Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men.
BACKGROUND
Inflammation and endothelial dysfunction are important risk factors for cardiovascular disease (CVD). We hypothesized that candidate genes selected for a study of asthma and chronic obstructive pulmonary disorder (COPD) are associated with markers of systemic inflammation and endothelial dysfunction in an aging population.


METHODS
Plasma levels of circulating C-reactive protein (CRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were obtained from 679 elderly male participants in the Normative Aging Study. Blood samples were analyzed for 202 single nucleotide polymorphisms (SNPs) in 25 candidate genes and included both haplotype tagSNPs and functional SNPs based on literature review. Data were stratified into discovery and replication cohorts for 2-stage analysis. In the discovery cohort, the relationship between biomarker level and genotype was analyzed using linear mixed effects with random intercepts for each subject and models were adjusted for age and BMI. A positive outcome in the discovery cohort was defined as a p-value <0.1 for the SNP. SNPs that met this criterion were analyzed in the replication cohort and confirmed for those which met a criterion of significance (p<0.025).


RESULTS
In our analyses, SNPs in the CRHR1, ITPR2, and VDR genes met significance criteria.


CONCLUSIONS
Our results suggest that genes thought to play a role in the pathogenesis of asthma and COPD may influence levels of serum markers of inflammation and endothelial dysfunction via novel SNP associations which have not previously been associated with cardiovascular disease.
Wilker
Elissa H
EH
Department of Environmental Health, Harvard School of Public Health, Boston, MA 02215, United States.
Alexeeff
Stacey E
SE
Poon
Audrey
A
Litonjua
Augusto A
AA
Sparrow
David
D
Vokonas
Pantel S
PS
Mittleman
Murray A
MA
Schwartz
Joel
J
D000368:Aged; D000375:Aging / Q000235:genetics*; D001249:Asthma / Q000235:genetics; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics*; D015331:Cohort Studies; D005340:Fibrinogen / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics; D012120:Respiration Disorders / Q000235:genetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D015415:Biomarkers; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen; D002097:C-Reactive Protein