LATE-BREAKING ABSTRACT: Effects of rare SERPINA1 variants on emphysema and airtrapping in SPIROMICS

Abstract

Background: PI type Z heterozygotes (Glu³⁶⁶Lys in SERPINA1) with a prior smoking history have been shown to have greater CT scan-based emphysema compared to PI MM wild types (Sorheim CHEST 2010). There are no studies evaluating the regional effects of rare SERPINA1 variants on CT scan-based emphysema or airtrapping.

Aims and Objectives: The effects of rare SERPINA1 variants on regional CT scan emphysema and airtrapping were evaluated in NHLBI SPIROMICS.

Methods: 1,715 non-Hispanic Whites(NHW), 392 African Americans, and 98 Hispanics with ≥20 pack-year smoking were genotyped for 24 rare coding variants (allele frequency≤5%). Regression-based models of CT scan emphysema (%lung area≤-950 HFU) and airtrapping (%≤-856 HFU) were performed.

Results: In NHW, PI Z was associated with bilateral emphysema (CC=7.8%, CT=12%, TT=24%, p =5.5x10^-8) and airtrapping (CC=25%, CT=34%, TT=54%, p =7.1x10^-9). PI Z heterozygotes (MZ, N=73), PI Z homozygotes (ZZ, N=9), and PI Z-containing compound heterozygotes (ZS/ZV_R, N=7) had greater bilateral emphysema (No Z=7.8%, MZ=12%, ZS/ZV_R=13%, ZZ=24%, p=2.0x10^-7), and airtrapping (No Z=25%, MZ=33%, ZS/V_R=49%, ZZ=54%, p=2.7x10^-8) compared to NHW without PI Z (No Z, N=1,499). Lower lung zone emphysema (p=0.008-0.04) and airtrapping (p=0.005-0.02) was lower in No Z compared to MZ. Upper and lower zone disease was lower in No Z versus ZZ (emphysema upper zones p=0.001-0.002, lower zones pp=1.2x10^-9-1.2x10^-8; airtrapping upper zones p=2.5x10^-5-0.0004, lower zones p=4.0x10^-9-9.9x10^-9). ZS/ZV_R had more upper zone airtrapping versus ZZ (p=0.03-0.04).

Conclusions: In NHW, PI Z-containing SERPINA1 genotypes have cumulative effects on emphysema and airtrapping in both the upper and lower lung zones.