronic lung disease, asthma, and diabetes. SNPs were chosen on the basis of being linkage disequilibrium-tag SNPs and prior reported associations with COPD. Participants were defined as having COPD when they met modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II criteria on 2 consecutive visits. Analyses of time to onset of COPD were performed using Cox proportional hazards models under an additive genetic model, and were adjusted for age, pack-years of smoking, and current smoking status. P values were adjusted for multiple comparisons using the false discovery rate method. Genotypes were tested for violation of the proportional hazards assumption using an interaction term, using a value of P < 0.05 as evidence of a significant violation. RESULTS: At baseline, 48.7% of the subjects were current smokers. The mean age was 41.6 (23.1-70.1) years. The mean (standard deviation) percent predicted FEV1 was 96.2% (12.1). The median duration of follow-up was 32.4 (3.3 D 40.4) years. A total of 191 (19.1%) subjects developed COPD during follow-up and the median years to COPD development or censorship was 31 (0 D 40.4) years. Of the 36 SNPs tested, SNP rs3847987 in VDR was associated with time to onset of COPD, with a hazard ratio of 1.604 (95% confidence interval, 1.257-2.047, adjusted P value =0.0052). CONCLUSION: Variant rs3847987, located at the 3O untranslated region of VDR, is associated with development of COPD in men, and provides support for the notion that vitamin D metabolic pathways may affect COPD risk. (Figure presented).