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Table 5 Gene-environment interaction of HLA-SE alleles and smoking in individuals prior to diagnosis of RA stratified for the presence of autoantibodies against various citrullinated peptides compared with controls

From: Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis

   All   
HLA-SE Smoking Cases/controls OR (95% CI)   
None Never 41/173 1.00 (Ref)   
None Ever 78/162 2.03 (1.32–3.14)   
Any Never 76/125 2.57 (1.65–4.00)   
Any Ever 150/92 6.88 (4.48–10.56)   
Interaction      
AP    0.48 (0.43–0.55)   
RERI    3.28 (1.43–6.16)   
SI    2.26 (1.36–3.76)   
MI    P = 0.35   
   Anti-CCP2 positive Anti-CCP2 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 10/173 1.00 (Ref) 31/173 1.00 (Ref)
None Ever 26/162 2.77 (1.30–5.94) 52/162 1.79 (1.09–2.94)
Any Never 24/125 3.32 (1.53–7.19) 52/125 2.32 (1.41–3.83)
Any Ever 66/92 12.41 (6.09–25.28) 84/92 5.10 (3.14–8.26)
Interaction      
AP    0.59 (0.53–0.67)   0.39 (0.32–0.50)
RERI    7.31 (3.35–17.90)   1.98 (0.21–4.41)
SI    2.78 (1.49–5.19)   1.94 (1.03–3.66)
MI    P = 0.53   P = 0.55
   Anti-CCP-1/Fil307-324 positive Anti-CCP-1/Fil307-324 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 8/173 1.00 (Ref) 33/173 1.00 (Ref)
None Ever 18/162 2.40 (1.02–5.68) 60/162 1.94 (1.21–3.13)
Any Never 24/125 4.15 (1.81–9.55) 52/125 2.18 (1.33–3.57)
Any Ever 46/92 10.81 (4.90–23.88) 104/92 5.93 (3.72–9.45)
Interaction      
AP    0.49 (0.40–0.60)   0.47 (0.41–0.56)
RERI    5.26 (0.52–15.71)   2.80 (1.02–5.55)
SI    2.15 (1.11–4.16)   2.32 (1.26–4.28)
MI    P = 0.88   P = 0.30
   Anti-Fibβ36-52 positive Anti-Fibβ36-52 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 10/173 1.00 (Ref) 31/173 1.00 (Ref)
None Ever 22/162 2.35 (1.08–5.11) 56/162 1.93 (1.18–3.14)
Any Never 22/125 3.04 (1.39–6.66) 54/125 2.41 (1.47–3.97)
Any Ever 53/92 9.97 (4.84–20.51) 97/92 5.88 (3.65–9.48)
Interaction      
AP    0.56 (0.48–0.66)   0.43 (0.37–0.52)
RERI    5.57 (1.95–14.16)   2.54 (0.68–5.31)
SI    2.64 (1.31–5.34)   2.09 (1.15–3.77)
MI    P = 0.50   P = 0.48
   Anti-CEP-1/Eno5-21 positive Anti-CEP-1/Eno5-21 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 8/173 1.00 (Ref) 33/173 1.00 (Ref)
None Ever 20/162 2.67 (1.14–6.23) 58/162 1.88 (1.16–3.03)
Any Never 20/125 3.46 (1.47–8.11) 56/125 2.35 (1.44–3.83)
Any Ever 54/92 12.69 (5.79–27.81) 96/92 5.47 (3.42–8.75)
Interaction      
AP    0.60 (0.52–0.69)   0.41 (0.34–0.51)
RERI    7.56 (3.14–20.18)   2.24 (0.47–4.77)
SI    2.83 (1.44–5.58)   2.00 (1.10–3.66)
MI    P = 0.54   P = 0.51
   Anti-Fibβ62-81a (72) positive Anti-Fibβ62-81a ( 72) negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 2/173 1.00 (Ref) 39/173 1.00 (Ref)
None Ever 6/162 3.20 (0.64–16.10) 72/162 1.97 (1.26–3.08)
Any Never 16/125 11.07 (2.50–49.02) 60/125 2.13 (1.34–3.39)
Any Ever 19/92 17.86 (4.07–78.38) 131/92 6.32 (4.08–9.79)
Interaction      
AP    0.26 (0.02–0.48)   0.51 (0.46–0.59)
RERI    4.59 (–32.49−55.67)   3.21 (1.47–5.96)
SI    1.37 (0.65–2.90)   2.53 (1.42–4.52)
MI    P = 0.45   P = 0.18
   Anti-Fibβ62-81b (74) positive Anti-Fibβ62-81b (74) negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 3/173 1.00 (Ref) 37/173 1.00 (Ref)
None Ever 11/162 3.92 (1.07–14.29) 66/162 1.90 (1.21–3.00)
Any Never 11/125 5.07 (1.39–18.57) 65/125 2.43 (1.53–3.87)
Any Ever 32/92 20.06 (5.98–67.28) 109/92 5.54 (3.53–8.69)
Interaction      
AP    0.60 (0.49–0.73)   0.40 (0.33–0.49)
RERI    12.07 (−0.05–53.96)   2.20 (0.47–4.63)
SI    2.72 (1.28–5.79)   1.94 (1.11–3.41)
MI    P = 0.99   P = 0.57
   Anti-Fibα580-600 positive Anti-Fibα580-600 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 4/173 1.00 (Ref) 36/173 1.00 (Ref)
None Ever 5/162 1.34 (0.35–5.06) 72/162 2.14 (1.36–3.36)
Any Never 10/125 3.46 (1.06–11.28) 66/125 2.54 (1.59–4.05)
Any Ever 29/92 4.70 (1.44–15.40) 131/92 6.84 (4.38–10.70)
Interaction      
AP    0.72 (0.60–0.87)   0.46 (0.41–0.54)
RERI    9.84 (3.70–33.71)   3.17 (1.25–6.16)
SI    4.52 (1.37–14.87)   2.19 (1.30–3.67)
MI    P = 0.17   P = 0.45
   Anti-citC1359-369 positive Anti-citC1359-369 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 3/173 1.00 (Ref) 37/173 1.00 (Ref)
None Ever 11/162 3.92 (1.07–14.29) 66/162 1.90 (1.21–3.00)
Any Never 7/125 3.23 (0.82–12.73) 69/125 2.58 (1.63–4.09)
Any Ever 25/92 15.67 (4.61–53.29) 116/92 5.89 (3.77–9.23)
Interaction      
AP    0.61 (0.46–0.77)   0.41 (0.35–0.49)
RERI    9.52 (−1.11–43.03)   2.41 (0.62–4.97)
SI    2.85 (1.16–6.98)   1.97 (1.14–3.39)
MI    P = 0.79   P = 0.56
   Anti-Vim60-75 positive Anti-Vim60-75 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 5/173 1.00 (Ref) 36/173 1.00 (Ref)
None Ever 6/162 1.28 (0.38–4.28) 72/162 2.14 (1.36–3.36)
Any Never 13/125 3.60 (1.25–10.35) 63/125 2.42 (1.51–3.87)
Any Ever 19/92 7.14 (2.58–19.76) 131/92 6.84 (4.38–10.70)
Interaction      
AP    0.46 (0.24–0.70)   0.48 (0.42–0.55)
RERI    3.27 (−2.87–13.75)   3.28 (1.38–6.29)
SI    2.13 (0.72–6.36)   2.28 (1.34–3.88)
MI    P = 0.55   P = 0.37
   Anti-Fibα563-583 positive Anti-Fibα561-583 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 2/173 1.00 (Ref) 38/173 1.00 (Ref)
None Ever 10/162 5.34 (1.15–24.74) 68/162 1.86 (1.19-2-92)
Any Never 6/125 4.15 (0.82–20.91) 71/125 2.48 (1.58–3.91)
Any Ever 21/92 19.74 (4.53–86.07) 129/92 6.22 (4.01–9.64)
Interaction      
AP    0.57 (0.39–0.76)   0.46 (0.41–0.54)
RERI    11.25 (−10.52–71.35)   2.87 (1.10–5.54)
SI    2.50 (1.05–5.95)   2.22 (1.29–3.85)
MI    P = 0.90   P = 0.33
   Anti-Vim2-17 positive Anti-Vim2-17 negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 1/173 1.00 (Ref) 40/173 1.00 (Ref)
None Ever 5/162 5.34 (0.62–46.20) 73/1162 1.95 (1.25–3.03)
Any Never 2/125 2.77 (0.25–30.87) 74/125 2.56 (1.64–4.01)
Any Ever 17/92 31.97 (4.19–244.04) 133/92 6.25 (4.05–9.66)
Interaction      
AP    0.77 (0.54–0.99)   0.47 (0.42–0.54)
RERI    24.86 (−16.43–230.81)   2.74 (0.96–5.38)
SI    5.07 (1.42–18.16)   2.02 (1.23–3.54)
MI    P = 0.56   P = 0.45
   Any ACPA positive Any ACPA negative
HLA-SE Smoking Cases/controls OR (95% CI) Cases/controls OR (95% CI)
None Never 23/173 1.00 (Ref) 16/173 1.00 (Ref)
None Ever 42/162 1.95 (1.12–3.39) 35/162 2.34 (1.25–4.38)
Any Never 52/125 3.13 (1.82–5.38) 25/125 2.16 (1.11–4.22)
Any Ever 88/92 7.19 (4.26–12.15) 53/92 6.23 (3.37–11.51)
Interaction      
AP    0.43 (0.37–0.52)   0.44 (0.35–0.56)
RERI    3.11 (0.77–6.90)   2.73 (0.21–6.81)
SI    2.01 (1.15–3.52)   2.09 (1.02–4.29)
MI    P = 0.65   P = 0.62
  1. OR for the development of RA. Attributable proportion due to interaction (AP), relative excess due to interaction (RERI), synergy index (SI), and multiple interaction (MI). HLA-SE= HLA shared epitope, OR= odds ratio, CI= confidence intervals, anti-CCP2=anti-cyclic citrullinated peptide antibodies, anti CEP-1/Eno5-21= antibodies against α-Enolase, anti-citC1359-369= antibodies against collagen type II aa 359-369 with two citrulline residues, anti- Fibα580-600=antibodies against fibrinogen (Fib) Fibα580-600, anti-Fibα561-583= antibodies against Fibα561-583, anti- Fibβ62-81a(72)=antibodies against Fibβ62-81a(72), anti-Fibβ62-81b(74)= antibodies against Fibβ62-81b(74), anti-Fibβ36-52= antibodies against Fibβ36-52, anti- CCP-1/Fil307-324= antibodies against filaggrin, anti- Vim60-75= antibodies against vimentin (Vim)60-75, anti-Vim2-17= antibodies against Vim 2-17, ACPA=anti-citrullinated peptide/protein antibody.
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Arthritis Research & Therapy

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