Table 3.
Mendelian randomization analysis: the effect of genetically predicted CRP (as log-transformed or categorized) on colorectal cancer risk by number of cigarettes per day
| Analytic method | All SNPs | After exclusion of pleiotropic SNPs | |||||||||||||||||
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| Stage 1 | Stage 2 | Stage 1 | Stage 2 | ||||||||||||||||
| Adjustment for age and 10 PCs | Adjustment for covariates* | Adjustment for age and 10 PCs | Adjustment for covariates* | ||||||||||||||||
| in addition to age and 10 PCs | in addition to age and 10 PCs | ||||||||||||||||||
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| HR | (95% CI) | p | p-het† | HR | (95% CI) | p | p-het† | HR | (95% CI) | p | p-het† | HR | (95% CI) | p | p-het† | ||||
| GWASs analyzing CRP as a continuous variable that was naturally log-transformed (mg/L) | |||||||||||||||||||
| <Never smokers> | |||||||||||||||||||
| Inverse-variance weighted | 1.48 | (1.01-2.18) | 0.045 | 0.795 | 1.51 | (0.97-2.37) | 0.069 | 0.309 | 1.53 | (1.02-2.30) | 0.041 | 0.742 | 1.57 | (0.97-2.54) | 0.063 | 0.235 | |||
| Weighted median | 1.82 | (1.02-3.26) | 0.044 | 1.59 | (0.85-2.96) | 0.146 | 1.82 | (0.97-3.44) | 0.064 | 1.75 | (0.91-3.34) | 0.092 | |||||||
| Penalized weighted median | 1.82 | (1.02-3.25) | 0.044 | 1.65 | (0.87-3.12) | 0.125 | 1.82 | (1.004-3.31) | 0.049 | 1.79 | (0.94-3.42) | 0.079 | |||||||
| MR-Egger: slope | 1.58 | (0.88-2.84) | 0.122 | 1.44 | (0.73-2.86) | 0.286 | 1.59 | (0.85-2.95) | 0.140 | 1.46 | (0.71-3.01) | 0.300 | |||||||
| intercept | 1.00 | (0.96-1.03) | 0.766 | 1.004 | (0.97-1.04) | 0.853 | 1.00 | (0.96-1.03) | 0.876 | 1.01 | (0.97-1.05) | 0.780 | |||||||
| GWAS examining CRP as a binary outcome reflecting high immune response and chronic inflammation (CRP > 3.0 mg/L) | |||||||||||||||||||
| <≥ 15 cigarettes/d> | |||||||||||||||||||
| Inverse-variance weighted¶ | 1.58 | (1.03-2.41) | 0.041 | 0.908 | 1.63 | (0.91-2.93) | 0.083 | 0.788 | |||||||||||
| Weighted median | 1.52 | (0.74-3.12) | 0.256 | 1.62 | (0.76-3.46) | 0.210 | |||||||||||||
| Penalized weighted median | 1.52 | (0.72-3.19) | 0.269 | 1.62 | (0.77-3.41) | 0.201 | |||||||||||||
| MR-Egger: slope | 0.36 | (0.04-3.26) | 0.236 | 0.29 | (0.01-10.57) | 0.351 | |||||||||||||
| intercept | 1.37 | (0.86-2.18) | 0.119 | 1.44 | (0.68-3.06) | 0.219 | |||||||||||||
| <MR G×E interaction: scaled GWA CRP weighted-genetic score€ × number of cigarettes/d> | |||||||||||||||||||
| G×E univariate slope§ | 2.59 | 1.13-5.91 | 0.032 | ||||||||||||||||
CI, confidence interval; CRP, C-reactive protein; GWAS, genome-wide association study; HR, hazard ratio; MR, Mendelian randomization; PCs, principal components; SFA, saturated fatty acid; SNP, single-nucleotide polymorphism. Numbers in bold face are statistically significant.
Covariates that were adjusted for in analyses of the association between GWA CRP-SNPs and colorectal cancer risk include education; annual family income; family history of colorectal cancer; cardiovascular disease ever; high cholesterol requiring medication ever; body mass index; waist-to-hip ratio; physical activity; % calories from SFA/day; dietary alcohol in g/day; number of cigarettes/day; age at menopause; duration of oral contraceptive use; and durations of exogenous estrogen (E)-only and E plus progestin use. Variable tested for stratification was not included as a covariate in the stage 2 analysis.
p value for heterogeneity test in estimates among GWA CRP-SNPs was evaluated with Cochran’s Q test with fixed effects.
The MR estimate was adjusted for a correlation between CRP phenotype and colorectal cancer within the same population.
The MR G×E slope reflects an MR estimate from univariate analysis that was corrected for G×E interaction with a modeled (cigarette) variable.
The scaled weighted-genetic score was estimated with 5 CRP SNPs whose effect size reflects chronic inflammation (CRP > 3.0 mg/L) per allele.