Clinical Implications of LTA₄H Genetic Polymorphism in Patients with Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1. Study roadmap. One hundred and eighty-three patients with COPD were included. After the exclusion of 28 patients, a total of 155 patients finally were enrolled into the COPD group. Meanwhile, 150 healthy subjects with normal pulmonary function were enrolled into the control group. Genetic polymorphism of LTA₄H between COPD and control groups was compared at the baseline. After 12-month follow-up for the COPD group, 4 patients were lost to the follow-up, 5 patients died due to AECOPD, whereas 146 patients finished the whole study. Clinical variables variation and hospitalizations during follow-up were compared among COPD subgroups with different genetic polymorphism of LTA₄H. Cumulative one-year hospitalizations and deaths were compared among COPD subgroups with different genetic polymorphism of LTA₄H. Correlation between genetic polymorphism of LTA₄H and clinical characteristics during follow-up were analyzed. Note: COPD, chronic obstructive pulmonary disease; AECOPD, acute exacerbation of chronic obstructive pulmonary disease.

Table 1. Demographics and characteristics of participants at the baseline.

Variables	COPD (n = 155)	Control (n = 150)	p value
Age-yr	71.5 (60.6–82.2)	70.3 (59.2–81.4)	0.915
Sex			0.956
Male-n (%)	110 (71.0)	106 (70.7)
Female-n (%)	45 (29.0)	44 (29.3)
Smoking			0.981
Nonsmoker-n (%)	39 (25.2)	38 (25.3)
Ex-smoker-n (%)	106 (68.4)	104 (69.3)
Current smoker-n (%)	10 (6.4)	8 (5.4)
Smoking index-pack-year	52.4 (41.6–64.5)	33.2 (25.3–41.7)	0.006
BODE	6.3 (4.4–8.2)
GOLD
GOLD 1-n (%)	16 (10.3)
GOLD 2-n (%)	30 (19.4)
GOLD 3-n (%)	58 (37.4)
GOLD 4-n (%)	51 (32.9)
COPD Group
Group A-n (%)	13 (8.4)
Group B-n (%)	35 (22.6)
Group C-n (%)	50 (32.3)
Group D-n (%)	57 (36.7)
Post-bronchodilator FEV1/FVC-%	55 (42–68)	84 (67–101)	0.001
FEV1-L	1.68 (1.21–2.15)	3.06 (1.81–4.31)	<0.001
FEV1/the predicted-%	50 (23–77)	85 (67–103)	<0.001
LTA4H rs7971150			0.001
AA	22 (14.2)	55 (36.7)	<0.001
GA	43 (27.7)	38 (25.3)	0.878
GG	90 (58.1)	57 (38.0)	0.001

Note: COPD, chronic obstructive pulmonary disease; BODE, body-mass index, obstruction, dyspnea, exercise capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LTA₄H, Leukotriene A₄ hydrolase; AA, wild-type; GA, mutant heterozygous; GG, mutant homozygous.

Table 2 Comparison of clinical variables variation and hospitalizations during follow-up among COPD subgroups with different genetic polymorphism of LTA₄H

Variables	AA (n = 20)	GA (n = 41)	GG (n = 85)	p value
FEV1-mL	−34 ± −9	−36 ± −11	−48 ± −14	0.005
FEV1/the predicted-%	−11 ± −3	−14 ± −4	−19 ± −7	0.001
MMRC	1.8 ± 0.4	2.0 ± 0.5	2.3 ± 0.4	0.100
6MWD-m	−32.4 ± −11.3	−36.7 ± −12.5	−55.9 ± −15.8	0.001
BODE	1.6 ± 0.4	1.8 ± 0.3	3.4 ± 0.7	0.001
Hospitalizations	1.7 ± 0.5	1.9 ± 0.5	3.6 ± 0.9	<0.001

Note: COPD, chronic obstructive pulmonary disease; LTA₄H, Leukotriene A₄ hydrolase; AA, wild-type; GA, mutant heterozygous; GG, mutant homozygous; FEV₁, forced expiratory volume in one second; MMRC, Modified Medical Research Council; 6MWD, 6 min walking distance; BODE, body-mass index, obstruction, dyspnea, exercise capacity.

Figure 2 Cumulative one-year hospitalizations and deaths among COPD subgroups with different genetic polymorphism of LTA₄H. The time-to-event cumulative hospitalization-free rate in patients with GG type is lower than those of patients with AA and GA types, whereas no difference is found between patients with AA, and GA types (P = 0.019) (Panel A). No difference is found with respect to time-to-event cumulative survival rate among patients with AA, GA, and GG types (P = 0.879) (Panel B). Note: COPD, chronic obstructive pulmonary disease; LTA₄H, Leukotriene A₄ hydrolase; AA, wild-type; GA, mutant heterozygous; GG, mutant homozygous.

Table 3 Correlation between genetic polymorphism of LTA₄H and clinical characteristics during follow-up

Variables	GG vs AA		p value	GG vs GA		p value
	HR (Univariate)	HR (Multivariate)		HR (Univariate)	HR (Multivariate)
Age-per increase of 10 years	1.128 (1.003–1.253)		0.816	1.238 (1.116–1.360)		0.573
Sex-female as 1.0	1.204 (1.106–1.302)		0.737	1.109 (1.047–1.171)		0.854
Smoking-nonsmoker as 1.0	2.536 (2.174–2.898)	2.653 (2.227–3.079)	<0.001	2.375 (2.076–2.674)	2.454 (2.115–2.793)	<0.001
Smoking index-per increase of 10 pack-year	1.587 (1.058–2.016)	1.743 (1.236–2.050)	0.015	1.173 (1.056–1.290)		0.147
FEV1-per decrease of 10 mL	2.018 (1.677–2.359)	2.324 (1.997–2.651)	0.001	2.331 (2.116–2.546)	2.276 (1.956–2.596)	0.001
FEV1-per decrease of 10%	2.153 (1.844–2.462)	2.246 (1.759–2.733)	0.001	2.390 (2.178–2.602)	2.457 (2.170–2.744)	0.001
MMRC-per increase of 1 score	1.274 (1.007–1.541)		0.427	1.209 (1.186–1.232)		0.356
6MWD-per decrease of 10 m	2.276 (2.015–2.537)	2.156 (1.774–2.538)	0.001	1.876 (1.546–2.206)	2.016 (1.668–2.364)	0.005
BODE-per increase of 1 score	2.673 (2.237–3.109)	2.774 (2.409–3.139)	<0.001	2.558 (2.170–2.946)	2.412 (2.137–2.6870	<0.001
Hospitalizations-per increase of one hospitalization	1.957 (1.433–2.461)	2.301 (2.138–2.464)	0.001	2.210 (1.996–2.424)	2.152 (1.659–2.645)	0.001
Deaths-survival as 1.0	1.245 (1.009–1.481)		0.857	1.078 (1.006–1.150)		0.991

Note: LTA₄H, Leukotriene A₄ hydrolase; AA, wild-type; GA, mutant heterozygous; GG, mutant homozygous; HR, hazard ratio; FEV₁, forced expiratory volume in one second; MMRC, Modified Medical Research Council; 6MWD, 6 min walking distance; BODE, body-mass index, obstruction, dyspnea, exercise capacity.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.