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The T Cell Regulator Gene SH2D2A Contributes to the Genetic Susceptibility of Multiple Sclerosis

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The T Cell Regulator Gene SH2D2A Contributes to the Genetic Susceptibility of Multiple Sclerosis Genes and Immunity (2001) 2, 263–268 2001 Nature Publishing Group All rights reserved 1466-4879/01 $15.00 www.nature.com/gene The T cell regulator gene SH2D2A contributes to the genetic susceptibility of multiple sclerosis K-Z Dai1, HF Harbo1, EG Celius2, A Oturai3, PS Sørensen3, LP Ryder4, P Datta4, A Svejgaard4, J Hillert5, S Fredrikson5, M Sandberg-Wollheim6, M Laaksonen7, K-M Myhr8, H Nyland8, F Vartdal1 and A Spurkland1 1Institute of Immunology, The National Hospital, N-0027 Oslo, Norway; 2Department of Neurology, Ulleva˚l Hospital, Oslo, Norway; Departments of 3Neurology and 4Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 5Department of Neurology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden; 6Department of Neurology, Lund University Hospital, Lund, Sweden; 7Turku Immunology Centre and Department of Virology, University of Turku, Turku, Finland; 8Department of Neurology, Haukeland Hospital, Bergen, Norway The T cell specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the control of T cell activation. The gene is located in the 1q21 region, which has been implicated in susceptibility to experimental allergic encephalomyelitis in the mouse. We therefore evaluated whether a polymorphic GA repeat (GA13–GA33) within the promoter region of the SH2D2A gene shows association to multiple sclerosis (MS). The frequency of the short alleles GA13–16 was increased among 313 Norwegian MS patients compared to 277 healthy controls (0.332 vs 0.249, OR 1.5, Pc = 0.03). Transmission disequilibrium analysis in 146 Scandinavian families with at least two affected sibs showed increased transmission of GA16 to MS patients. No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed. After activation of naive CD4+ T cells, T cells homozygous for MS associated short alleles displayed lower level of TSAd ex vivo than T cells carrying at least one long allele, which were not associated to MS. Since the SH2D2A protein modulates T cell activation, this may be a mechanism for how short SH2D2A alleles confer susceptibility to develop MS. Genes and Immunity (2001) 2, 263–268. Keywords: adapter protein; signal transduction; T cell; genetic susceptibility; multiple sclerosis Introduction SH2D2A gene.9 Such length polymorphisms in the regu- latory regions of genes have been implied in the genetic Multiple sclerosis (MS) is a chronic inflammatory disease susceptibility to diseases.15–17 We therefore studied of the central nervous system. Both environmental and whether the SH2D2A gene contributes to the genetic sus- 1 genetic factors contribute to the disease. Several genome- ceptibility to MS by analyzing unrelated Norwegian MS wide screenings have suggested that over 20 genetic patients and controls, as well as Scandinavian families 2–6 regions could encompass susceptibility genes, but the with at least two affected siblings. Our results indicate only genetic factor which firmly has been shown to con- that short alleles of the SH2D2A gene contribute to the 7 tribute to MS is HLA. genetic susceptibility to develop MS. Interestingly, we 8 Recently, we cloned the cDNA as well as the SH2D2A also found that the MS associated short alleles confer 9 gene encoding a T cell specific adapter protein (TSAd), lower expression of TSAd in activated T cells than the which appears to be involved in inhibiting early T cell long alleles not associated with MS. signaling events.10 The SH2D2A gene is located close to the CD1 region on chromosome 1q21.9 This region con- fers susceptibility to develop chronic allergic encephalo- Results myelitis11 and viral induced encephalomyelitis12 as well 13 as chronic collagen induced arthritis in the mouse (as MS is associated with short alleles of the GA repeat 14 reviewed in Holmdahl ). A variable number of tandem in the SH2D2A promoter repeat (VNTR) is located in the promoter region of the Length polymorphisms in promoter regions have been shown to modulate the expression of the accompanying gene,15,16,18 as well as the genetic susceptibility to various Correspondence: Dr A Spurkland, Institute of Immunology, The National diseases.15–17 The SH2D2A gene is located in a genetic Hospital, N-0027 Oslo, Norway. E-mail: anne.spurklandȰlabmed.uio.no region, which has been implicated in the genetic suscepti- The project has received financial support from Statens La˚nekasse, bility to EAE in the mouse. We therefore postulated that EU-Commission (Project no. BMH4-CT97–2422), the Health and the GA13–33 repeat polymorphism in the SH2D2A pro- Rehabilitation Research Fund, Norwegian Research Council (NFR 9 project: 129081/310), Odd Fellow MS Society, Medinnova, and the moter region, which has a characteristic bimodal fre- MS Society of A˚ lesund. quency distribution (Figure 1), could confer susceptibility Received 22 March 2001; revised and accepted 1 June 2001 to develop MS. Multiple sclerosis and the SH2D2A gene K-Z Dai et al 264 Table 2 Transmission disequilbrium of SH2D2A promoter alleles in 146 Scandinavian MS sib pairs ␹2 a GA repeat Observed Expected ldf P alleles GA13 49 55 2.10 NS GA14 1 1 0.06 NS GA16 180 159 17.10 0.00004 GA17 14 11 3.09 NS GA18 5 5 0.01 NS GA19 4 2 3.64 NS GA20 26 35 7.84 0.005 GA21 16 17 0.17 NS GA22 119 119 0.01 NS GA23 115 119 0.65 NS GA24 55 60 1.61 NS GA25 16 17 0.12 NS GA26 2 2 0.33 NS GA27 3 2 0.60 NS GA30 0 1 3.42 NS GA31 1 1 0.06 NS Figure 1 Two modal frequency distribution of SH2D2A GA repeat GA33 2 1 1.82 NS alleles among 277 healthy controls and 313 MS patients in Norway. ␹2 = = Overall 16df 39.07 P 0.001 We first examined the distribution of the SH2D2A a␹2 values presented are calculated on the basis of probability alleles among 313 Norwegian MS patients and 277 values for expected transmissions, according to the trans- Norwegian healthy controls. The frequency of short mission/disequilibrium test for uncertain-haplotype trans- mission.27 The ␹2 values are therefore not directly comparable to (GA13–16) repeats was increased among MS patients (0.332 28 = traditional TdT test. When performing TdT test with the 59 famil- vs 0.249; OR 1.5; Pc 0.03; Table 1; Figure 1). Accordingly, ies with one or two parents present, the GA16 allele was transmitted 2 the frequency of short GA13–16 homozygotes was 35 times, and not transmitted 15 times (␹ = 8.0, P Ͻ 0.005), whereas increased among the MS patients (12% vs 6%; OR 2.0; P the GA20 was transmitted four times, and not transmitted 12 times = (␹2 = 4.0, P Ͻ 0.05). 0.025; Table 1), while the frequency of the long GA17–33 homozygotes was decreased (45% vs 56%; OR 0.6; P = 0.01; Table 1). The frequency of GA13–16 homozygotes was higher among HLA-DR2+ patients than HLA-DR2− ted one patient from each of the 92 Swedish and Danish patients (14% (25/179) vs 9% (10/116)). This difference sibling pairs. The frequency of GA13–16 alleles among however did not reach statistical significance. these unrelated patients was 0.385 compared to 0.302 We then performed a transmission disequilibrium test among 158 unrelated Swedish and Danish controls (OR of the SH2D2A alleles in 146 Scandinavian MS sib pair 1.4, P = 0.06). Correspondingly, 16% of the patients were families with two affected sibs. The overall transmission homozygous for GA13–16 alleles compared to 7% among of GA repeat alleles among the patients was skewed the controls (OR 2.6, P = 0.03). Thus, although statistically ␹2 = ( 16df 39.07; P 0.001). The short GA16 allele made the borderline, the strength of association of MS to GA13–16 largest contribution to the overall ␹2 statistic (Table 2). alleles as assessed by OR among the Swedish and Danish The transmission distortion was independent of the sex MS patients were comparable to that observed in the of the parent (data not shown). When the analysis was Norwegian case-control material. repeated with alleles grouped into short or long alleles, the short GA13–16 alleles were significantly more often Linkage analysis of the SH2D2A chromosomal region ␹2 = transmitted than the long alleles ( 1df 4.77; P 0.03). 1q21 In order to assess whether the observed transmission To investigate whether the observed association to distortion was mainly due to the Norwegian contribution SH2D2A alleles was due to linkage disequilibrium with to the Scandinavian sibling material, we randomly selec- another disease contributing gene in the vicinity of Table 1 Distribution of short (GA13–16) and long (GA17–28) SH2D2A GA promoter alleles and the corresponding genotypes among Norwegian MS patients and controls SH2D2A alleles and genotypes Norwegian OR 95% CI ␹2 MS patients Controls = = GA13–16 2n 626 2n 554 Pc 0.332 0.249 1.5 1.2–2.0 9.4 0.03 n = 313 n = 277 P Homozygotes GA13–16 12% 6% 2.0 1.1–3.9 5.05 0.025 Heterozygotes GA13–16/GA17–28 43% 38% 1.3 0.9–1.8 1.48 NS Homozygotes GA17–28 45% 56% 0.6 0.5–0.9 6.62 0.010 Genes and Immunity Multiple sclerosis and the SH2D2A gene K-Z Dai et al 265 SH2D2A, we performed a multi-point linkage analysis of a region extending approximately 15 cM to each side of the SH2D2A locus among the Scandinavian sib pair fam- ilies using four additional markers. Only a very weak positive LOD score was observed for the SH2D2A locus itself. None of the four other markers in the SH2D2A region on 1q21 tested in the families showed evidence of transmission distortion in MS patients (figure not shown).
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