Table 2:
Primary analysis of selected OSA pathways: Covariate-adjusted odds of CAD per s.d. of standardized PS-PRSs with effect-measure modification by OSA status
| PS-PRS | OSA main effect | PS-PRS effect in OSA Controls | PS-PRS effect in OSA Cases | OSA × PS-PRS interaction effect | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | OR | 95% CI | p-value | OR | 95% CI | p-value | OR | p-value | |
| A) Selected pathways: core-gene modules | ||||||||||
| HIF1 core genes | 1.50 | (1.38, 1.64) | 1.022 | (1.009, 1.035) | 1.06E-03 | 1.114 | (1.025, 1.212) | 1.10E-02 | 1.090 | 4.46E-02* |
| VEGF core genes | 1.51 | (1.38, 1.64) | 1.032 | (1.019, 1.045) | 1.66E-06 | 0.952 | (0.874, 1.037) | 2.58E-01 | 0.922 | 6.70E-02 |
| NFκB core genes | 1.51 | (1.38, 1.64) | 1.031 | (1.018, 1.045) | 4.45E-06 | 0.981 | (0.903, 1.066) | 6.54E-01 | 0.952 | 2.45E-01 |
| TNF core genes | 1.51 | (1.38, 1.64) | 1.019 | (1.006, 1.033) | 4.44E-03 | 1.013 | (0.931, 1.102) | 7.59E-01 | 0.994 | 8.94E-01 |
| B) Selected pathways: KEGG signaling pathways | ||||||||||
| HIF1 KEGG | 1.51 | (1.38, 1.64) | 1.062 | (1.048, 1.076) | 6.81E-20 | 1.089 | (1.001, 1.185) | 4.84E-02 | 1.025 | 5.66E-01 |
| VEGF KEGG | 1.51 | (1.38, 1.64) | 1.040 | (1.027, 1.054) | 4.30E-09 | 0.894 | (0.821, 0.974) | 1.02E-02 | 0.860 | 5.98E-04† |
| NFκB KEGG | 1.51 | (1.38, 1.64) | 1.058 | (1.044, 1.072) | 3.26E-17 | 0.998 | (0.919, 1.085) | 9.71E-01 | 0.944 | 1.74E-01 |
| TNF KEGG | 1.51 | (1.38, 1.64) | 1.052 | (1.038, 1.065) | 1.65E-14 | 0.994 | (0.916, 1.079) | 8.86E-01 | 0.945 | 1.85E-01 |
| C) Selected aggregated pathway comparators | ||||||||||
| CAD PRS | 1.52 | (1.39, 1.67) | 1.695 | (1.672, 1.719) | <1.0E-99 | 1.664 | (1.525, 1.816) | 3.30E-30 | 0.982 | 6.80E-01 |
| OSA genes | 1.50 | (1.37, 1.63) | 1.102 | (1.087, 1.116) | 1.17E-46 | 1.222 | (1.122, 1.330) | 3.81E-06 | 1.109 | 1.83E-02* |
Each row depicts a separate PS-PRS model showing the odds ratio-scale OSA and PS-PRS main effects and the PS-PRS × OSA interaction effect from a model of the form logit(CAD) = OSA β1 + PS-PRS β2 + PS-PRSxOSA β3 + covariates. The OSA main effect (the OSA effect in subjects with a 0 value of the centered PS-PRS) is β1, the PS-PRS main effect (the PS-PRS effect in OSA controls) is β2, and the OSA × PS-PRS interaction effect is β3. The PS-PRS effect in OSA Cases, β4, is therefore defined as β4 = β2 + β3. Odds ratios are obtained by exponentiating the corresponding β’s. The primary analysis tests for GxE, i.e. effect-measure modification of the genetic PS-PRS effect by OSA, in the ten pathways shown, as quantified by the p-value for the OSA × PS-PRS interaction effect. OSA main effects and PS-PRS effects in OSA cases and controls are shown for context. Nominally significant (*) GxE results do not pass Bonferroni-corrected significance (†) level 5E-3. Three groupings representing different types of pathways are included: A) core-gene modules B) KEGG-defined signaling pathways, and C) aggregate pathways. Covariates adjusted in a logistic generalized additive model: mutual interaction of age and BMI by sex (via tensor-product thin plate cubic penalty regression splines) as well as smoking and its interaction with sex, self-reported white race, the first 5 genetic PCs, genotype platform (BiLEVE), asthma and chronic obstructive pulmonary disease. OR: odds ratio; CI: confidence interval; OSA: Obstructive sleep apnea, CAD: coronary artery disease, KEGG: Kyoto encyclopedia of genes and genomes, HIF1: hypoxia inducible factor 1, VEGF: vascular endothelial growth factor, NFκB: nuclear factor kappa- beta, TNF: tumor necrosis factor, PRS: polygenic risk score, PS-PRS: pathway-specific polygenic risk score.