Background
Methods
Subjects
Doetinchem cohort (n = 1,152) | Vlagtwedde-Vlaardingen cohort (n = 1,390) | |
---|---|---|
Total duration of follow-up (years) | 10 | 25 |
Number of visits (median) | 3 | 7 |
The total number of FEV
1
measurements across all visits
| 3,115 | 8,159 |
Follow-up time frame, years | 1997–2007 | 1965–1990 |
Males, n (%) | 541 (47.0) | 714 (51.4) |
FEV
1
change in ml/year, mean (SD) | -26.2 (33.4) | -20.8 (22.9) |
Last available:
| ||
FEV
1
level in liters, mean (SD) | 3.31 (0.80) | 2.86 (0.77) |
Age in years, median (range) | 53.7 (32–76) | 52.0 (35–79) |
Never smokers, n (%) | 372 (32.3) | 445 (32.0) |
Packyears smoked in ever smokers, median (range) | 13.2 (0.004–84.0) | 18.9 (0.1–262.2) |
Selection/genotyping of Single Nucleotide Polymorphisms (SNPs)
Statistics
SNPs in NFE2L2 and KEAP1 and level of FEV1
SNPs in NFE2L2 and KEAP1 and course of FEV1
Analysis on the pooled cohorts
Interaction with smoking
Software
Results
Genetic structure of NFE2L2 and KEAP1
Doetinchem cohort (n = 1,152) | Vlagtwedde-Vlaardingen cohort (n = 1,390) | ||||||||
---|---|---|---|---|---|---|---|---|---|
The total SNP call rate, % | 97.5 | 96.4 | |||||||
The total unique haplotype call rate, % | 93.7 | 90.6 | |||||||
Genotypes distribution, n(%): | Heterozygotes | Homozygotes mutant | MAF | HWE p value | Heterozygotes | Homozygotes mutant | MAF | HWE p value | |
NFE2L2
| rs6726395 | 561 (49.6) | 256 (22.7) | 47.5 | 0.91 | 670 (49.6) | 277 (20.5) | 45.3 | 0.82 |
rs4243387 | 210 (18.8) | 10 (0.9) | 10.3 | 0.69 | 191 (14.1) | 14 (1.0) | 8.1 | 0.07 | |
rs1806649 | 454 (40.5) | 72 (6.4) | 26.7 | 0.27 | 510 (39.1) | 83 (6.4) | 25.9 | 0.55 | |
rs13001694 | 530 (47.3) | 178 (15.9) | 39.6 | 0.74 | 647 (48.1) | 223 (16.6) | 40.6 | 0.82 | |
rs2364723 | 499 (44.6) | 105 (9.4) | 31.7 | 0.38 | 574 (42.8) | 156 (11.6) | 33.0 | 0.42 | |
HaplotypeC | 326 (30.4) | 41 3.8) | 18.9 | 0.72 | 402 (32.6) | 44 (3.6) | 19.1 | 0.42 | |
HaplotypeD | 237 (22.1) | 13 1.2) | 12.4 | 0.47 | 283 (22.9) | 14 (1.1) | 13.0 | 0.13 | |
KEAP1
| rs1048290 | 507 (45.5) | 147 (13.2) | 36.0 | 0.77 | 671 (50.6) | 164 (12.4) | 37.6 | 0.01 |
rs11085735 | 117 (10.4) | 5 (0.4) | 5.6 | 0.56 | 129 (9.6) | 2 (0.1) | 4.9 | 0.77 | |
rs1048287 | 203 (18.0) | 18 (1.6) | 10.6 | 0.14 | 248 (18.4) | 11 (0.8) | 10.0 | 0.51 | |
HaplotypeA | 520 (47.9) | 197 (18.1) | 57.7 | 0.64 | 659 (51.2) | 222 (17.3) | 57.0 | 0.13 | |
HaplotypeB | 401 (36.9) | 80 (7.4) | 26.1 | 0.27 | 541 (42.1) | 88 (6.8) | 28.0 | 0.14 |
Gene | Haplotype | SNP* | Frequency [%] | |
---|---|---|---|---|
rs6726395-rs4243387-rs1806649- rs13001694-rs2364723 |
Doetinchem cohort
|
Vlagtwedde-Vlaardingen cohort
| ||
NFE2L2
| A | 0-0-0-0-1 | 31.0 | 32.5 |
B | 1-0-1-1-0 | 25.0 | 24.5 | |
C | 0-0-0-0-0 | 18.9 | 19.1 | |
D | 1-0-0-1-0 | 12.4 | 13.0 | |
E | 1-1-0-0-0 | 9.3 | 7.0 | |
- | Rare pooled | 3.6 | 3.9 | |
rs1048290-rs11085735-rs1048287 | ||||
KEAP1
| A | 0-0-0 | 57.7 | 57.0 |
B | 1-0-0 | 26.1 | 28.0 | |
C | 1-0-1 | 9.8 | 9.7 | |
D | 0-1-0 | 5.5 | 4.9 | |
- | Rare pooled | 0.9 | 0.4 |
NFE2L2 and KEAP1 variations and level of FEV1
Gene | Variation | Doetinchem cohort | Vlagtwedde-Vlaardingen cohort | Pooled cohorts | ||||
---|---|---|---|---|---|---|---|---|
B [ml]
|
95% CI
|
p
|
B [ml]
|
95% CI
|
p
|
p
| ||
NFE2L2
| rs6726395 | -13.8 | -51.0 – 23.4 | 0.47 | 14.1 | -17.9 – 46.1 | 0.39 | 0.827 |
rs4243387 | 0.2 | -61.9 – 62.3 | 0.99 | 20.6 | -36.5 – 77.7 | 0.48 | 0.620 | |
rs1806649 | -44.5 | -87.3 – -1.7 |
0.04
| 0.2 | -36.7 – 37.1 | 0.99 | 0.150 | |
rs13001694 | -20.9 | -58.7 – 16.9 | 0.28 | 13.0 | -19.5 – 45.5 | 0.43 | 0.948 | |
rs2364723 | -22.9 | -63.6 – 17.8 | 0.27 | -32.1 | -65.4 – 1.2 | 0.06 |
0.026
| |
Haplotype C | 44.8 | -3.4 – 93.0 | 0.07 | 24.3 | -17.8 – 66.4 | 0.26 |
0.040
| |
Haplotype D | 47.0 | -12.1 – 106.1 | 0.11 | 21.2 | -29.7 – 72.1 | 0.41 | 0.064 | |
KEAP1
| rs1048290 | 12.4 | -26.3 – 51.1 | 0.53 | -6.5 | -40.8 – 27.8 | 0.71 | 0.784 |
rs11085735 | 69.9 | -9.3 – 149.1 | 0.08 | 97.1 | 22.4 – 171.8 |
0.01
|
0.003
| |
rs1048287 | -11.9 | -70.8 – 47.0 | 0.69 | -33.2 | -86.3 – 19.9 | 0.22 | 0.287 | |
Haplotype A* | 23.9 | -13.8 – 61.6 | 0.21 | 7.0 | -26.5 – 40.5 | 0.68 | 0.206 | |
Haplotype B | 8.9 | -33.2 – 51.0 | 0.68 | 4.6 | -32.5 – 41.7 | 0.81 | 0.601 |
Interaction between SNPs in NFE2L2 and KEAP1
Interaction between smoking and NFE2L2 and KEAP1 variations and level of FEV1
Doetinchem cohort (n = 1,152)
second survey
| Vlagtwedde-Vlaardingen cohort (n = 1,390)
last survey
| ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Gene
|
Variation
|
Never smokers
|
Ever smokers
|
Never smokers
|
Ever smokers
| ||||||||
B [ml]
|
SE
|
p
|
B [ml]
|
SE
|
p
|
B [ml]
|
SE
|
p
|
B [ml]
|
SE
|
p
| ||
NFE2L2
| rs6726395 | -33.1 | 34.1 | 0.33 | -3.4 | 24.2 | 0.89 | 9.7 | 28.3 | 0.73 | 6.4 | 22.7 | 0.78 |
rs4243387 | 15.5 | 55.5 | 0.78 | -1.2 | 41.1 | 0.98 | 3.9 | 56.0 | 0.94 | 12.8 | 38.6 | 0.74 | |
rs1806649 | -97.1 | 37.7 | 0.01 | -19.0 | 28.4 | 0.50 | 40.6 | 31.5 | 0.20 | -13.1 | 26.6 | 0.62 | |
rs13001694 | -54.5 | 34.7 | 0.12 | -16.0 | 24.5 | 0.52 | 13.5 | 28.2 | 0.63 | 5.6 | 23.3 | 0.81 | |
rs2364723 | 21.5 | 37.3 | 0.56 | -36.6 | 26.8 |
0.17
| -3.2 | 28.4 | 0.91 | -36.2 | 24.0 |
0.13
| |
Haplotype C | 3.5 | 44.6 | 0.94 | 54.2 | 31.3 |
0.08
| -22.9 | 35.2 | 0.52 | 47.5 | 30.5 |
0.12
| |
Haplotype D | 86.7 | 59.1 | 0.14 | 19.5 | 37.0 | 0.60 | -40.3 | 42.5 | 0.34 | 38.7 | 37.1 | 0.30 | |
KEAP1
|
rs1048290
| -0.8 | 35.3 | 0.98 | 17.0 | 25.5 | 0.51 | -21.8 | 29.2 | 0.46 | 44.6 | 24.6 | 0.07 |
rs11085735 | 116.2 | 75.8 |
0.13
| 64.6 | 50.4 | 0.20 | 112.2 | 60.8 |
0.07
| 23.5 | 54.5 | 0.67 | |
rs1048287 | -25.0 | 53.8 | 0.64 | -10.4 | 38.7 | 0.79 | -56.8 | 44.0 | 0.20 | 5.1 | 38.6 | 0.90 | |
Haplotype A* | 25.8 | 34.0 | 0.45 | 22.1 | 24.9 | 0.38 | 4.8 | 28.8 | 0.87 | 36.7 | 23.8 | 0.12 | |
Haplotype B
| 12.3 | 38.3 | 0.75 | 2.3 | 27.8 | 0.93 | 3.6 | 30.7 | 0.91 | 46.3 | 26.7 | 0.08 |
SNPs in NFE2L2 and KEAP1 and course of FEV1
Gene | Variation | Doetinchem cohort | Vlagtwedde-Vlaardingen cohort | Pooled cohorts | ||||
---|---|---|---|---|---|---|---|---|
B [ml/yr]
|
95% CI
|
p
|
B [ml/yr]
|
95% CI
|
p
|
p
| ||
NFE2L2
| rs6726395 | 0.2 | -2.5 – 2.9 | 0.88 | 0.1 | -1.5 – 1.7 | 0.90 | 0.873 |
rs4243387 | -1.2 | -5.6 – 3.2 | 0.60 | -1.9 | -4.8 – 1.1 | 0.21 | 0.106 | |
rs1806649 | 1.5 | -1.6 – 4.5 | 0.35 | 1.0 | -1.0 – 3.0 | 0.31 | 0.151 | |
rs13001694 | 0.0 | -2.7 – 2.7 | 1.00 | 0.7 | -1.0 – 2.4 | 0.40 | 0.337 | |
rs2364723 | -0.3 | -3.2 – 2.6 | 0.84 | -0.6 | -2.3 – 1.1 | 0.50 | 0.368 | |
Haplotype C | -0.3 | -3.8 – 3.1 | 0.85 | 0.9 | -1.3 – 3.1 | 0.40 | 0.401 | |
Haplotype D | -2.3 | -6.6 – 2.0 | 0.29 | 0.0 | -2.6 – 2.5 | 0.98 | 0.627 | |
KEAP1
| rs1048290 | -2.0 | -4.7 – 0.8 | 0.16 | 1.0 | -0.8 – 2.8 | 0.28 | 0.907 |
rs11085735 | 3.6 | -2.1 – 9.4 | 0.22 | -0.7 | -4.7 – 3.3 | 0.72 | 0.774 | |
rs1048287 | -1.8 | -5.9 – 2.4 | 0.41 | -0.4 | -3.1 – 2.4 | 0.80 | 0.614 | |
Haplotype A | -1.3 | -4.0 – 1.4 | 0.35 | 0.8 | -1.0 – 2.5 | 0.38 | 0.817 | |
Haplotype B | -1.6 | -4.6 – 1.4 | 0.30 | 1.5 | -0.5 – 3.4 | 0.14 | 0.573 |