title: Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Dentistry--Periodontics, University of Bergen, Bergen, Norway. anne.bolstad@iko.uib.no
authors.forename: Anne Isine
authors.initials: AI
authors.lastname: Bolstad
authors.forename: Stephanie
authors.initials: S
authors.lastname: Le Hellard
authors.forename: Gudlaug
authors.initials: G
authors.lastname: Kristjansdottir
authors.forename: Lilian
authors.initials: L
authors.lastname: Vasaitis
authors.forename: Marika
authors.initials: M
authors.lastname: Kvarnström
authors.forename: Christopher
authors.initials: C
authors.lastname: Sjöwall
authors.forename: Svein Joar Auglænd
authors.initials: SJ
authors.lastname: Johnsen
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Roald
authors.initials: R
authors.lastname: Omdal
authors.forename: Johan G
authors.initials: JG
authors.lastname: Brun
authors.forename: Marie
authors.initials: M
authors.lastname: Wahren-Herlenius
authors.forename: Elke
authors.initials: E
authors.lastname: Theander
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Roland
authors.initials: R
authors.lastname: Jonsson
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000276:immunology; D053308:Lymphotoxin-beta / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012469:Salivary Glands / Q000276:immunology; D012859:Sjogren's Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D013548:Sweden / Q000453:epidemiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
chemical_list: D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D014409:Tumor Necrosis Factor-alpha