SNPs associated with ALI/ARDS in Stage II
| SNP | Gene | Minor allele | Human 610-quad* | MAF Case/Ctrl | OR† (95% CI) | p† |
|---|---|---|---|---|---|---|
| SNPs associated with extrapulmonary injury-related ARDS in Stage I and tested for validation in Stage II using a trauma-related ALI population (Population I, Harborview trauma cohort) | ||||||
| SNPs replicated in Stage II | ||||||
| rs324420‡ | FAAH | A | Typed | 0.23/0.16 | 1.59 (1.10 to 2.31) | 0.0131 (0.0007)‡ |
| SNPs not replicated in Stage II | ||||||
| rs198977 | KLK2 | T | Typed | 0.38/0.22 | 1.23 (0.89 to 1.70) | 0.2019 |
| rs9645765 | VWF | G | Imputed | 0.08/0.08 | 0.98 (0.60 to 1.61) | 0.942 |
| rs2889490 | SFRS16 | G | Imputed | 0.48/0.49 | 1.03 (0.77 to 1.37) | 0.8319 |
| rs3128126 | ISG15 | G | Imputed | 0.33/0.36 | 0.77 (0.52 to 1.16) | 0.2112 |
| rs16980496 | ADRBK2 | A | Imputed | 0.07/0.09 | 1.05 (0.60 to 1.86) | 0.8509 |
| rs2070887 | VWF | G | Typed | 0.08/0.08 | 1.14 (0.69 to 1.88) | 0.5928 |
| rs10490072 | BCL11A | C | Imputed | 0.24/0.23 | 1.09 (0.78 to 1.52) | 0.6125 |
| SNPs associated with pulmonary injury-related ARDS in Stage I and tested for validation in Stage II using a pneumonia/pulmonary sepsis-related ARDS population (Population II, MGH/ARDS net) | ||||||
| SNPs replicated in Stage II | ||||||
| rs1190286‡ | POPDC3 | C | Imputed | 0.14/0.20 | 0.65 (0.46 to 0.90) | 0.0094 (0.0007)‡ |
| SNPs not replicated in Stage II | ||||||
| rs7807769 | PRKAG2 | A | Imputed | 0.42/0.39 | 1.08 (0.85 to 1.38) | 0.5082 |
| rs7801616 | PRKAG2 | T | Typed | 0.42/0.40 | 1.08 (0.85 to 1.37) | 0.5195 |
| rs9960450 | TNFRSF11A | C | Typed | 0.05/0.03 | 1.64 (0.91 to 3.00) | 0.1009 |
| rs2254358 | HSPG2 | C | Imputed | 0.33/0.31 | 0.98 (0.75 to 1.28) | 0.8977 |
| rs732821 | HTR2A | A | Imputed | 0.46/0.47 | 0.99 (0.78 to 1.25) | 0.9171 |
| rs6970522 | PRKAG2 | G | Typed | 0.47/0.44 | 1.07 (0.84 to 1.35) | 0.5847 |
| rs3887893 | ABCC1 | G | Typed | 0.39/0.36 | 1.23 (0.97 to 1.58) | 0.0912 |
| rs17069902 | TNFRSF11A | T | Typed | 0.06/0.04 | 1.51 (0.91 to 2.50) | 0.1098 |
| rs2671222 | IL8RA | A | Imputed | 0.06/0.07 | 0.96 (0.59 to 1.58) | 0.8890 |
| rs12080701 | PDE4B | G | Imputed | 0.09/0.09 | 1.27 (0.81 to 1.98) | 0.2204 |
| rs8112223 | HAS1 | A | Typed | 0.40/0.35 | 1.06 (0.82 to 1.35) | 0.6609 |
| rs6451620 | GHR | A | Typed | 0.05/0.04 | 0.98 (0.54 to 1.77) | 0.9416 |
| rs17419964 | PDE4B | G | Imputed | 0.25/0.27 | 1.24 (0.94 to 1.62) | 0.12 |
| rs802440 | GRM3 | T | Imputed | 0.32/0.31 | 0.96 (0.75 to 1.25) | 0.7879 |
| rs4075731 | MAP3K6 | A | Imputed | 0.37/0.41 | 0.93 (0.73 to 1.18) | 0.547 |
| rs2854386 | IL8RA | C | Imputed | 0.06/0.07 | 0.96 (0.59 to 1.58) | 0.8806 |
SNPs associated with extrapulmonary and pulmonary injury-related ARDS in Stage I (p≤0.0005) were tested for validation in Stage II using two different populations with indirect (Population I) and direct (Population II) lung injury as risk factor for ALI/ARDS. Both populations were genotyped with the Human 610-quad platform.
In Stage II, SNPs rs324420 and rs1190286 demonstrated a reproducible association with increased risk of ALI from indirect insult (trauma) and decreased risk of ARDS from pulmonary injury (pneumonia/pulmonary sepsis), respectively, and those associations were robust after adjusting for clinical variables (p=0.0131 and p=0.0094, respectively).
*Indicates whether the SNP was directly genotyped by the Human 610-quad. For those ITMAT-Broad_CARe, SNPs not directly genotyped on the genome-wide array, imputation was performed.
†OR and p values were adjusted for clinical covariates (age, ISS and APACHE II score in Population I and age, gender and top six principal components in Population II).
‡Only rs324420 in Population I, and rs1190286 in Population II met these thresholds (unadjusted p values displayed in italics).
The threshold of significance in Stage II was established in p≤0.006 (0.05/8 SNPs) and p≤0.003 (0.05/17 SNPs) for SNPs previously associated with ARDS from indirect and direct insults, respectively.
ALI, acute lung injury; APACHE, acute physiology and chronic health evaluation; ARDS, acute respiratory distress syndrome; Case/Ctrl, Case/Control; LD, linkage disequilibrium; MAF, minor allele frequency; MGH, Massachusetts General Hospital; SNP, single nucleotide polymorphism.