Supplemental Table 1: The 77 single nucleotide polymorphisms (SNPs) included in this study
GWAS
Region
1q23.2
SNPs
N
1
2p13.3
SNP rs number**
rs2808630*
Local loci***
CRP
References
[1]
1
rs4254535
GKN2||GKN1
[2]
3p24.1
1
rs1530057
RBMS3
[2]
3q28
1
rs7626795
IL1RAP
[1]
4q22.1
2
rs2869967 rs7671167*
FAM13A
[3]
4q31.21
7
rs2202507 rs12504628 rs13147758 rs1489759 rs1828591
rs1980057 rs13118928
5p15.33
13
rs2242652 rs2736100 rs2853676 rs2853668 rs2735845 rs4635969
rs4975616 rs1801075 rs7727912 rs451360 rs402710 rs401681
rs31489
TERT, CLPTM1L
[2,9-11]
6p21.33
22
rs1052486 rs3117582 rs805297 rs805262 rs707974* rs7029
rs3117578 rs3115667 rs2280800 rs2295663 rs6916278 rs385306
rs805284 rs805293 rs805292 rs805304 rs3131382 rs3117572
rs2299851 rs3131379 rs707939 rs1802127
APOM, BAG6, C6orf47, CSNK2B,
GPANK1, LY6G5C, ABHD16A, MIR4646,
LY6G6F, LY6G6D, LY6G6E, C6orf25,
LY6G6C, CLIC1, DDAH2, MSH5,
SAPCD1
[2,9,11]
6p22.1
1
rs4324798
TRNAF-GAA||TRNAA-AGC
[9]
10q23.31
1
rs1926203
ACTA2
[2]
13q31.3
1
rs2352028
GPC5
[12]
15q15.2
9
rs3917223 rs12050604 rs35985214 rs504417 rs11853991
rs748404 rs2602141 rs689647 rs560191
UBR1, TGM5, TP53BP1
[2,9,13]
15q25.1
17
rs13180 rs4362358 rs8034191 rs4461039 rs3885951 rs11858230
rs16969968 rs660652 rs12914385 rs12443170 rs8042374 rs1948
rs7178270 rs950776 rs12440014 rs11636753 rs1316971
IREB2, HYKK (previously LOC123688),
PSMA4, CHRNA5, CHRNA3, CHRNB4
[1,2,4,5,9,11,
14,15]
[3-8]
* Failed genotype assay (call rate <0.95) or Hardy-Weinberg equilibrium test (P<0.001).
** Bolded rs numbers signify SNPs identified by GWAS. The other rs numbers signify putatively functional SNPs or tagSNPs for genes in the
GWAS-identified region. The tagSNPs capture common variants (minor allele frequency ≥0.05).
*** Based on dbSNP Human Build 142 (GRCh38).
1
REFERENCES – Supplemental Table 1
1. Amos CI, Wu X, Broderick P, et al. Genome-wide association scan of tag SNPs identifies a
susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008;40:616-22.
2. Broderick P, Wang Y, Vijayakrishnan J, et al. Deciphering the impact of common genetic
variation on lung cancer risk: A genome-wide association study. Cancer Res 2009;69:663341.
3. Hancock DB, Eijgelsheim M, Wilk JB, et al. Meta-analyses of genome-wide association
studies identify multiple loci associated with pulmonary function. Nat Genet 2010;42:45-52.
4. Cho MH, Boutaoui N, Klanderman BJ, et al. Variants in FAM13A are associated with
chronic obstructive pulmonary disease. Nat Genet 2010;42:200-2.
5. Pillai SG, Ge D, Zhu G, et al. A genome-wide association study in chronic obstructive
pulmonary disease (COPD): Identification of two major susceptibility loci. PLoS Genet
2009;5:e1000421.
6. Repapi E, Sayers I, Wain LV, et al. Genome-wide association study identifies five loci
associated with lung function. Nat Genet 2010;42:36-44.
7. Wilk JB, Chen TH, Gottlieb DJ, et al. A genome-wide association study of pulmonary
function measures in the Framingham Heart Study. PLoS Genet 2009;5:e1000429.
8. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and
cumulative effects of GWAS susceptibility loci in lung cancer: Associations after subphenotyping for COPD. PLoS One 2011;6:e16476.
9. Landi MT, Chatterjee N, Yu K, et al. A genome-wide association study of lung cancer
identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum
Genet 2009;85:679-91.
10. McKay JD, Hung RJ, Gaborieau V, et al. Lung cancer susceptibility locus at 5p15.33. Nat
Genet 2008;40:1404-6.
11. Wang Y, Broderick P, Webb E, et al. Common 5p15.33 and 6p21.33 variants influence lung
cancer risk. Nat Genet 2008;40:1407-9.
12. Li Y, Sheu CC, Ye Y, et al. Genetic variants and risk of lung cancer in never smokers: A
genome-wide association study. Lancet Oncol 2010;11:321-30.
13. Rafnar T, Sulem P, Besenbacher S, et al. Genome-wide significant association between a
sequence variant at 15q15.2 and lung cancer risk. Cancer Res 2011;71:1356-61.
14. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to
nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008;452:633-7.
15. Liu P, Vikis HG, Wang D, et al. Familial aggregation of common sequence variants on
15q24-25.1 in lung cancer. J Natl Cancer Inst 2008;100:1326-30.
2
Supplemental Table 2: Risk factor points for duration of smoking, age, smoking status, and
smoking intensity
Risk factor
Duration of smoking, in years
Age, in yearsa
Smoking statusb
Smoking intensity, in cigarettes/day
Points
-10
0
8
14
0
4
0
-3
-4
0
2
5
<30
30-39
40-49
≥50
younger
older
current
former
<20
20-29
30-39
≥40
Older age defined as age ≥57, ≥59, ≥61, and ≥68 years for persons smoking <30, 30-39, 40-49,
and ≥50 years, respectively.
b
The quit smoking category includes former smokers with current attained age at least one year
greater than age quit
a
3
Supplemental Table 3: Characteristics of controls (N=1166) placed in high and low risk groupsa
according to the two-SNP 5p15.33 classifier
N
Year
2002
2003
2004-2005
Sex
male
female
Age, in years
50-59
60-69
70-79
Family historyb
no
yes
Symptoms, N
0
1
2
3
Duration of
smoking, in years
<30
30-39
40-49
≥50
Cigarettes/day
<20
20-29
30-39
≥40
Pack-years
<35
35-49
50-64
≥65
COPD
no
yes
High Risk
N
%
428 100.0
Low Risk
N
%
738 100.0
Pc
0.23
104
192
132
24.3
44.9
30.8
211
301
226
28.6
40.8
30.6
225
203
52.6
47.4
377
361
51.1
48.9
0.62
0.22
243
137
48
56.8
32.0
11.2
422
255
61
57.2
34.6
8.3
0.28
348
77
81.9
18.1
618
115
84.3
15.7
0.19
152
110
96
70
35.5
25.7
22.4
16.4
237
221
181
99
32.1
29.9
24.5
13.4
0.25
29
180
171
48
6.8
42.1
40.0
11.2
47
348
254
89
6.4
47.2
34.4
12.1
0.20
109
194
75
50
25.5
45.3
17.5
11.7
229
299
132
78
31.0
40.5
17.9
10.6
98
108
117
105
22.9
25.2
27.3
24.5
194
192
181
171
26.3
26.0
24.5
23.2
343
85
80.1
19.9
587
151
79.5
20.5
0.50
0.81
4
High Risk
N
%
Low Risk
N
%
Pc
0.22
Emphysema
none
239 55.8
411 55.7
trace
73 17.1
155 21.0
mild
62 14.5
100 13.6
mod-severe
54 12.6
72
9.8
GOLD
0.89
no limitation
234 54.7
418 56.6
mild
60 14.0
105 14.2
moderate
102 23.8
163 22.1
severe
32
7.5
52
7.0
LEGEND: Symptoms – symptom (cough, phlegm, wheeze) count; COPD – doctor diagnosis of
emphysema or bronchitis; GOLD – Global Initiative for Chronic Obstructive Lung Disease
severity of airflow limitation.
a
The High Risk group consisted of carriers of the rs7727912 minor allele and homozygotes for
the rs2736100 common allele.
b
First-degree relative with lung cancer (data missing in three high-risk and five low-risk
controls).
c
Differences in characteristics between high and low risk groups were assessed using Chi-square
tests.
5
Supplemental Table 4: Characteristics of controls (N=1113) placed in high and low risk groupsa
according to the two-SNP 6p21.33 classifierb
N
Year
2002
2003
2004-2005
Sex
male
female
Age, in years
50-59
60-69
70-79
Family historyc
no
yes
Symptoms, N
0
1
2
3
Duration of
smoking, in years
<30
30-39
40-49
≥50
Cigarettes/day
<20
20-29
30-39
≥40
Pack-years
<35
35-49
50-64
≥65
COPD
no
yes
High Risk
N
%
489 100.0
Low Risk
N
%
624 100.0
Pd
0.34
134
228
127
27.4
46.6
26.0
181
264
179
29.0
42.3
28.7
0.13
241
248
49.3
50.7
336
288
53.8
46.2
282
157
50
57.7
32.1
10.2
360
209
55
57.7
33.5
8.8
0.69
0.83
409
77
84.2
15.8
518
101
83.7
16.3
169
134
112
74
34.6
27.4
22.9
15.1
201
185
149
89
32.2
29.6
23.9
14.3
0.76
0.22
39
223
165
62
8.0
45.6
33.7
12.7
35
284
237
68
5.6
45.5
38.0
10.9
128
199
97
65
26.2
40.7
19.8
13.3
192
271
102
59
30.8
43.4
16.3
9.5
114
127
120
128
23.3
26.0
24.5
26.2
164
160
164
136
26.3
25.6
26.3
21.8
0.046
0.32
0.0014
368
121
75.3
24.7
518
106
83.0
17.0
6
High Risk
N
%
Low Risk
N
%
Pd
0.0088
Emphysema
none
261 53.4
355 56.9
trace
82 16.8
135 21.6
mild
83 17.0
75 12.0
mod-severe
63 12.9
59
9.5
GOLD
0.038
no limitation
266 54.4
355 56.9
mild
57 11.7
99 15.9
moderate
122 24.9
131 21.0
severe
44
9.0
39
6.3
LEGEND: Symptoms – symptom (cough, phlegm, wheeze) count; COPD – doctor diagnosis of
emphysema or bronchitis; GOLD – Global Initiative for Chronic Obstructive Lung Disease
severity of airflow limitation.
a
The High Risk group consisted of carriers of the rs1802127 minor allele and the homozygotes
for the rs805297 common allele.
b
Fifty-three subjects could not be classified because of missing genotype data.
c
First-degree relative with lung cancer (data missing in three high-risk and five low-risk
controls).
d
Differences in characteristics between high and low risk groups were assessed using Chi-square
tests.
7
Supplemental Table 5: Characteristics of controls (N=1165) placed in high and low risk groupsa
according to the two-SNP 15q25.1 classifierb
N
Year
2002
2003
2004-2005
Sex
male
female
Age, in years
50-59
60-69
70-79
Family historyc
no
yes
Symptoms, N
0
1
2
3
Duration of
smoking, in years
<30
30-39
40-49
≥50
Cigarettes/day
<20
20-29
30-39
≥40
Pack-years
<35
35-49
50-64
≥65
COPD
no
yes
Emphysema
High Risk
N
%
481
Low Risk
N
%
684
Pd
0.66
130 27.0
210 43.7
141 29.3
185 27.0
283 41.4
216 31.6
0.12
235 48.9
246 51.1
366 53.5
318 46.5
281 58.4
162 33.7
38 7.9
383 56.0
230 33.6
71 10.4
0.34
0.59
402 84.1
76 15.9
563 82.9
116 17.1
161
135
108
77
228
196
169
91
0.56
33.5
28.1
22.5
16.0
33.3
28.7
24.7
13.3
0.59
36 7.5
222 46.2
169 35.1
54 11.2
40 5.8
305 44.6
256 37.4
83 12.1
123
206
91
61
25.6
42.8
18.9
12.7
215 31.4
286 41.8
116 17.0
67 9.8
103
134
118
126
21.4
27.9
24.5
26.2
189
165
180
150
0.10
0.038
27.6
24.1
26.3
21.9
0.26
376 78.2
105 21.8
553 80.8
131 19.2
0.0011
8
High Risk
N
%
241 50.1
100 20.8
70 14.6
70 14.6
Low Risk
N
%
408 59.6
128 18.7
92 13.5
56 8.2
Pd
none
trace
mild
mod-severe
GOLD
0.63
no limitation
260 54.1
391 57.2
mild
68 14.1
97 14.2
moderate
114 23.7
151 22.1
severe
39 8.1
45 6.6
LEGEND: Symptoms – symptom (cough, phlegm, wheeze) count; COPD – doctor diagnosis of
emphysema or bronchitis; GOLD – Global Initiative for Chronic Obstructive Lung Disease
severity of airflow limitation.
a
The High Risk group consisted of rs12440014 common allele homozygotes with one or two
copies of the rs8034191 minor allele.
b
One subject could not be classified because of missing genotype data.
c
First-degree relative with lung cancer (data missing in three high-risk and five low-risk
controls).
d
Differences in characteristics between high and low risk groups were assessed using Chi-square
tests.
9
Supplemental Figure 1: Decision trees
10