MedWire News: IL10 has been identified as a potential modifier gene of chronic obstructive pulmonary disease (COPD) in patients with severe α1-antitrypsin (AAT) deficiency, according to US research.
"Identifying modifier genes for COPD in AAT deficiency may result in improved risk assessment and clinical management of patients with severe AAT deficiency," write Dawn DeMeo (Brigham and Women's Hospital, Boston, Massachusetts) and colleagues in the American Journal of Respiratory Cell and Molecular Biology.
Severe AAT deficiency has been shown to be a monogenic cause of COPD, and affects about 1% of COPD patients, the authors explain. Homozygosity for the Z deficiency allele (PI ZZ) is associated with an increased risk for severe early-onset COPD, especially among smokers. However, the development of COPD among PI ZZ individuals is highly variable even after controlling for smoking, which indicates a potential role for modifier genes.
Based on these findings, DeMeo and colleagues proposed that "polymorphisms in genes previously associated with asthma and/or COPD may be modifiers of COPD in individuals genetically at risk for COPD due to severe AAT deficiency."
To identify potential modifier genes, DeMeo and team performed family-based association analyses in a cohort of 378 PI ZZ individuals from 167 families for 10 genes known to be associated with asthma and/or COPD: IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1.
Six out of 11 single-nucleotide polymorphisms (SNPs) in IL10 and three out of five SNPs in TNF were associated with reduced FEV1 and/or FEV1/forced vital capacity (FVC). IL10 SNPs were also associated with a moderate-to-severe COPD phenotype (qualitatively defined as FEV1 ≤50% predicted).
IL10 SNPs remained significantly associated with reduced FEV1 and FEV1/FVC after individuals with a physician's diagnosis of asthma were excluded from the analyses, indicating that the association with airflow obstruction was independent of an association with asthma.
Sliding window haplotype analysis using the 11 IL10 SNPs showed that the IL10 promoter SNP rs1800871 was most strongly associated with the quantitative phenotypes FEV1 % predicted and FEV1/FVC.
"We conclude that IL10 is a potential modifier gene of COPD in individuals with severe AAT deficiency," write DeMeo and team.
They add that identifying further modifier genes for COPD in severely AAT-deficient patients might improve disease assessment and management, and may "provide insight into the variable risk for COPD in non-AAT-deficient individuals."
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