ADAM33 Gene Polymorphisms and Mortality. A Prospective Cohort Study

Abstract

The ADAM33 gene is associated with the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. In this study we investigated all-cause, COPD and cardiovascular mortality, in relation to single nucleotide polymorphisms (SNPs) in ADAM33 (Q_1, S_1, S_2, T_1 and T_2) that were genotyped in 1,390 subjects from the Vlagtwedde/Vlaardingen cohort. Participants were examined at entry in 1989/1990 and followed up till evaluation of the vital status on December 31st, 2008. Using Cox proportional hazards regression we estimated the risk of the SNPs in relation to mortality, adjusting for gender, age, FEV1, height, place of residence and packyears of smoking. Additionally, we performed stratified analyses according to gender and smoking habits. After 18 years, 284 (20.4%) subjects had died (107 due to cardiovascular disease and 20 due to COPD). Individuals homozygous for the minor allele of SNP T_2 had an increased risk of all-cause and cardiovascular mortality compared to wild types: hazard ratio 3.6 (95% confidence interval 2.0 to 6.7) and 3.4 (1.2 to 9.5) respectively. Individuals homozygous for the minor allele of S_1, S_2, T_2 or Q_1 had a significantly increased risk of COPD mortality. In stratified analyses the risk of all-cause mortality associated with SNP T_2 did not change: females 3.5 (1.5 to 8.3), males 3.1 (1.2 to 7.6), never smokers 3.8 (0.9 to 16.3), ever smokers 3.6 (1.8 to 7.2). This study shows for the first time that ADAM33 is a pleiotropic gene that is associated with all-cause, COPD and cardiovascular mortality, independent of potential confounders.

Genetic variants in ADAM33 are associated with airway inflammation and lung function in COPD

“…We first found that T1, T2 and Q-1 were significantly associated with COPD, while Figarsk et al revealed that S1, S2, T2 and Q-1 were significantly associated with COPD in Vlagtwedde/Vlaardingen cohort [25]. Since no association was found between S1 and COPD in our previous study in a northeastern Chinese population [29], we did not include S1 in this study.…”

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship

“…In 2013, investigators of the GRACE Genetics Study [ 26 ] evaluated 23 susceptibility loci for CAD and their association with recurrent MI or cardiac death; a variant upstream of ABO (rs579459) was significantly associated in initial and replication analyses with both endpoints in 2,099 acute coronary syndrome patients followed for a median five years. In studies of CAD and chronic obstructive pulmonary disease, ADAM33 was related to both all-cause and cardiovascular-related mortality in 1,390 subjects followed for 18 years [ 27 ]. In the MASS-II clinical trial of CAD and preserved left ventricular function, the 9p21 variant rs2383206 was associated with higher incidence of all-cause and cardiac-related mortality in 611 patients with established multi-vessel CAD [ 28 ].…”

“…Clinically, we are poor at predicting survival in coronary artery disease [ 38 ]; accurate estimation of survival outcomes is difficult, at best. Evidence has accumulated for the identification of genetic determinants of mortality in complex (non-Mendelian) diseases such as sudden cardiac death [ 39 , 40 ]; acute coronary syndrome [ 26 , 41 ]; cardiac-related death and all-cause mortality [ 27 , 28 ]; as well as all-cause mortality after acute coronary syndromes [ 42 ] [ 43 ]. These studies present candidate markers for events in samples with those at-risk but largely undiagnosed for CAD.…”

Whole-Genome Linkage Scan Combined With Exome Sequencing Identifies Novel Candidate Genes for Carotid Intima-Media Thickness

“…Several genes under the linkage peak have previously been implicated in the pathogenesis of cardiovascular disease. The base to base peak at chromosome 19 encompassed FCAR and TNNT1 genes associated with coronary heart disease ( Iakoubova et al, 2006 ; Guay et al, 2016 ) and OSCAR and FPR2 genes associated with atherosclerosis plaque phenotype ( Goettsch et al, 2011 ; Petri et al, 2015 ), whereas the base to base peak at chromosome 20 encompassed ADAM33 and TRIB3 associated with extent and promotion of atherosclerosis ( Holloway et al, 2010 ; Formoso et al, 2011 ; Wang et al, 2012 ; Figarska et al, 2013 ; Prudente et al, 2015 ) and HSPA12B which is found to be enriched in atherosclerotic lesions ( Han et al, 2003 ).…”