Male Restricted Genetic Association of Variant R620W in PTPN22 with Psoriatic Arthritis

LETTER TO THE EDITOR

Male Restricted Genetic Association of Variant R620W in PTPN22 with Psoriatic Arthritis Journal of Investigative Dermatology (2006) 126, 936–938. doi:10.1038/sj.jid.5700179; published online 2 February 2006

TO THE EDITOR Protein tyrosine phosphatase N22 (PTPN22) is a key regulator of TCR signalling in memory/effector T lymphocytes (Hasegawa et al., 2004). A common, immunologically relevant missense mutation R620W (c.1858CT) has consistently been associated with several autoimmune diseases, for example, diabetes and rheumatoid arthritis (Begovich et al., 2004; Bottini et al., 2004). Recently, Nistor et al. (2005) reported lack of association of this variant in a large study group of psoriasis vulgaris families. These findings confirmed two smaller previous studies of (i) multiple autoimmune families with psoriasis phenotype (Criswell et al., 2005) and (ii) 279 patients with an early-onset form of chronic plaques psoriasis and 455 patients with psoriatic arthritis (PsA) (Hinks et al., 2005). In a further study on rheumatoid arthritis (Orozco et al., 2005b), differences regarding carriers of PTPN22*620W in clinical subgroups of patients were observed. As rheumatoid arthritis and PsA share some clinical similarities, we were interested in whether PTPN22*620W might be a relevant genetic factor in a subgroup of PsA patients as well. The patient sample with PsA as well as the control group has been described previously (Lascorz et al., 2005). In brief, the 375 PsA patients of German descent were recruited through four different rheumatological centers in Germany and the diagnosis was made by a board-certified rheumatologist according to the criteria of Moll and Wright (1973). Average age of onset for psoriasis vulgaris was 30.1713.0 years and diagnosis of PsA was made X3 years before recruitment

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Table 1. Genotype frequencies of PTPN22*R620W (c.1858C-T) in PsA patients and controls PTPN22*620 genotype C-C C-T and T-T

PsA patients1 (no. (%))

Healthy controls1 (no. (%))

281 (78.3)

299 (81.7)

78 (21.7)

67 (18.3)

w2 (1df)

1.326

P-value

0.250

1

Owing to genotyping rates of 95.7% in PsA patients and 97.1% in controls, the total number of genotypic data eligible for statistical analysis slightly differs from the total number of patients included. Individuals homozygous for the C allele were compared to individuals heterozygous and homozygous for the mutant T allele.

Abbreviations: PsA, psoriatic arthritis; PSORS1, psoriasis susceptibility locus 1

nor in controls significant deviation from Hardy–Weinberg equilibrium was found. To determine significant differences in genotype frequencies, statistics was based on 2  2 table comparing carriers homozygous for the wild-type allele with the group of heterozygous and homozygous risk allele carriers. To address the multiple testing problem and correct for the number of separate tests performed, we derived adjusted P-values using the permutation resampling method from the MULTTEST procedure with Fisher’s exact test for two-group comparisons in the SAS software package (version 9.1). The minor allele nt 1858T of variant R620W was not associated with susceptibility to PsA (Table 1), which is in accordance with previous studies (Hinks et al., 2005; Nistor et al., 2005). Association of the PTPN22 variant has been detected in a variety of autoimmune disorders, but it does not seem to be of equal importance for all complex diseases with a proposed autoimmune pathogenesis. Thus, only a minor or no relevance has been observed inter alia for multiple sclerosis, Crohn’s disease (van Oene et al., 2005)/ inflammatory bowel disease (Martin

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in 78% of patients. The control cohort consisted of 376 German (Caucasian) healthy blood donors without psoriasis vulgaris and no history or signs of inflammatory joint disease at the time of recruitment, when average age was 32710 years. Written informed consent was obtained from each patient and control proband before enrolment. The investigations were conducted according to the Declaration of Helsinki Principles. The medical ethical committee of the universities of Munster and of Erlangen had approved the described studies. We genotyped R620W with a Taqman assay on 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). Taqman genotypes could be confirmed through direct sequencing in a set of 24 randomly chosen probands. Sequences of primers were F: 50 -CCAG CTTCCTCAACCACAATAAATG-30 and R: 50 -CAACTGCTCCAAGGATAGATG ATGA-30 , sequences of minor groove binding probes were 50 - TCAGGTGTC CaTACAGG-30 and 50 -TCAGGTGTCCg TACAGG-30 , labelled with VICTM and 6-FAMTM, respectively. Neither in cases

U Hu¨ffmeier et al. PTPN22 in Psoriatic Arthritis

et al., 2005), psoriasis vulgaris, and ankylosing spondylitis (Orozco et al., 2005a), an inflammatory disease of the axial skeleton and peripheral joints showing some clinical overlap with PsA. Results for several diseases are inconclusive: for example, juvenile idiopathic arthritis (Hinks et al., 2005; Seldin et al., 2005; Viken et al., 2005). In coeliac disease, evidence for association to PTPN22*620W was identified only in a subgroup of patients with an early-onset form (Zhernakova et al., 2005). Therefore, we tested the hypothesis that PTPN22*620W might be a risk factor in a subgroup of patients carrying the major genetic risk factor for psoriatic skin disease at psoriasis susceptibility locus 1 (PSORS1) located at HLA-C or within its neighboring region. Owing to the extraordinary high linkage disequilibrium within this region, the disease-causing variant has not yet been identified. We stratified for a risk haplotype HCR*WWCC consisting of two variants of the a-helix coiled-coil rod homologue (CCHCR1 gene), as previously described (Asumalahti et al., 2003; Huffmeier et al., 2005c). HCR*WWCC is in such strong linkage disequilibrium with the HLA-Cw6 risk allele at PSORS1 that it can be used as an estimate of the risk allele (Asumalahti et al., 2003). After stratification for PSORS1 risk allele, we found no evidence for association with

PTPN22*620W neither in carriers nor in non-carriers of PSORS1 risk allele (Table 2). Next, we tested whether subgroups with certain clinical characteristics of PsA were associated with PTPN22*620W (Table 2). The patient group was stratified according to the following criteria: manifestation as oligo- (p5 joints) or polyarthritis, spinal involvement, erosive joint disease, and sex. No significant differences were observed for any of the features but for male sex. Interestingly, the proportion of male PsA patients in the PTPN22*620W carriers was significantly higher than in the subgroup of female patients (Padj ¼ 0.0065). This sex-specific association with PTPN22*620W was not biased by differences in disease manifestation, as male and female PsA patients did not differ significantly with regard to oligoor polyarticular involvement of peripheral joints, sacroiliitis/spondylitis, or onset of disease (data not shown). Interestingly, when using a similar stratification strategy in rheumatoid arthritis patients, a sex-specific trend was observed, with males being more prone to carry the risk allele (Orozco et al., 2005b). In that study, though, this effect was not significant after correction for multiple testing, whereas in a further rheumatoid arthritis study group association of R620W was not affected

by sex (van Oene et al., 2005). Interestingly, when we stratified an earlier described cohort of 375 single patients with an early-onset form of psoriasis vulgaris without signs of arthritis (Huffmeier et al., 2005a), we did not detect this sex-specific difference (Hu¨ffmeier et al., 2005b). These results might indicate a specificity of the PTPN22*620W association for joint manifestation in psoriasis. Certainly, this sex-specific effects of PTPN22*620W on arthritic disease susceptibility require further independent confirmation for PsA. However, the results of the present study already raise questions concerning possible underlying mechanisms. Known effects of estrogens on the enhancement of T-cell responses (Maret et al., 2003) might provide a hypothetical explanation as to why in females the genetic impact of PTPN22*620W as a reinforcing factor of T-cell receptor signaling might be less important for PsA manifestation than in males. A comparable sex-specific effect has been reported for a polymorphism of the cytosolic acid phosphatase as a susceptibility factor for female patients with diabetes mellitus type I (Bottini et al., 2002). To our knowledge, it has not been investigated yet if males are at higher risk in diseases other than rheumatoid arthritis that show association to PTPN22*620W (eg diabetes, etc).

Table 2. Distribution of genotypes in PsA patients after stratification for genetic markers at PSORS1 and clinical characteristics Phenotype PSORS1 risk allele

1

Poly-/oligoarthritis

1

Spinal involvement1

Erosive joint changes1

Sex1

Positive (no. (%))

Negative (no. (%))

Polyarthritis (no. (%))

Oligoarthritis (no. (%))

Positive (no. (%))

Negative (no. (%))

Positive (no. (%))

Negative (no. (%))

Male (no. (%))

Female (no. (%))

153 (80.5)

128 (75.7)

201 (77.6)

68 (82.9)

57 (79.2)

197 (78.5)

145 (75.5)

89 (83.2)

156 (72.6)

125 (86.8)

37 (19.5)

41 (24.3)

58 (22.4)

14 (17.1)

15 (20.8)

54 (21.5)

47 (24.5)

18 (16.8)

59 (27.4)

19 (13.2)

Genotype C-C C-T+T-T Praw-value

0.31

0.35

1.00

0.14

0.0016

Padj-value

0.79

0.83

1.00

0.46

0.0065

1

Owing to 95.7% genotyping rate and partly incomplete clinical documentation, the total number of genotypic data eligible for statistical analysis in each subgroup differed from the total number of patients included. PsA: psoriatic arthritis; PSORS1: psoriasis susceptibility locus 1; PSORS1 risk allele was inferred from HCR*WWCC haplotype at CCHCR1. After stratification for each of the traits, Fisher’s exact test was used to determine differences between CC versus CT and TT genotypes, Padj-values correspond to permutation adjusted P-values. Significant values are indicated in bold.

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U Hu¨ffmeier et al. PTPN22 in Psoriatic Arthritis

In summary, variant R620W of PTPN22 does not seem to play a major role in susceptibility to PsA in general, but if sex-specific differences are replicated, they suggests that it might be a relevant susceptibility factor in male patients. ACKNOWLEDGMENTS We are grateful to all patients and controls for participation in this study. We thank Verena Popp for excellent technical assistance. This work was supported in part by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft DFG, Tr 228/5-4 and Re 679/10-4) and from the Interdisciplinary Centre for Clinical Research (IZKF B32/A8) of the University of Erlangen-Nuremberg with a grant from The German Federal Ministry of Education and Research (Grant no. 01 KS 0002).

Ulrike Hu¨ffmeier1, Andre´ Reis1, Michael Steffens2, Jesu´s Lascorz1, Beate Bo¨hm3, Jo¨rg Lohmann4, Jo¨rg Wendler5, Heiko Traupe6, Wolfgang Ku¨ster7, Thomas F. Wienker2 and Harald Burkhardt3 1

Institute of Human Genetics, University Erlangen-Nuremberg, Erlangen, Germany; 2 Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Erlangen, Germany; 3Department of Internal Medicine III, Institute for Clinical Immunology and Rheumatology, University ErlangenNuremberg, Erlangen, Germany; 4Psoriasis Rehabilitation Hospital, Bad Bentheim, Erlangen, Germany; 5Rheumatologische Schwerpunktpraxis, Erlangen, Germany; 6 Department of Dermatology, University of Mu¨nster, Erlangen, Germany and 7TOMESA Clinics, Bad Salzschlirf, Erlangen, Germany. E-mail: [email protected]

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