Gene–environment interaction of human leukocyte antigen shared epitope (HLA-SE) and smoking in the Nurses’ Health Studies
| HLA-SE | Smoking status | All RA | Seropositive RA | Seronegative RA |
| OR (95% CI)* | OR (95% CI)†‡ | OR (95% CI)†§¶ | ||
| None | Never | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| None | Ever | 0.99 (0.65 to 1.51) | 1.05 (0.66 to 1.68) | 1.04 (0.64 to 1.69) |
| Any | Never | 1.65 (1.05 to 2.61) | 1.78 (1.08 to 2.95) | 1.18 (0.67 to 2.08) |
| Any | Ever | 2.14 (1.39 to 3.29) | 2.94 (1.84 to 4.69) | 1.23 (0.72 to 2.10) |
| Additive interaction: | ||||
| AP (95% CI) | 0.23 (−0.14 to 0.61) | 0.38 (0.05 to 0.70) | 0.004 (−0.69 to 0.70) | |
| p For interaction | padd = 0.23 | padd = 0.02 | padd = 0.99 | |
| RERI | 0.49 (−0.35 to 1.33) | 1.10 (−0.02 to 2.22) | 0.005 (−0.85 to 0.86) | |
| Synergy Index | 1.77 (0.50 to 6.25) | 2.32 (0.72 to 7.47) | 1.02 (0.02 to 47.34) | |
| Multiplicative interaction: | ||||
| p For interaction | pmulti = 0.38 | pmulti = 0.18 | pmulti = 1.00 | |
| OR (95% CI)* | OR (95% CI)†‡ | OR (95% CI) | ||
| None | ⩽10 pack-years smoking | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| None | >10 pack-years smoking | 1.10 (0.73 to 1.67) | 1.08 (0.67 to 1.72) | 1.16 (0.72 to 1.89) |
| Any | ⩽10 pack-years smoking | 1.58 (1.08 to 2.33) | 1.72 (1.13 to 2.61) | 1.09 (0.68 to 1.77) |
| Any | >10 pack-years smoking | 2.75 (1.75 to 4.31) | 3.61 (2.26 to 5.78) | 1.45 (0.81 to 2.56) |
| Additive interaction: | ||||
| AP (95% CI) | 0.39 (0.08 to 0.69) | 0.50 (0.24 to 0.77) | 0.13 (−0.49 to 0.75) | |
| p For interaction | padd = 0.01 | padd<0.001 | padd = 0.68 | |
| RERI | 1.06 (−0.06 to 2.17) | 1.82 (0.35 to 3.30) | 0.19 (−0.75 to 1.13) | |
| Synergy index | 2.54 (0.81 to 7.97) | 3.30 (1.06 to 10.33) | 1.74 (0.07 to 42.22) | |
| Multiplicative interaction: | ||||
| p For interaction | pmulti = 0.14 | pmulti = 0.05 | pmulti = 0.74 | |
padd is the p value for the attributable proportion due to interaction, pmulti is the p value for multiplicative interaction term between binary smoking variable and binary HLA-SE genotype with 1 degree of freedom.
*Conditional logistic regression, adjusting for parity, breast feeding and menstrual irregularity, and age at menarche, menopausal status and postmenopausal hormone use. †Unconditional logistic regression adjusting for year of birth, parity, breast feeding and menstrual irregularity, and age at menarche, menopausal status and postmenopausal hormone use. ‡Seropositive RA cases and all controls; §seronegative RA cases and all controls.
AP, attributable proportion due to interaction, an index of additive interactions between binary smoking variable and binary HLA-SE genotype; RA, rheumatoid arthritis; RERI, relative excess risk due to interaction.