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Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjögren's syndrome in Scandinavian samples
  1. Anne Isine Bolstad1,2,
  2. Stephanie Le Hellard3,4,
  3. Gudlaug Kristjansdottir5,
  4. Lilian Vasaitis5,
  5. Marika Kvarnström6,
  6. Christopher Sjöwall7,
  7. Svein Joar Auglænd Johnsen8,
  8. Per Eriksson7,
  9. Roald Omdal8,
  10. Johan G Brun9,
  11. Marie Wahren-Herlenius6,
  12. Elke Theander10,
  13. Ann-Christine Syvänen11,
  14. Lars Rönnblom5,
  15. Gunnel Nordmark5,
  16. Roland Jonsson2
  1. 1Department of Clinical Dentistry – Periodontics, University of Bergen, Bergen, Norway
  2. 2Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
  3. 3Dr Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  4. 4Center of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  5. 5Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  6. 6Karolinska Institute, Stockholm, Sweden
  7. 7Rheumatology/AIR, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  8. 8Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
  9. 9Section for Rheumatology, Institute of Medicine, University of Bergen, Bergen, Norway
  10. 10Department of Rheumatology, Skåne University Hospital, Lund University, Malmö, Sweden
  11. 11Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  1. Correspondence to Anne Isine Bolstad, Department of Clinical Dentistry – Periodontics, University of Bergen, Aarstadveien 17, N-5009 Bergen, Norway; anne.bolstad{at}iko.uib.no

Abstract

Objectives Lymphotoxin β (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS.

Methods 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing.

Results Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS.

Conclusions A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

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Footnotes

  • Funding Funding for this study was received from the Western Norway Regional Health Authority, the Research Council of Norway, the Strategic Research Program at Helse Bergen, the Broegelmann Foundation, University of Bergen, Bergens forskningsstiftelse, University of Bergen, the Swedish Research Council, Stockholm County Council, the Göran Gustafsson Foundation, the Torsten and Ragnar Söderberg Foundation, the King Gustaf the Vth 80-year Foundation, Anna-Greta Crafoord Foundation, Malmö University Hospital Cancer Research Foundation, Vinnova, Vårdalstiftelsen, the Swedish Foundation for Strategic Research, the Swedish Rheumatism Association, Invest in Sweden Agency, KK-stiftelsen. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Ethics approval The study protocol was approved by the local committees of ethics in both Norway and Sweden, and the investigation has been conducted according to the principles expressed in the Declaration of Helsinki.

  • Patient consent Obtained.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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