Genetic influences on lung function decline in AATD

Background: Single nucleotide polymorphisms (SNPs) of family with sequence familiarity 13, member A (FAM13A), hedgehog interacting protein (HHIP) and iron regulatory binding protein 2 (IREB2) are associated with emphysema on computed tomography scan in alpha-1 antitrypsin deficiency (AATD) [Khiroya et al. Am J Respir Crit Care Med 189; 2014 A5783]. Along with emphysema, rate of lung function decline also enables us to identify patients who are likely to have poorer outcomes. Aim: To determine if there is a relationship between these SNPs and lung function decline in the AATD population. Methods: 662 PiZZ and PiZnull AATD subjects were genotyped for rs2568494 ( IREB2 ), rs7671167 and rs1903003 ( FAM13A ), and rs1542725 and rs13118928 ( HHIP ). Genotyping was carried out using TaqMan technologies (Applied Biosystems, UK). Linear regressions were performed to look for genetic associations with KCO and post-bronchodilator FEV1 at baseline assessment. Logistic regressions were performed to look for associations with rapid decline in KCO and FEV1. Rapid decline was defined as loss of ≥1% in the % predicted value of these parameters per year. Results: All SNPs were in Hardy-Weinburg equilibrium. rs1903003 ( FAM13A ) showed a trend towards KCO at baseline assessment ( p =0.062). None of the SNPs were significantly associated with post-bronchodilator FEV1 or rapid FEV1 or KCO decline. Conclusions: rs7671167 and rs1903003 ( FAM13A ) are in significant linkage disequilibrium, as are rs1542725 and rs13118928 ( HHIP ). Therefore it is difficult to say whether one SNP is responsible for emphysema and KCO, or if it is a combined effect. Future work should target these SNPs to understand their pathological role with a view to determining new therapies.