Background
Methods
Study subjects
Statistical analysis
Results
GWAS of post-bronchodilator pulmonary function
Cases | Controls | P value | |||||
---|---|---|---|---|---|---|---|
All | Current smokers | Former smokers | All | Current smokers | Former smokers | ||
n | 1086 | 325 | 761 | 559 | 210 | 349 | NA |
Age at enrollment, years | 66.2 ± 7.6 | 62.9 ± 8.1 | 67.7 ± 6.9 | 63.6 ± 9.0 | 58.0 ± 9.1 | 66.9 ± 7.0 | < 0.0001 |
Female, n (%) | 437 (40) | 137 (42) | 300 (39) | 294 (53) | 122 (58) | 172 (49) | < 0.0001 |
Body mass index | 27.4 ± 5.1 | 25.7 ± 4.9 | 28.1 ± 5.0 | 28.6 ± 5.0 | 27.5 ± 5.1 | 29.2 ± 4.8 | < 0.0001 |
Current smokers, n (%) | 325 (30) | 325 (100) | 0 (0) | 210 (38) | 210 (100) | 0 (0) | 0.0019 |
Pack-years of cigarette smoking | 55.0 ± 25.7 | 52.6 ± 24.7 | 56.0 ± 26.1 | 46.3 ± 27.3 | 45.3 ± 31.1 | 46.9 ± 24.8 | < 0.0001 |
Post-bronchodilator FEV1/FVC | 0.52 ± 0.13 | 0.55 ± 0.11 | 0.50 ± 0.13 | 0.77 ± 0.05 | 0.78 ± 0.05 | 0.77 ± 0.05 | < 0.0001 |
Post-bronchodilator FEV1, % predicted | 60.1 ± 22.5 | 63.6 ± 19.7 | 58.6 ± 23.5 | 94.4 ± 13.9 | 93.4 ± 13.2 | 95.0 ± 14.3 | < 0.0001 |
SNP | Gene | Chr | Location | Minor (Effect)/Major Allele | Minor AlleleFrequency | Post-bronchodilator FEV1/FVC | Post-bronchodilator % predicted FEV1 | ||
---|---|---|---|---|---|---|---|---|---|
β | P value | β | P value | ||||||
rs28929474 |
SERPINA1
| 14 | coding | T/C | 0.029 | −0.087 | 1.2 × 10−8 | −13.6 | 3.5 × 10− 8 |
rs4537555 |
HHAT
| 1 | intron | G/A | 0.11 | − 0.044 | 2.1 × 10− 7 | − 6.3 | 4.1 × 10− 6 |
rs8079868 |
MYH3
| 17 | 3’ | C/T | 0.12 | − 0.034 | 3.5 × 10− 5 | −6.7 | 5.9 × 10− 7 |
rs1980057 |
HHIP
| 4 | 5’ | T/C | 0.37 | 0.011 | 0.049 | 1.4 | 0.13 |
rs2070600 |
AGER
| 6 | coding | A/G | 0.047 | 0.026 | 0.047 | 3.4 | 0.10 |
rs2869967 |
FAM13A1
| 4 | intron | C/T | 0.41 | −0.014 | 0.016 | −1.4 | 0.12 |
rs1435867 |
PID1
| 2 | 3’ | C/T | 0.075 | 0.021 | 0.043 | 1.9 | 0.26 |
rs12477314 |
HDAC4
| 2 | 3’ | T/C | 0.21 | 0.014 | 0.033 | 2.3 | 0.035 |
rs1529672 |
RARB
| 3 | intron | A/C | 0.15 | 0.026 | 5.1 × 10−4 | 3.4 | 5.0 × 10− 3 |
rs12914385 |
CHRNA3
| 15 | intron | T/C | 0.43 | −0.014 | 0.014 | −2.2 | 0.014 |
rs10498635 |
RIN3
| 14 | intron | T/C | 0.18 | 0.021 | 2.6 × 10−3 | 3.7 | 1.5 × 10− 3 |
rs615098 |
MMP12
| 11 | 3’ | A/C | 0.18 | 0.013 | 0.056 | 2.4 | 0.034 |
Association of SERPINA1 with lung function, COPD, and COPD severity
Phenotype | CC (n = 1559) | CT (n = 78) | TT (n = 8) | TT vs. CT vs. CC | CT vs. CC | TT vs. CT | TT vs. CC | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
β or OR | P value | β or OR | P value | β or OR | P value | β or OR | P value | ||||
Age at enrollment, years | 65.4 ± 8.2 | 64.5 ± 8.1 | 53.7 ± 3.9 | −2.38 | 0.0029 | −0.92 | 0.33 | −10.8 | 3.6 × 10−4 | −11.7 | 5.7 × 10−5 |
Sex (Female vs. Male), n | 696 vs. 863 | 33 vs. 45 | 2 vs. 6 | 0.83 | 0.35 | 0.91 | 0.69 | 0.46 | 0.35 | 0.41 | 0.28 |
Pack-years of cigarette smoking | 52.3 ± 26.6 | 48.9 ± 26.4 | 35.2 ± 13.4 | −3.97 | 0.12 | −3.10 | 0.3 | −6.62 | 0.52 | −12.3 | 0.19 |
Post-bronchodilator FEV1/FVC | 0.61 ± 0.16 | 0.54 ± 0.18 | 0.39 ± 0.09 | −0.087 | 1.2 × 10−8 | − 0.077 | 2.3 × 10− 5 | −0.090 | 0.21 | −0.23 | 3.2 × 10− 5 |
Pre-bronchodilator FEV1/FVC | 0.59 ± 0.15 | 0.52 ± 0.17 | 0.37 ± 0.09 | −0.081 | 9.9 × 10− 8 | −0.069 | 1.7 × 10− 4 | − 0.086 | 0.22 | −0.22 | 3.5 × 10− 5 |
Post-bronchodilator % predicted FEV1 | 72.5 ± 25.6 | 61.3 ± 26.4 | 33.5 ± 7.89 | −13.6 | 3.5 × 10− 8 | − 11.4 | 9.1 × 10− 5 | −22.5 | 0.037 | −38.1 | 2.2 × 10− 5 |
Post-bronchodilator FEV1, ml | 2115 ± 888 | 1841 ± 860 | 1210 ± 240 | − 439 | 2.1 × 10−9 | − 329 | 1.4 × 10− 4 | − 1066 | 1.5 × 10− 4 | − 1395 | 1.4 × 10−7 |
Pre-bronchodilator % predicted FEV1 | 65.6 ± 26.1 | 54.8 ± 26.9 | 30.2 ± 7.57 | −12.9 | 8.3 × 10− 7 | −10.9 | 5.0 × 10− 4 | −17.5 | 0.12 | −34.7 | 1.6 × 10− 4 |
Pre-bronchodilator FEV1, ml | 1916 ± 883 | 1629 ± 833 | 1091 ± 240 | − 426 | 1.1 × 10− 8 | − 339 | 1.2 × 10− 4 | − 924 | 8.1 × 10− 4 | − 1263 | 2.9 × 10− 6 |
% change in FEV1 (BDR) | 13.6 ± 13.5 | 17.1 ± 18.1 | 11.6 ± 9.75 | 2.08 | 0.13 | 3.49 | 0.030 | −3.56 | 0.65 | −2.77 | 0.57 |
Post-bronchodilator % predicted FVC | 90.7 ± 17.7 | 86.9 ± 17.2 | 71.5 ± 21.1 | −5.23 | 0.0024 | −3.83 | 0.060 | −18.0 | 0.019 | −17.0 | 0.0070 |
Post-bronchodilator FVC, ml | 3518 ± 1011 | 3482 ± 1036 | 3365 ± 1015 | − 236 | 4.6 × 10− 4 | − 162 | 0.042 | − 661 | 0.023 | − 822 | 7.1 × 10− 4 |
Pre-bronchodilator % predicted FVC | 84.4 ± 19.4 | 78.9 ± 18.6 | 68.7 ± 21.7 | −6.07 | 0.0018 | −5.55 | 0.017 | −12.6 | 0.13 | −14.2 | 0.038 |
Pre-bronchodilator FVC, ml | 3274 ± 1032 | 3145 ± 1015 | 3240 ± 1071 | −277 | 2.0 × 10− 4 | − 249 | 0.0046 | − 434 | 0.16 | − 683 | 0.011 |
COPD (GOLD stage 2–4 vs. 0), n | 803 vs. 539 | 53 vs. 20 | 8 vs. 0 | 2.31 | 7.8 × 10−4 | 1.91 | 0.019 | NA | NA | NA | NA |
COPD severity (GOLD stage 3–4 vs. 1), n | 331 vs. 217 | 32 vs. 5 | 8 vs. 0 | 4.08 | 0.0036 | 3.79 | 0.0081 | NA | NA | NA | NA |
Prediction of post-bronchodilator pulmonary function
Post-bronchodilator FEV1/FVC | Post-bronchodilator % predicted FEV1 | |||||
---|---|---|---|---|---|---|
β | R2 | P value | β | R2 | P value | |
Genetic Score (8–18)a | − 0.018 | 0.0363 | 8.6 × 10− 15 | −2.6 | 0.0296 | 2.7 × 10− 12 |
Age at enrollment, years | −0.0024 | 0.0145 | 1.1 × 10− 6 | − 0.042 | 0.000176 | 0.59 |
Sex (Male = 0, Female = 1) | 0.044 | 0.0186 | 3.1 × 10− 8 | 1.88 | 0.000132 | 0.14 |
Pack-years of cigarette smoking | − 0.0011 | 0.0304 | 1.3 × 10− 12 | −0.017 | 0.0294 | 3.2 × 10− 12 |
All | NA | 0.0859 | < 2.2 × 10− 16 | NA | 0.0583 | < 2.2 × 10− 16 |
Joint analysis of 10 SNPs with emphysema, clinical symptoms, and exacerbation
Genetic Scorea | 8–11 (n = 228) | 12–13 (n = 643) | 14–15 (n = 612) | 16–18 (n = 149) | P valueǂ |
---|---|---|---|---|---|
CT Evidence of Emphysema (TLC % Area < − 950 HUb) | 5.54 ± 6.59 | 7.60 ± 9.84 | 8.67 ± 10.4 | 12.5 ± 12.4 | < 0.0001 |
CT Evidence of Airtrapping (RV % Area < − 856 HUb) | 21.8 ± 18.1 | 24.0 ± 20.6 | 27.6 ± 21.0 | 33.9 ± 23.2 | < 0.0001 |
BODE Index | 1.15 ± 1.62 | 1.33 ± 1.75 | 1.61 ± 1.98 | 2.21 ± 2.41 | < 0.0001 |
COPD Assessment Test (CAT) | 12.7 ± 8.0 | 13.0 ± 8.0 | 14.0 ± 8.2 | 13.5 ± 7.9 | 0.07 |
St. George’s Respiratory Questionnaire (SGRQ) Total Score | 30.4 ± 19.7 | 30.3 ± 19.6 | 32.9 ± 20.0 | 35.5 ± 20.6 | 0.0044 |
6-Minute Walk Distance (6MWD, meters) | 416 ± 114 | 415 ± 111 | 418 ± 124 | 390 ± 126 | 0.0086 |
Exacerbations requiring ED Visit or Hospitalization in last 12 months (% Yes) | 7.5% | 6.5% | 11% | 14% | 0.001 |