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- Isine Bolstad, Anne, et al.
(författare)
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Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:6, s. 981-988
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogrens 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. less thanbrgreater than less thanbrgreater thanMethods 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. less thanbrgreater than less thanbrgreater thanResults 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. less thanbrgreater than less thanbrgreater thanConclusions 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.
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- Lundtoft, Christian, et al.
(författare)
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The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population
- 2024
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Ingår i: RMD Open. - 2056-5933. ; 10:2, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.
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