. 2019 Oct 29;201(5):540–554. doi: 10.1164/rccm.201904-0769OC

Table 4.

Effects of SERPINA1 PI Z Genotype on Lung Function, Emphysema, and Related Phenotypes in Non-Hispanic White Individuals

	PI Z (C/T) Genotype			Additive P Value	CC vs. CT		CT vs. TT		CC vs. TT
	CC	CT	TT		β (SE)/OR (95% CI)	P Value	β (SE)/OR (95% CI)	P Value	β (SE)/OR (95% CI)	P Value
Total non-Hispanic white individuals, n	1,601	81	9		—		—		—
Post-BD lung function
Post-BD, FEV₁% predicted	72.4 (25.5)	63.1 (27.3)	37.9 (15.3)	2.50 × 10⁻⁷	−4.25 (1.38)	0.002	−8.37 (5.42)	0.13	−19.1 (4.05)	2.68 × 10⁻⁶
Post-BD, FVC % predicted	90.6 (17.7)	87.2 (17.3)	73.6 (20.7)	0.006	−1.20 (0.93)	0.2	−5.87 (3.65)	0.11	−8.13 (2.76)	0.003
Post-BD FEV₁/FVC, ratio	0.59 (0.16)	0.53 (0.18)	0.40 (0.12)	1.02 × 10⁻⁷	−0.03 (0.01)	0.0006	−0.04 (0.04)	0.26	−0.12 (0.02)	3.16 × 10⁻⁶
Post-BD, FEF_25–75 % predicted	55.1 (39.9)	47.3 (43.4)	16.0 (10.1)	5.05 × 10⁻⁵	−0.04 (0.02)	0.01	−0.06 (0.06)	0.38	−0.18 (0.05)	0.0002
GOLD grade 2 or higher, n (%)	857 (53.5)	55 (67.9)	9 (100)	2.45 × 10⁻⁵	1.86 (1.14–3.11)	0.01	9.07 (0.51–162)	0.05^*	16.5 (0.96–284)	0.005^*
3-yr longitudinal lung function, n	1,376	69	8		—		—		—
Annual rate of change FEV₁, L/yr	−0.04 (0.13)	−0.05 (0.13)	−0.11 (0.21)	0.15	−0.002 (0.008)	0.78	−0.05 (0.03)	0.11	−0.05 (0.02)	0.05
Annual rate of change FVC, L/yr	−0.04 (0.22)	−0.08 (0.26)	−0.07 (0.43)	0.13	−0.02 (0.01)	0.15	−0.09 (0.06)	0.14	−0.06 (0.04)	0.14
Rate of change FEV₁/FVC per yr	−0.007 (0.03)	−0.003 (0.02)	−0.02 (0.01)	0.3	−0.001 (0.002)	0.46	−0.003 (0.005)	0.52	−0.007 (0.005)	0.17
Computed tomography scan–based measures
Emphysema, TLC % area ≤ −950 HFU	7.89 (9.87)	12.3 (12.7)	24.3 (13.8)	6.34 × 10⁻⁸	0.08 (0.03)	0.01	0.34 (0.12)	0.01	0.48 (0.09)	1.43 × 10⁻⁷
Air trapping, residual volume % area ≤ −856 HFU	25.4 (20.7)	33.6 (23.9)	54.2 (16.9)	1.00 × 10⁻⁸	0.06 (0.03)	0.01	0.28 (0.09)	0.004	0.42 (0.07)	2.18 × 10⁻⁸
Small airway disease, PRM^fSAD, %	21.6 (14.9)	26.1 (15.9)	35.8 (8.3)	5.84 × 10⁻⁷	0.05 (0.02)	0.02	0.21 (0.07)	0.006	0.30 (0.06)	1.22 × 10⁻⁶
Alpha-1 antitrypsin concentration, n	1,037	54	6
Alpha-1 antitrypsin concentration, mg/ml^†	2.02 (0.45)	1.19 (0.27)	0.88 (0.70)	5.84 × 10⁻⁴⁶	−0.42 (0.03)	3.84 × 10⁻⁴¹	−0.20 (0.09)	0.03	−0.54 (0.09)	2.29 × 10⁻⁹

Definition of abbreviations: BD = bronchodilator; CI = confidence interval; FEF_25–75 = forced expiratory flow, midexpiratory phase; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HFU = Hounsfield units; OR = odds ratio; PI = protease inhibitor; PRM^fSAD = parametric response mapping of functional small airway disease.

Homozygotes for the major allele (CC), heterozygotes for one minor or rare variant allele (CT), and homozygotes for the minor allele (TT) of PI type Z (Glu³⁶⁶Lys) were compared. Data are shown as mean (SD) unless otherwise indicated. Regression-based analyses were adjusted by study site, age, sex, body mass index, and pack-years smoking history for lung function. Log-transformed percentage predicted FEF_25–75 was also adjusted for post-BD percentage predicted FVC 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 Hounsfield units or less at TLC (TLC % lung area ≤ −950), log-transformed computed tomography scan air trapping based on percentage of the area in bilateral lungs with density of −856 Hounsfield units or less at residual volume (residual volume % lung area ≤ −856), and log-transformed functional small airway disease (PRM^fSAD). Analysis of African Americans and Hispanics also adjusted for global African and Native American genetic ancestry.

Owing to 100% of TT homozygotes with chronic obstructive pulmonary disease, the OR was calculated using the Haldane–Anscombe method, 95% CI using Woolf’s method, and P value using the two-tail Fisher exact test.

^{^†}

Alpha-1 antitrypsin concentrations also adjusted for C-reactive protein.