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| 2. |
- Kozyrev, Sergey V, et al.
(författare)
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Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:2, s. 211-216
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.
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| 3. |
- Linga-Reddy, M. V. Prasad, et al.
(författare)
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A polymorphic variant in the MHC2TA gene is not associated with systemic lupus erythematosus
- 2007
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Ingår i: Tissue Antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 70:5, s. 412-414
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Tidskriftsartikel (refereegranskat)abstract
- Single-nucleotide polymorphisms (SNPs) in the major histocompatibility complex class II transactivator (MHC2TA) gene encoding the class II transactivator have been associated with multiple sclerosis, rheumatoid arthritis, and myocardial infarction in the Swedish population. We used a case-control approach to investigate the prevalence of a relevant variant in Swedish systemic lupus erythematosus (SLE) cohorts to determine whether SLE shares the same MHC2TA susceptibility allele as the other diseases. No differences were observed between cases and control subjects at either the allele or genotype levels. Furthermore, no significant correlations were found when comparing different clinical and serological SLE phenotypes. This particular polymorphism rs3087456 of the MHC2TA gene does not appear to influence genetic susceptibility to SLE in the Swedish population. We conclude that our data support neither allelic nor genotype association between the MHC2TA SNP and SLE.
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| 4. |
- Prokunina, Ludmila, et al.
(författare)
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A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans
- 2002
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 32:4, s. 666-669
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.
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| 5. |
- Wang, Ning, et al.
(författare)
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Serological Assessment for Celiac Disease in IgA Deficient Adults
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:4, s. 0093180-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet. Methods: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-even IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected. Results: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti- DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not. Conclusions: IgG anti- tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.
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| 6. |
- Nordmark, Gunnel, et al.
(författare)
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Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome
- 2009
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 10:1, s. 68-76
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjögren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 × 10−9. The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.
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| 7. |
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| 8. |
- Wang, Chuan, et al.
(författare)
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Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility
- 2013
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 14:4, s. 217-222
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Tidskriftsartikel (refereegranskat)abstract
- The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10−5). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10−3). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.
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| 9. |
- Pesonen, Erkki, et al.
(författare)
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Mannose-binding lectin as a risk factor for acute coronary syndromes.
- 2009
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 41, s. 591-598
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Tidskriftsartikel (refereegranskat)abstract
- Background. Mannose-binding lectin (MBL) is a multifunctional protein involved in innate immunity. We tested whether MBL and elevated viral and bacterial antibodies were risk factors for acute coronary events. Design. Controlled cohort study. Methods. A total of 354 patients with unstable angina pectoris (UA) or acute myocardial infarction (AMI) were compared with 334 paired controls. Results. Enterovirus titres were associated with increased risk of UA (odds ratio 10.04, P<0.001) and AMI (odds ratio 3.18, P=0.003), but titres did not correlate with either MBL concentration or genotype. Chlamydia pneumoniae heat shock protein 60 IgG concentrations were also associated with increased risk of UA (odds ratio 1.63, P=0.049). Compared to asymptomatic controls, patients had lower complement C3 serum concentrations (P<0.001), higher MBL serum concentration, and more frequently had MBL genotypes that determined high MBL levels (P<0.001). High MBL genotypes had odds ratios of 1.16 (P=0.010) for UA and 1.12 (P=0.007) for AMI. The elevation of MBL concentrations in the acute phase correlated with MBL concentrations after recovery (r=0.85, P<0.001). Conclusions. Elevated microbial titres, indicating an on-going inflammation, were associated with cardiovascular events. MBL might have a dual role both decreasing susceptibility to infections and increasing the risk of acute coronary syndromes.
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| 10. |
- Wang, Chuan, et al.
(författare)
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Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations
- 2013
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group: Open Access Hybrid Model Option B. - 1018-4813 .- 1476-5438. ; 21:9, s. 994-999
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.
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