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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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