Genetic Variants Associated with the Risk of Chronic Obstructive Pulmonary Disease with and without Lung Cancer

Mariza de Andrade; Yan Li; Randolph S. Marks; Claude Deschamps; Paul D. Scanlon; Curtis L. Olswold; Ruoxiang Jiang; Stephen J. Swensen; Zhifu Sun; Julie M. Cunningham; Jason A. Wampfler; Andrew H. Limper; David E. Midthun; Ping Yang

doi:10.1158/1940-6207.CAPR-11-0243

DOI: 10.1158/1940-6207.CAPR-11-0243 Published March 2012

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Figure 1.
Predicting risk of COPD with and without lung cancer. A and C, COPD risk prediction curve (female). B and D, COPD risk prediction curve (male).

Table 1.

Demographic and clinic characteristics

	COPD cases, N (%)			Number of controls
Characteristics	With lung cancer (N = 432)	Without lung cancer (N = 188)	Total (N = 620)	(%; without COPD and lung cancer) N = 893	P^a	P^b	P^c	P^d
Sex
Male	240 (55.56)	82 (43.62)	322 (51.94)	348 (38.97)	0.008	<0.001	0.271	<0.001
Female	192 (44.44)	106 (56.38)	298 (48.06)	545 (61.03)
Age ± SD, y	66.99 ± 8.54	67.27 ± 9.67	67.08 ± 8.89	64.97 ± 9.97	0.731	<0.001	0.004	<0.001
Smoking status
Never	31 (7.18)	29 (15.43)	60 (9.67)	564 (63.16)	0.004	<0.001	<0.001	<0.001
Former	217 (50.23)	94 (50.00)	311 (50.16)	195 (21.84)
Current	184 (42.59)	65 (34.57)	249 (40.16)	134 (15.01)
Pack-years
0 and never-smoker	31 (7.18)	33 (17.55)	64 (10.32)	570 (63.83)	<0.001	<0.001	<0.001	<0.001
1–20	29 (6.71)	15 (7.98)	44 (7.10)	32 (3.58)
21–40	75 (17.36)	43 (22.87)	118 (19.03)	121 (13.55)
>40	297 (68.75)	97 (51.60)	394 (63.55)	170 (19.04)

↵^aP value for the comparison between COPD cases with and without lung cancer.
↵^bP value for the comparison between COPD cases with lung cancer and controls.
↵^cP value for the comparison between COPD cases without lung cancer and controls.
↵^dP value for the comparison between all COPD cases and controls.

Table 2.

Significant results in SNP analysis adjusting for clinical variables

			Most significant results in 3 genetic models
			Whole case–control data set		COPD patients without lung cancer and healthy control data set		COPD patients with lung cancer and healthy control data set
Pathway	Gene	rs ID	OR (99% CI)	P*	OR (99% CI)	P*	OR (99% CI)	P*	Minimum P*
GSH	ABCC1	rs16967755	1.51 (1.08–2.10)	1.60 × 10⁻³	1.50 (0.95–2.38)	2.36 × 10⁻²	1.45 (1.00–2.10)	1.01 × 10⁻²	1.60 × 10⁻³
GSH	ABCC4	rs7324283	1.90 (1.07–3.37)	3.93 × 10⁻³	2.40 (1.17–4.91)	1.60 × 10⁻³	1.58 (0.83–3.04)	6.88 × 10⁻²	1.60 × 10⁻³
GSH	GCLC	rs12524550	2.42 (1.11–5.28)	3.54 × 10⁻³	2.60 (0.92–7.34)	1.79 × 10⁻²	2.11 (0.91–4.90)	2.28 × 10⁻²	3.54 × 10⁻³
GSH	GCLC	rs2100375	0.75 (0.58–0.97)	3.66 × 10⁻³	0.33 (0.10–1.04)	1.25 × 10⁻²	0.78 (0.58–1.03)	2.29 × 10⁻²	3.66 × 10⁻³
GSH	ABCC3	rs8075406	0.70 (0.50–0.97)	4.88 × 10⁻³	0.65 (0.41–1.02)	1.45 × 10⁻²	0.70 (0.48–1.01)	1.17 × 10⁻²	4.88 × 10⁻³
GSH	ABCC4	rs1729786	1.61 (1.01–2.56)	8.91 × 10⁻³	1.43 (1.03–2.00)	5.67 × 10⁻³	1.59 (0.94–2.70)	2.29 × 10⁻²	5.67 × 10⁻³
GSH	GCLC	rs542914	0.78 (0.62–0.99)	6.26 × 10⁻³	0.80 (0.58–1.11)	7.70 × 10⁻²	0.78 (0.60–1.02)	1.68 × 10⁻²	6.26 × 10⁻³
GSH	GCLC	rs4712035	1.37 (1.01–1.86)	7.01 × 10⁻³	1.38 (0.86–2.21)	8.41 × 10⁻²	1.36 (0.97–1.90)	1.76 × 10⁻²	7.01 × 10⁻³
GSH	GSTP1	rs1138272	0.64 (0.41–1.00)	9.80 × 10⁻³	0.76 (0.42–1.36)	2.20 × 10⁻¹	0.60 (0.36–0.99)	8.19 × 10⁻³	8.19 × 10⁻³
GSH	ABCC2	rs717620	1.28 (0.96–1.72)	2.77 × 10⁻²	1.87 (0.57–6.12)	1.74 × 10⁻¹	1.39 (1.01–1.94)	8.80 × 10⁻³	8.80 × 10⁻³
GSH	GSS	rs6088659	0.29 (0.09–0.99)	9.22 × 10⁻³	0.39 (0.07–2.06)	1.47 × 10⁻¹	0.23 (0.05–1.01)	1.06 × 10⁻²	9.22 × 10⁻³
GSH	ABCC2	rs2756109	0.79 (0.62–1.00)	9.34 × 10⁻³	0.69 (0.43–1.11)	4.35 × 10⁻²	0.80 (0.61–104)	2.55 × 10⁻²	9.34 × 10⁻³
GSH	ABCC1	rs215100	0.65 (0.38–1.12)	3.99 × 10⁻²	0.65 (0.30–1.41)	1.52 × 10⁻¹	0.76 (0.58–1.00)	9.69 × 10⁻³	9.69 × 10⁻³
DNA	MSH3	rs12513549	4.04 (0.72–22.80)	3.75 × 10⁻²	8.68 (1.36–55.26)	2.63 × 10⁻³	1.35 (0.89–2.05)	6.64 × 10⁻²	2.63 × 10⁻³
DNA	XPA	rs1800975	0.85 (0.62–1.18)	2.05 × 10⁻¹	0.60 (0.38–0.94)	3.33 × 10⁻³	0.99 (0.69–1.42)	9.26 × 10⁻¹	3.33 × 10⁻³
DNA	PARP	rs11842915	1.26 (0.93–1.69)	4.79 × 10⁻²	1.53 (1.02–2.28)	6.43 × 10⁻³	1.14 (0.77–1.68)	3.81 × 10⁻¹	6.43 × 10⁻³
DNA	ERCC2	rs3916874	1.31 (1.01–1.70)	7.40 × 10⁻³	1.56 (1.00–2.46)	1.08 × 10⁻²	1.28 (0.96–1.71)	2.63 × 10⁻²	7.40 × 10⁻³
DNA	MSH3	rs33013	0.72 (0.52–1.00)	1.01 × 10⁻²	0.80 (0.51–1.26)	2.11 × 10⁻¹	0.69 (0.48–0.99)	8.42 × 10⁻³	8.42 × 10⁻³
DNA	MSH3	rs12522132	2.17 (0.58–8.09)	1.31 × 10⁻¹	4.49 (1.03–19.52)	8.54 × 10⁻³	1.22 (0.83-1.82)	1.86 × 10⁻¹	8.54 × 10⁻³
DNA	MSH3	rs2897298	2.28 (0.62–8.32)	1.03 × 10⁻¹	4.48 (1.03–19.47)	8.58 × 10⁻³	1.21 (0.81–1.79)	2.17 × 10⁻¹	8.58 × 10⁻³
Inflammation	PTGS2	rs689470	2.26 (0.96–5.36)	1.47 × 10⁻²	3.02 (1.05–8.71)	7.03 × 10⁻³	1.96 (0.72–5.32)	8.41 × 10⁻²	7.03 × 10⁻³

*Bold P-values mean below significant value of 0.01.

Table 3.

Significant results adjusting for clinical variables in gene-based analysis*

			Minimum P value in 3 genetic models
Pathway	Gene	Number of SNPs tested	Whole case–control data set	COPD patients without lung cancer and healthy control data set	COPD patients with lung cancer and healthy control data set	Minimum P Value
GSH	GCLC	13	4.04 × 10⁻⁷	1.81 × 10⁻⁴	7.16 × 10⁻⁴	4.04 × 10⁻⁷
GSH	GSS	7	3.61 × 10⁻²	1.14 × 10⁻⁴	1.75 × 10⁻²	1.14 × 10⁻⁴
GSH	GSTO2	6	3.30 × 10⁻³	5.05 × 10⁻¹	1.06 × 10⁻³	1.06 × 10⁻³
DNA	ERCC1	5	5.26 × 10⁻¹	8.11 × 10⁻³	8.28 × 10⁻¹	8.11 × 10⁻³
DNA	RRM1	6	9.66 × 10⁻³	2.09 × 10⁻²	8.71 × 10⁻²	9.66 × 10⁻³

*Bold P-values mean below significant value of 0.01.

Table 4.

Cumulative risk prediction model for COPD based on multiple independent high-risk htSNP combination

Number of risk alleles	Number of COPD cases	Number of healthy controls	OR	S × 10	Z	P
Whole case–control data set (12 risk htSNPs included)
First level (0, 9)	99	219	1.00 (reference)
Second level (10, 12)	280	424	1.62	0.17	2.91	3.60 × 10⁻³
Third level (13, 24)	241	250	2.73	0.18	5.61	2.07 × 10⁻⁸
Per-allele risk (trend test)			1.21	0.03	6.71	1.95 × 10⁻¹¹
COPD patients without lung cancer and healthy control data set (8 risk htSNPs included)
First level (0, 2)	30	247	1.00 (reference)
Second level (3, 5)	108	496	1.67	0.24	2.19	2.83 × 10⁻²
Third level (6, 16)	50	150	3.08	0.28	4.08	4.60 × 10⁻⁵
Per-allele risk (trend test)			1.25	0.05	4.76	1.94 × 10⁻⁶
COPD patients with lung cancer and healthy control data set (4 risk htSNPs included)
First level (0, 4)	124	324	1.00 (reference)
Second level (5, 6)	264	509	1.89	0.15	4.19	2.81 × 10⁻⁵
Third level (7, 8)	44	60	2.32	0.27	3.10	1.94 × 10⁻³
Per-allele risk (trend test)			1.30	0.06	4.44	9.16 × 10⁻⁶

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