HLA class II associated risk and protection against multiple sclerosis—a Finnish family study

Laaksonen, Mikko; Pastinen, Tomi; Sjöroos, Minna; Kuokkanen, Satu; Ruutiainen, Juhani; Sumelahti, Marja Liisa; Reijonen, Helena; Salonen, R.; Wikström, Juhani; Panelius, M.; Partanen, Jukka; Tienari, Pentti J.; Ilonen, Jorma

doi:10.1016/s0165-5728(01)00456-8

Cited by 71 publications

(56 citation statements)

References 33 publications

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“…Genotyping The methods and the resolutions for the HLA DQB1 'full house' for the DQA1 and DRB1*04 typing were described earlier [27][28][29]. The INS −23 HphI and the CTLA4+49 polymorphisms were analysed using PCR and a lanthanide-labelled oligonucleotide hybridisation method [27,30].…”

Section: Methodsmentioning

confidence: 99%

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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Aims/hypothesis: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. Subjects and methods: We analysed the effect of HLA class II, insulin (INS; −23 HphI variant) and cytotoxic T-lymphocyteassociated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies ). Those who developed betacell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). Results: IAA emerged at a higher rate in children with the −23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. Conclusions/interpretation: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.

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Section: Methodsmentioning

confidence: 99%

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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“…The genotypes obtained with the two methods were 100% identical. The methods for the HLA-DQB1 'full house' and for DQA1 and DRB1*04 typing have been described [36][37][38]. For the gene-gene interaction analysis in the case-control material, HLA genotypes were grouped among cases according to the presence or absence of the two major HLA risk haplotypes, as follows: HLA DR3-DQ2/DR4-DQ8, DR4-DQ8/non-DR3-DQ2, DR3-DQ2/ non-DR4-DQ8, non-DR4-DQ8/non-DR3-DQ2.…”

Section: Genotypingmentioning

confidence: 99%

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

et al. 2006

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Aims/hypothesis: We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cellspecific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset. Subjects and methods: A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n=574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case-control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms. Results: The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio=4.6, 95% CI 2.4-9.0; p=0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5-11.6; and 1.6, 95% CI 1.1-2.4, respectively; p=0.003). The strong effect of PTPN22 on disease susceptibility (p=2.1×10 −8

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“…1 In the present study, 59% of the patients in the Bothnia families were HLA-DR2 positive, which matches well with previous studies from Finland. 41,42 Taken together, subtle differences in the clinical and demographic profile have been found in the Southern Ostrobothnian patients, but these do not allow us to delineate any distinct subtype of MS characteristic to this region.…”

Section: Genes and Immunitymentioning

confidence: 99%

“…28 HLA-DR2 typing was based on allele-specific PCR or hybridization with sequence-specific oligonucleotide probes using the previously described protocols. 41,48 Sequencing Eight alleles were sequenced for the whole length of the STR and 77 additional alleles were sequenced for the STR-A. The whole STR sequencing was accomplished via cloning of the PCR-amplified STR-long and its shorter fragments generated with alternate combinations of the previously published primers 17,27,28 and by digestion of the STR-long into two fragments with SphI.…”

Section: Genotypingmentioning

confidence: 99%

Linkage disequilibrium between the MBP tetranucleotide repeat and multiple sclerosis is restricted to a geographically defined subpopulation in Finland

et al. 2003

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We have previously found evidence for linkage as well as allelic and haplotype association between the myelin basic protein (MBP) gene and multiple sclerosis (MS). These findings have, however, not been reproduced in other populations. Here, we have analyzed association between MBP and MS in a new set of 349 Finnish triad families. Families with a parent born in the Southern Ostrobothnian region in western Finland (Bothnia families, n ¼ 98) were analyzed as a separate group since our previous studies included a high proportion of patients and families from this high-incidence region. Other families (n ¼ 251) were collected at five hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia families, the previously detected associations with the 1.27 kb allele and haplotype 1.27-B10 were confirmed (P ¼ 0.01 and 0.02, respectively), whereas in the other families there was not even a trend toward association. These results demonstrate a geographic/genealogical restriction in the association between MS and the MBP short tandem repeat, highlight the importance of genealogical information in genetic studies of complex traits, and may provide an explanation why the association has not been found in many other populations.

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HLA class II associated risk and protection against multiple sclerosis—a Finnish family study

Cited by 71 publications

References 33 publications

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

Linkage disequilibrium between the MBP tetranucleotide repeat and multiple sclerosis is restricted to a geographically defined subpopulation in Finland

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