E x t e n d e d r e p o r t Pack-years smoking HLA-SE 0 (10 1 (10 2 (10 0 .10 1 .10 2 .10 Additive: AP1 (95% CI) p For interaction RERI Synergy index AP2 (95% CI) p For interaction RERI Synergy index Multiplicative: p For interaction1 All RA 119/161 86/94 32/19 86/103 78/46 24/6 Pack-years HLA-SE smoking None (10 None 10 to 20 None .20 Any (10 Any 10 to 20 Any .20 Additive: AP1 (95% CI) p For interaction RERI Synergy index Multiplicative: p For interaction Additive: AP2 (95% CI) p For interaction RERI Synergy index Multiplicative: p For interaction 58 Table 4 Gene–environment interaction between HLA-SE (none, single and double copies) and heavy smoking in all rheumatoid arthritis (RA) groups and in groups stratified by serological status in the Nurses’ Health Studies Cases/controls OR* (95% CI) OR{ (95% CI) Cases/controls OR{ (95% CI) Seropositive RA Seronegative RA Cases/controls OR1 (95% CI) 1.00 (reference) 1.00 (reference) 64/161 1.26 (0.85 to 1.88) 1.33 (0.88 to 2.00) 52/94 2.61 (1.37 to 4.97) 2.96 (1.51 to 5.80) 25/19 1.13 (0.75 to 1.69) 1.07 (0.70 to 1.62) 44/103 2.26 (1.42 to 3.62) 2.24 (1.38 to 3.62) 57/46 5.43 (2.14 to 13.77) 6.60 (2.49 to 17.46) 18/6 0.39 (0.05 to 0.72) 0.38 (0.03 to 0.73) 0.02 0.04 0.88 (20.11 to 1.86) 0.84 (20.16 to 1.85) 3.26 (0.52 to 20.25) 3.15 (0.48 to 20.54) 0.50 (20.03 to 1.02) 0.54 (0.05 to 1.04) 0.06 0.03 2.70 (22.34 to 7.73) 3.57 (22.75 to 9.90) 2.56 (0.63 to 10.40) 2.77 (0.69 to 11.06) 0.13 0.20 ,0.001 0.07 0.07 1.00 (reference) 1.36 (0.87 to 2.15) 3.56 (1.81 to 7.02) 1.08 (0.68 to 1.73) 3.14 (1.91 to 5.17) 7.47 (2.77 to 20.11) 0.54 (0.26 to 0.82) 1.70 (0.29 to 3.11) 4.81 (0.71 to 32.54) 0.51 (20.03 to 1.06) 3.83 (23.59 to 11.24) 2.45 (0.62 to 9.72) 55/161 34/94 7/19 42/103 21/46 6/6 0.98 0.11 0.52 1.00 (reference) 1.08 (0.65 to 1.79) 1.21 (0.47 to 3.08) 1.16 (0.72 to 1.89) 1.25 (0.67 to 2.32) 2.97 (0.90 to 9.79) 0.01 (20.75 to 0.77) 0.01 (20.94 to 0.97) 1.06 (0.02 to 54.35) 0.54 (20.12 to 1.20) 1.60 (22.00 to 5.20) 5.32 (0.11 to 252.71) *Conditional logistic regression. {Conditional logistic regression, adjusting for parity, breast feeding and menstrual irregularity, and age at menarche, menopausal status and postmenopausal hormone use at diagnosis. {Unconditional logistic regression adjusting for year of birth, parity, breast feeding and menstrual irregularity, and age at menarche, menopausal status and postmenopausal hormone use at blood draw and at diagnosis. 1p Value calculated from HLA-SE6pack-years interaction term. AP, attributable proportion due to interaction, an index of additive interactions between binary smoking variable and binary HLA-SE genotype; RERI, relative excess risk due to interaction. copy of HLA-SE.19 This finding suggests that these two important risk factors may interact along one or more biological pathways.29 The statistical interaction between smoking and HLA-SE alleles in CCP-positive RA is consistent with the hypothesis that cigarette smoking modulates the immunogenicity of citrulline and related peptides in individuals with specific HLA alleles. This hypothesis has been strengthened by demonstration that smoking can cause citrullination of peptides in lung macrophages19 and is associated with an increased expression of peptidyl arginine deiminase 2 (PADI2) in bronchoalveolar cells.33 In HLA-DRB1 0401 transgenic mice, citrullination of certain peptides increases binding to HLA class II molecules with the SE, triggering immune responses to citrullinated peptides.34 Table 5 Gene–environment interaction between HLA-SE (none, any) and pack-years of smoking ((10, 10–20, .20) in all rheumatoid arthritis (RA) groups and in groups stratified by serological status in the Nurses’ Health Studies Seropositive RA Seronegative RA Cases/controls OR{ (95% CI) Cases/controls OR{ (95% CI) All RA 119/161 25/33 61/70 118/113 29/12 73/40 Cases/controls OR* (95% CI) 1.00 (reference) 0.98 (0.54 to 1.77) 1.22 (0.78 to 1.91) 1.49 (1.03 to 2.17) 3.42 (1.60 to 7.28) 2.50 (1.54 to 4.07) OR{ (95% CI) 1.00 (reference) 1.04 (0.56 to 1.93) 1.13 (0.71 to 1.80) 1.58 (1.08 to 2.32) 3.55 (1.62 to 7.78) 2.52 (1.53 to 4.14) 0.57 (0.20 to 0.94) 0.003 1.94 (20.61 to 4.49) 5.10 (0.72 to 36.36) 0.54 (0.14 to 0.94) 0.008 1.93 (20.81 to 4.66) 4.09 (0.74 to 22.56) 0.09 0.33 0.32 (20.05 to 0.68) 0.09 0.79 (20.36 to 1.93) 2.10 (0.65 to 6.80) 0.32 (20.05 to 0.70) 0.09 0.81 (20.37 to 1.99) 2.15 (0.64 to 7.23) 0.13 0.30 64/161 15/33 29/70 77/113 21/12 54/40 0.003 0.13 0.002 0.09 *Conditional logistic regression. {Conditional logistic regression, adjusting for smoking (pack-years), parity, breast feeding and menstrual irregularity, and age at menarche, menopausal status and postmenopausal hormone use at diagnosis. {Unconditional logistic regression adjusting for year of birth, smoking (pack-years), parity, breast feeding and menstrual irregularity, and age at menarche, menopausal status and postmenopausal hormone use at blood draw and at diagnosis. AP, attributable proportion due to interaction, an index of additive interactions between binary smoking variable and binary HLA-SE genotype; RERI, relative excess risk due to interaction. 1.00 (reference) 1.14 (0.57 to 2.26) 1.04 (0.61 to 1.79) 1.72 (1.13 to 2.60) 4.31 (1.97 to 9.42) 3.39 (2.02 to 5.69) 0.57 (0.20 to 0.95) 2.46 (20.81 to 5.72) 3.89 (0.86 to 17.64) 0.48 (0.17 to 0.79) 1.63 (0.04 to 3.22) 3.16 (0.89 to 11.21) 55/161 10/33 32/70 41/113 8/12 19/40 0.25 0.39 0.98 0.95 1.00 (reference) 0.93 (0.43 to 2.04) 1.27 (0.74 to 2.17) 1.09 (0.68 to 1.77) 1.76 (0.67 to 4.64) 1.35 (0.71 to 2.57) 0.42 (20.29 to 1.13) 0.74 (21.06 to 2.53) 31.55 (0.00 to 2.072E19) 20.01 (20.80 to 0.78) 20.02 (21.07 to 1.04) 0.96 (0.05 to 19.07) Ann Rheum Dis 2010;69:54–60. doi:10.1136/ard.2008.102962