The inheritance of resistance alleles in multiple sclerosis.
Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identif...
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Public Library of Science (PLoS)
2007-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.0030150&type=printable |
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| author | Sreeram V Ramagopalan Andrew P Morris David A Dyment Blanca M Herrera Gabriele C DeLuca Matthew R Lincoln Sarah M Orton Michael J Chao A Dessa Sadovnick George C Ebers |
| author_facet | Sreeram V Ramagopalan Andrew P Morris David A Dyment Blanca M Herrera Gabriele C DeLuca Matthew R Lincoln Sarah M Orton Michael J Chao A Dessa Sadovnick George C Ebers |
| author_sort | Sreeram V Ramagopalan |
| collection | DOAJ |
| description | Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex-associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex-associated susceptibility. |
| format | Article |
| id | doaj-art-ad8d63e5ccb14b6095f3b074af48426f |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2007-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-ad8d63e5ccb14b6095f3b074af48426f2025-08-20T02:00:51ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042007-09-01391607161310.1371/journal.pgen.0030150The inheritance of resistance alleles in multiple sclerosis.Sreeram V RamagopalanAndrew P MorrisDavid A DymentBlanca M HerreraGabriele C DeLucaMatthew R LincolnSarah M OrtonMichael J ChaoA Dessa SadovnickGeorge C EbersMultiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex-associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex-associated susceptibility.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.0030150&type=printable |
| spellingShingle | Sreeram V Ramagopalan Andrew P Morris David A Dyment Blanca M Herrera Gabriele C DeLuca Matthew R Lincoln Sarah M Orton Michael J Chao A Dessa Sadovnick George C Ebers The inheritance of resistance alleles in multiple sclerosis. PLoS Genetics |
| title | The inheritance of resistance alleles in multiple sclerosis. |
| title_full | The inheritance of resistance alleles in multiple sclerosis. |
| title_fullStr | The inheritance of resistance alleles in multiple sclerosis. |
| title_full_unstemmed | The inheritance of resistance alleles in multiple sclerosis. |
| title_short | The inheritance of resistance alleles in multiple sclerosis. |
| title_sort | inheritance of resistance alleles in multiple sclerosis |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.0030150&type=printable |
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