Table 4.
Step 2 Mendelian Randomization Results for the Association Between the DNA Methylation Levels of cg03636183 in the F2RL3 Gene and the Inflammatory Markers log(CRP), log(IL-6), log(IL-18), and Fibrinogen, GENOA Study, Jackson, Mississippi, 2000–2005a
| Gene and Instrument SNPb | Inflammatory Marker | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| log(CRP) | log(IL-6) | log(IL-18) | Fibrinogen | ||||||
| βc | 95% CI | βc | 95% CI | βc | 95% CI | P Value | βc | 95% CI | |
| F2RL3 | |||||||||
| rs2227341d | 0.04 | −0.08, 0.16 | 0.002 | −0.07, 0.07 | −0.11 | −0.19, −0.04 | 4.1 × 10−3 | 1.09 | −8.30, 10.49 |
| rs2227353 | 0.04 | −0.08, 0.17 | −0.01 | −0.08, 0.07 | −0.12 | −0.20, −0.05 | 1.8 × 10−3 | 2.55 | −7.10, 12.20 |
| rs773905 | −0.05 | −0.24, 0.15 | −0.05 | −0.16, 0.07 | −0.21 | −0.33, −0.10 | 3.4 × 10−4 | −8.91 | −23.90, 6.08 |
| CPAMD8 | |||||||||
| rs2227368 | 0.01 | −0.15, 0.18 | 0.01 | −0.08, 0.11 | −0.17 | −0.26, −0.07 | 1.2 × 10−3 | −2.26 | −15.03, 10.50 |
| rs10418195 | 0.03 | −0.14, 0.20 | 0.004 | −0.10, 0.10 | −0.18 | −0.28, −0.08 | 6.9 × 10−4 | −0.44 | −13.59, 12.71 |
| rs773901 | −0.05 | −0.25, 0.15 | −0.05 | −0.16, 0.06 | −0.22 | −0.34, −0.11 | 1.8 × 10−4 | −9.93 | −24.99, 5.13 |
| rs7245967 | −0.05 | −0.26, 0.15 | −0.04 | −0.16, 0.07 | −0.20 | −0.32, −0.09 | 8.3 × 10−4 | −10.05 | −25.47, 5.37 |
| rs2981474 | −0.04 | −0.24, 0.16 | −0.04 | −0.15, 0.08 | −0.22 | −0.33, −0.10 | 2.8 × 10−4 | −10.34 | −25.60, 4.92 |
| rs2608732 | −0.06 | −0.26, 0.14 | −0.05 | −0.17, 0.06 | −0.22 | −0.34, −0.11 | 2.3 × 10−4 | −10.68 | −25.92, 4.55 |
| SIN3B | |||||||||
| rs773895 | 0.01 | −0.19, 0.20 | —e | — | −0.20 | −0.32, −0.09 | 6.3 × 10−4 | — | — |
| rs773899 | 0.00 | −0.20, 0.20 | — | — | −0.20 | −0.31, −0.08 | 8.0 × 10−4 | — | — |
| rs1044773 | 0.00 | −0.20, 0.20 | — | — | −0.20 | −0.31, −0.08 | 8.0 × 10−4 | — | — |
| GRSf | 0.06 | −0.10, 0.21 | 0.01 | −0.08, 0.10 | −0.15 | −0.24, −0.06 | 1.4 × 10−3 | 1.39 | −10.34, 13.11 |
Abbreviations: CI, confidence interval; CPAMD8, C3 and PZP-like, α-2-macroglobulin domain containing 8; CRP, C-reactive protein; F2RL3, coagulation factor II (thrombin) receptor-like 3; GENOA, Genetic Epidemiology Network of Arteriopathy; GRS, genetic risk score; IL-6, interleukin-6; IL-18, interleukin-18; PZP, pregnancy zone protein; SIN3B, SIN3 transcription regulator family member B; SNP, single nucleotide polymorphism.
a Because results for log(CRP), log(IL-6), and fibrinogen were not statistically significant, P values are not presented.
b All of the instrument SNPs were located within 10 kilobases of the F2RL3 gene and satisfied the assumptions of Mendelian randomization in GENOA.
c β coefficient for the exposure (cg03636183) in the second stage of 2-stage least-squares regression analysis. In all models, results were adjusted for age, sex, plate, 4 principal components, 5 cell proportions, and random intercepts for family.
d A SNP identified as a methylation quantitative trait locus for cg03636183 in an independent cohort and in GENOA.
e Missing data for the Mendelian randomization results because of the violation of assumption 2.
f GRS = [(2 − rs2227341) + (2 − rs10418195) + (2 − rs773895) + rs7245967 + (2 − rs2981474)]/5. When the coded allele was negatively associated with the DNA methylation levels of cg03636183, we coded for the other allele by subtracting the allele dosage from 2.