Table 5.
Effects of Rare SERPINA1 Variant Genotypes on Lung Function, Emphysema, and Related Phenotypes in Non-Hispanic White Individuals
| Rare SERPINA1 Variant–based Genotypes |
P Values |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No Z/S/VR | MS/MVR | MZ | SS/VRVR/SVR | ZS/ZVR | ZZ | Additive trend | No Z/S/VR vs. MS/MVR | No Z/S/VR vs. MZ | No Z/S/VR vs. SS/VRVR/SVR | No Z/S/VR vs. ZS/ZVR | No Z/S/VR vs. ZZ | |
| Total white individuals, n | 1,411 | 185 | 74 | 5 | 7 | 9 | ||||||
| Post-BD lung function | ||||||||||||
| FEV1, % predicted | 72.6 (25.6) | 70.9 (25.0) | 64.3 (27.6) | 73.1 (33.6) | 49.8 (21.9) | 37.9 (15.3) | 7.82 × 10−6 | 0.64 | 0.007 | 0.97 | 0.07 | 2.11 × 10−6 |
| FVC, % predicted | 90.5 (17.7) | 91.2 (17.9) | 87.0 (17.3) | 98.6 (12.4) | 89.2 (18.7) | 73.6 (20.7) | 0.03 | 0.19 | 0.22 | 0.47 | 0.92 | 0.003 |
| FEV1/FVC, ratio | 0.60 (0.16) | 0.58 (0.16) | 0.54 (0.18) | 0.54 (0.21) | 0.42 (0.14) | 0.40 (0.12) | 8.49 × 10−7 | 0.12 | 0.003 | 0.58 | 0.02 | 2.52 × 10−6 |
| FEF25–75, % predicted | 55.7 (40.2) | 50.6 (36.3) | 49.9 (44.5) | 56.8 (54.3) | 20.1 (13.1) | 16.1 (10.1) | 2.88 × 10−5 | 0.03 | 0.05 | 0.49 | 0.009 | 0.0002 |
| GOLD grade ≥ 2, n % | 748 (53) | 106 (57) | 49 (66) | 3 (60) | 6 (86) | 9 (100) | 4.0 × 10−4 | 0.41 | 0.02* | 0.72 | 0.21 | 0.004† |
| 3-yr longitudinal, n | 1,214 | 158 | 65 | 4 | 4 | 8 | ||||||
| Rate of change, FEV1, L/yr | −0.04 (0.13) | −0.05 (0.15) | −0.04 (0.14) | −0.20 (0.10) | −0.12 (10) | −0.11 (0.21) | 0.06 | 0.36 | 0.98 | 0.04 | 0.15 | 0.03 |
| Rate of change, FVC, L/yr | −0.04 (0.22) | −0.03 (0.19) | −0.07 (0.26) | −0.24 (0.21) | −0.26 (0.22) | −0.07 (0.43) | 0.14 | 0.65 | 0.42 | 0.22 | 0.04 | 0.18 |
| Rate of change, FEV1/FVC | −0.006 (0.03) | −0.009 (0.03) | −0.003 (0.02) | −0.03 (0.03) | −0.008 (0.02) | −0.02 (0.01) | 0.12 | 0.28 | 0.45 | 0.03 | 0.65 | 0.15 |
| Computed tomography scan–based measures | ||||||||||||
| Emphysema, TLC% ≤ −950 HFU | 7.83 (9.86) | 8.29 (9.83) | 12.3 (13.2) | 10.6 (14.3) | 12.7 (7.03) | 24.3 (13.8) | 1.84 × 10−6 | 0.30 | 0.02 | 0.93 | 0.17 | 8.52 × 10−8 |
| Air trapping, residual volume area% ≤ −856 HFU | 25.4 (20.8) | 25.4 (19.9) | 32.1 (23.4) | 29.6 (27.1) | 48.7 (19.1) | 54.2 (16.9) | 3.56 × 10−7 | 0.41 | 0.03 | 0.9 | 0.12 | 1.15 × 10−8 |
| Small airways disease, PRMfSAD | 21.6 (15.1) | 21.2 (13.9) | 24.6 (15.4) | 22.4 (14.5) | 41.1 (13.6) | 35.8 (8.29) | 1.30 × 10−5 | 0.59 | 0.05 | 0.88 | 0.07 | 6.83 × 10−7 |
| Alpha-1 antitrypsin, n | 922 | 113 | 49 | 2 | 5 | 6 | ||||||
| Alpha-1 antitrypsin, mg/ml† | 2.05 (0.45) | 1.79 (0.37) | 1.22 (0.24) | 1.20 (0) | 0.87 (0.39) | 0.88 (0.70) | 7.56 × 10−56 | 1.23 × 10−11 | 2.92 × 10−37 | 0.005 | 2.73 × 10−10 | 7.13 × 10−10 |
Definition of abbreviations: BD = bronchodilator; FEF25–75 = forced expiratory flow, midexpiratory phase; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HFU = Hounsfield units; PRMfSAD = parametric response mapping of functional small airway disease.
Regression-based association testing compared white individuals without PIs (protease inhibitors) Z, S, or other rare variants (No Z/S/VR), heterozygotes for non–PI Z rare variants (MS and MVR heterozygotes), PI Z heterozygotes without another rare variant (MZ), PI S and VR compound heterozygotes (SS, SVR, and VRVR), PI Z–containing compound heterozygotes with PI S or additional rare variants (ZS/ZVR), and PI Z homozygotes (ZZ). White compound heterozygotes with PI type Z and S or additional rare variants (ZS/ZVR) include three PI type ZS, one PI type Z/PI M6Passau, one PI type Z/PI I, and two PI type Z/Ala308Ser. White compound heterozygotes without PI type Z (SS, SVR, and VRVR) included two PI type S homozygotes (SS), one PI type S/Ile317Thr, one PI type S/PI type F, and one PI type F/Ala308Ser. Regression-based analyses were adjusted by study site, age, sex, body mass index, and pack-years smoking history. Log-transformed percentage predicted FEF25–75 also adjusted for post-BD FVC% predicted and longitudinal, annualized rate of change for baseline lung function as a percentage of predicted. Models also included height for log-transformed computed tomography scan–based emphysema based on percentage of the area in bilateral lungs with density of −950 HFU or less at TLC (TLC % lung area ≤ −950 HFU), log-transformed computed tomography scan air trapping based on percentage of the area in bilateral lungs with density of −856 HFU or less at residual volume (residual volume % lung area ≤ −856 HFU), and log-transformed functional small airway disease (PRMfSAD). Data are shown as mean (SD) unless otherwise indicated.
Owing to 100% of ZZ homozygotes having chronic obstructive pulmonary disease, the odds ratio was calculated using the Haldane–Anscombe method, 95% confidence interval using Woolf’s method, and P value using the two-tailed Fisher Exact test: odds ratio = 16.82; 95% confidence interval = 0.98–298.5; P = 0.004.
Alpha-1 antitrypsin concentrations also adjusted for C-reactive protein.