The PTPN22 620W is associated with many autoimmune diseases that are characterized by a prominent humoral component

Since the original reports of the association of PTPN22 with type 1 diabetes and rheumatoid arthritis, a number of groups have confirmed these associations [9, 55-61]. The importance of replication in an independent sample collection should be emphasized, as the vast majority of candidate gene association studies fail to

Table 1 - Summary of PTPN22 associations with autoimmune diseases

Disease

cases

controls

First author

TT

TC

CC

TT

TC

CC

OR (allele)

OR (CT vs. CC)

OR (TT vs. CC)

Begovich

6

119

350

3

78

394

1.65 (1.24-2.20)

1.72 (1.25-2.36)

2.25 (0.56-9.07)

Begovich

21

241

578

9

143

774

2.13 (1.73-2.61)

2.26 (1.79-2.85)

3.12 (1.42-6.87)

Lee et al.

41

287

1085

12

221

1168

1.57 (1.32-1.86)

1.40 (1.15-1.70)

3.68 (1.92-7.04)

Orozco

8

155

663

7

139

890

1.45 (1.15-1.82)

1.50 (1.17-1.92)

1.53 (0.55-4.25)

Hinks

27

262

597

9

105

481

1.88 (1.51-2.35)

2.01 (1.56-2.60)

2.42 (1.15-5.07)

Zhernakova

2

40

109

4

84

440

1.79 (1.22-2.61)

1.92 (1.26-2.94)

2.02 (0.38-10.80)

Steer

12

72

218

1

61

312

2.05 (1.47-2.87)

1.69 (1.15-2.47)

17.17 (3.79-77.80)

Plenge

43

389

1081

16

187

671 pooled

1.30 (1.09-1.54) 1.75 (1.60-1.91)

1.29 (1.06-1.58) 1.72 (1.56-1.91)

1.67 (0.94-2.97) 3.05 (2.15-4.34)

BottinLN.Am 11 90 193 4 84 307 1.79 (1.33-2.40) 1.70 (1.21-2.41) 4.37 (1.50-12.72)

Bottinijtalian

Smyth

Zhernakova

Zheng

97

158 1077 226 290

0 18 4 8

323 84 186

205 1377 440 984 pooled

2.39 (1.08-5.31) 1.76 (1.52-2.03) 2.29 (1.71-3.07) 1.81 (1.42-2.31) 1.84 (1.66-2.05)

2.16 (0.94^.98) 1.81 (1.53-2.13) 2.22 (1.60-3.09) 1.77 (1.34-2.33) 1.84 (1.63-2.08)

2.84 (1.62-4.98) 5.84 (1.86-18.32) 3.82 (1.46-9.98) 3.54 (2.33-5.37)

Kyogoku Orozco

2

136 62

548 274

12 4

315 63

1634 445 pooled

1.53 (1.26-1.85) 1.45 (1.02-2.06) 1.51 (1.27-1.79)

1.29 (1.03-1.61) 1.60 (1.09-2.34) 1.36 (1.12-1.65)

5.22 (2.74-9.94) 0.81 (0.15-4.45) 3.73 (1.97-7.05)

Graves'

6

222 90 139

3

154 68 61

669 238 365 pooled

1.43 (1.17-1.76) 1.71 (1.25-2.35) 1.88 (1.40-2.54) 1.60 (1.38-1.85)

1.46 (1.16-1.84) 1.67 (1.16-2.40) 2.06 (1.48-2.86) 1.64 (1.39-1.95)

1.82 (0.84-3.93) 3.46 (1.16-10.35) 1.81 (0.46-7.14) 2.16 (1.21-3.88)

Hinks

16

166

479

9

105

481

1.53 (1.20-1.94)

1.59 (1.21-2.09)

1.79 (0.78-4.08)2

replicate [62]. The association of PTPN22 to disease susceptibility has been extended to other autoimmune diseases such as autoimmune thyroid disease [9, 10, 63] and systemic lupus [8, 61] and juvenile inflammatory arthritis [60]. However, neither multiple sclerosis [64] nor Crohn's disease [65] appear to be associated with the PTPN22 620W allele. In all associated diseases, inheritance fits best under a multiplicative genetic model: 620W/W homozygotes have a substantial increase in relative risk compared to heterozygotes. This observation is consistent with a threshold effect of the risk allele on signaling in T-cells. The results from a variety of case-control studies are summarized in Table 1.

Interestingly, the PTPN22 associated disorders (T1D, RA, SLE, and AITD) are also diseases that tend to cluster together in families, as discussed in the first sections of this review. Indeed, these PTPN22 associations have been replicated directly in such multiplex families [11]. In addition, all of these diseases are accompanied by a prominent humoral component. In some cases these autoantibodies are clearly pathogenic (Grave's disease and some lupus autoantibodies), whereas a direct pathogenic role for autoantibodies is less clear for RA, Hashimotos thyroiditis and T1D. Nevertheless, in all of these disorders, autoantibodies appear months or years prior to the onset of clinical disease. In view of the increased germinal centers and elevated immunoglobulin levels in the PEP knockout mouse [51], it is tempting to speculate that PTPN22 620W allele may predispose to the development of these autoan-tibodies. However, this issue has not yet been directly addressed. Specifically, there is no information on whether PTPN22 620W is associated with the development of the autoantibodies in the absence of clinical disease, or in contrast, whether PTPN22 might be associated with progression to overt autoimmunity rather than autoantibody development per se. These questions will require additional studies in the appropriate human populations.

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