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Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogren's syndrome in Scandinavian samples

Bolstad, Anne Isine; Le Hellard, Stephanie; Kristjansdottir, Gudlaug; Vasaitis, Lilian; Kvarnstrom, Marika; Sjowall, Christopher; Johnsen, Svein Joar Auglaend; Eriksson, Per; Omdal, Roald and Brun, Johan G., et al. (2012) In Annals of the Rheumatic Diseases 71(6). p.981-988
Abstract
Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogren'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 alpha (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... (More)
Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogren'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 alpha (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/TNF alpha 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. (Less)
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published
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Annals of the Rheumatic Diseases
volume
71
issue
6
pages
981 - 988
publisher
British Medical Association
external identifiers
  • wos:000303756400033
  • scopus:84860918960
ISSN
1468-2060
DOI
10.1136/annrheumdis-2011-200446
language
English
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yes
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180bb2f2-6327-4a52-878c-87123f91a1fe (old id 2826432)
date added to LUP
2012-07-03 10:26:38
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2017-09-10 03:52:41
@article{180bb2f2-6327-4a52-878c-87123f91a1fe,
  abstract     = {Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogren'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 alpha (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/TNF alpha 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.},
  author       = {Bolstad, Anne Isine and Le Hellard, Stephanie and Kristjansdottir, Gudlaug and Vasaitis, Lilian and Kvarnstrom, Marika and Sjowall, Christopher and Johnsen, Svein Joar Auglaend and Eriksson, Per and Omdal, Roald and Brun, Johan G. and Wahren-Herlenius, Marie and Theander, Elke and Syvanen, Ann-Christine and Ronnblom, Lars and Nordmark, Gunnel and Jonsson, Roland},
  issn         = {1468-2060},
  language     = {eng},
  number       = {6},
  pages        = {981--988},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogren's syndrome in Scandinavian samples},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2011-200446},
  volume       = {71},
  year         = {2012},
}