A DISINTEGRIN AND METALLGPROTSASE 33 POLYMORPHISMS AND LUNG, FUNCTION DECLINE IN THE GENERAL POPULATION

摘要

ADAM33 (A Disintegrin and Metalloprotease 33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excess decline of lung function in nsthmatics.To assess whether SNPs in ADAM33 are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD).We have collected DNAfrom subjects of the VlagtweddeVlaardingen cohort participating in the last survey in 1989 1990 after a follow up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. 1390 subjects from the cohort were genotyped for the following SNPs in ADAM33: F 1. Q-1, s_1, S_2. T_1, T_2, V_4. ST 5. Differences in prevalence of SNPs were analyzed with chi-square tests. Linear mixed effects models were used to analyze FEV decline according to genotype.In the whole population mean adjusted decline was 18.7 and 12.7 ml y in females and males respectively. Individuals homozygous for minor alleles of SNPs S 2 and Q-1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV of respectively 4.9. 9.6 and 3.6 ml y compared with wild type. We found a significantly higher prevalence of SNPs F+1. S_1, S_2 and T_2 in subjects with COPD.We demonstrated that SNPs in ADAM33 are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.