Pleiotropic effects of heterozygosity for theSERPINA1Z allele in the UK Biobank

Abstract

Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear. We conducted the largest population-based study to date to determine Z allele effects on >2,400 phenotypes using the UK Biobank study (N>303,353). We detected strong associations between heterozygosity and non-respiratory phenotypes including increased height, increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher lung function in non-smokers, but smoking appears to abolish this protective effect. Individuals heterozygous for the Z allele may therefore have altered risk of smoking-induced lung disease and other, non-respiratory conditions.

Smoking Interaction with a Polygenic Risk Score for Reduced Lung Function

“…In a family-based study of the rs28929474 variant (Z allele) in SERPINA1, which leads to alpha-1 antitrypsin deficiency (AATD) and greatly increased risk of emphysema, there was a significant genotype-by-smoking interaction on FEV 1 30 . A strong smoking interaction of rs28929474 heterozygote status with ever-smoking on lung function and COPD has been reported in UK Biobank 31 . Genome-wide interaction studies have confirmed the interaction of smoking with rs28927474 on risk to COPD 11 , and identified gene-by-smoking interactions at several other loci [8][9][10][11][12][13][14] .…”

Interaction of Cigarette Smoking and Polygenic Risk Score on Reduced Lung Function

“…29 A strong smoking interaction of rs28929474 heterozygote status with ever-smoking on lung function and COPD has been reported in UK Biobank. 30 GWAS have confirmed the interaction of smoking with rs28927474 on risk to COPD, 11 and identified gene-bysmoking interactions at several other loci. [8][9][10][11][12][13][14] Recently, a study of incident COPD found evidence for a gene-by-smoking interaction, further supporting our findings and suggesting that the relationship of the PRS to other related phenotypes or outcomes may also interact with smoking or other measures.…”