The effects of rare genetic variants and genetic ancestry on drug response and severity in airways diseases
Abstract (summary)
Background: Genetic studies in asthma and COPD have identified common genetic variants that explain a small proportion of inter-individual variability in drug response and severity. Genetic ancestry could be associated with disease severity in individuals from recently admixed ethnic groups, such as African Americans where a higher percentage of African ancestry was associated with lower lung function. Rare genetic variants (allele frequency <0.05) with strong effects and genetic ancestry have the potential to be genetic factors that determine drug response and severity in asthma and COPD.
Methods: 1,165 asthmatics were genotyped for six rare variants in the β 2-adrenergic receptor gene (ADRB2). Genome-wide genotype data from 325 African Americans from NHLBI SARP1-2 and 139 from CSGA were used to estimate ancestry. We analyzed ?16 rare coding variants in the α1-antitrypsin gene (SERPINA1), including PI type Z (Glu366Lys), in 1,715 non-Hispanic Whites, 392 African Americans, and 98 Hispanics from NHLBI SPIROMICS and 523 White and 264 African American asthmatics from SARP1-2.
Findings: LABA-treated White asthmatics with the rare Thr164Ile variant and African American asthmatics with a rare promoter insertion had increased exacerbations requiring hospitalizations (p=0.01 and 0.006). African ancestry was inversely related to lung function in asthmatics, particularly in severe asthmatics (-20.3ml change in FEV1 per %African ancestry, p=0.0002). In SPIROMICS, White PI type Z heterozygotes, PI Z homozygotes, and PI Z-containing compound heterozygotes had lower FEV1 (p=2.6x10-7), lower FEV1/FVC ratio (p=2.62x10-8) and higher CT emphysema (p=2.0x10 -7) compared to those without PI type Z. In White asthmatic ex-smokers, PI type Z heterozygotes had a lower pre-bronchodilator FEV1 as a percentage of predicted (p=0.02) and an increased risk for hospitalization (p=0.002) compared to ex-smokers without PI type Z. 100 percent of three African American compound heterozygotes required ≥ three corticosteroid bursts for asthma exacerbations.
Interpretation: Rare ADRB2 variants were associated with adverse events during LABA therapy. In African American asthmatics, the magnitude of decreased lung function associated with African ancestry was higher than in general population studies. Rare SERPINA1 variants had detrimental effects on COPD and asthma severity in the setting of cigarette smoking primarily determined by PI type Z genotypes.
Indexing (details)
Medicine
0564: Medicine