A second major histocompatibility complex susceptibility locus for multiple sclerosis

Tai Wai Yeo, Philip L. De Jager, Simon G. Gregory, Lisa F. Barcellos, Amie Walton, An Goris, Chiara Fenoglio, Maria Ban, Craig J. Taylor, Reyna S. Goodman, Emily Walsh, Cara S. Wolfish, Roger Horton, James Traherne, Stephan Beck, John Trowsdale, Stacy J. Caillier, Adrian J. Ivinson, Todd Green, Susan Pobywajlo & 10 others Eric S. Lander, Margaret A Pericak-Vance, Jonathan L. Haines, Mark J. Daly, Jorge R. Oksenberg, Stephen L. Hauser, Alastair Compston, David A. Hafler, John D. Rioux, Stephen Sawcer

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Objective: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRBl gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. Methods: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DKB1* 1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. Results: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 X 10 -5). Interpretation: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.

Original languageEnglish
Pages (from-to)228-236
Number of pages9
JournalAnnals of Neurology
Volume61
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

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HLA Antigens
Major Histocompatibility Complex
Multiple Sclerosis
Genes
MHC Class II Genes
Linkage Disequilibrium
Microsatellite Repeats
Haplotypes
Single Nucleotide Polymorphism
Chromosomes
Alleles

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Yeo, T. W., De Jager, P. L., Gregory, S. G., Barcellos, L. F., Walton, A., Goris, A., ... Sawcer, S. (2007). A second major histocompatibility complex susceptibility locus for multiple sclerosis. Annals of Neurology, 61(3), 228-236. https://doi.org/10.1002/ana.21063

A second major histocompatibility complex susceptibility locus for multiple sclerosis. / Yeo, Tai Wai; De Jager, Philip L.; Gregory, Simon G.; Barcellos, Lisa F.; Walton, Amie; Goris, An; Fenoglio, Chiara; Ban, Maria; Taylor, Craig J.; Goodman, Reyna S.; Walsh, Emily; Wolfish, Cara S.; Horton, Roger; Traherne, James; Beck, Stephan; Trowsdale, John; Caillier, Stacy J.; Ivinson, Adrian J.; Green, Todd; Pobywajlo, Susan; Lander, Eric S.; Pericak-Vance, Margaret A; Haines, Jonathan L.; Daly, Mark J.; Oksenberg, Jorge R.; Hauser, Stephen L.; Compston, Alastair; Hafler, David A.; Rioux, John D.; Sawcer, Stephen.

In: Annals of Neurology, Vol. 61, No. 3, 01.03.2007, p. 228-236.

Research output: Contribution to journalArticle

Yeo, TW, De Jager, PL, Gregory, SG, Barcellos, LF, Walton, A, Goris, A, Fenoglio, C, Ban, M, Taylor, CJ, Goodman, RS, Walsh, E, Wolfish, CS, Horton, R, Traherne, J, Beck, S, Trowsdale, J, Caillier, SJ, Ivinson, AJ, Green, T, Pobywajlo, S, Lander, ES, Pericak-Vance, MA, Haines, JL, Daly, MJ, Oksenberg, JR, Hauser, SL, Compston, A, Hafler, DA, Rioux, JD & Sawcer, S 2007, 'A second major histocompatibility complex susceptibility locus for multiple sclerosis', Annals of Neurology, vol. 61, no. 3, pp. 228-236. https://doi.org/10.1002/ana.21063
Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Annals of Neurology. 2007 Mar 1;61(3):228-236. https://doi.org/10.1002/ana.21063
Yeo, Tai Wai ; De Jager, Philip L. ; Gregory, Simon G. ; Barcellos, Lisa F. ; Walton, Amie ; Goris, An ; Fenoglio, Chiara ; Ban, Maria ; Taylor, Craig J. ; Goodman, Reyna S. ; Walsh, Emily ; Wolfish, Cara S. ; Horton, Roger ; Traherne, James ; Beck, Stephan ; Trowsdale, John ; Caillier, Stacy J. ; Ivinson, Adrian J. ; Green, Todd ; Pobywajlo, Susan ; Lander, Eric S. ; Pericak-Vance, Margaret A ; Haines, Jonathan L. ; Daly, Mark J. ; Oksenberg, Jorge R. ; Hauser, Stephen L. ; Compston, Alastair ; Hafler, David A. ; Rioux, John D. ; Sawcer, Stephen. / A second major histocompatibility complex susceptibility locus for multiple sclerosis. In: Annals of Neurology. 2007 ; Vol. 61, No. 3. pp. 228-236.
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abstract = "Objective: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRBl gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. Methods: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DKB1* 1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. Results: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 X 10 -5). Interpretation: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.",
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AU - Yeo, Tai Wai

AU - De Jager, Philip L.

AU - Gregory, Simon G.

AU - Barcellos, Lisa F.

AU - Walton, Amie

AU - Goris, An

AU - Fenoglio, Chiara

AU - Ban, Maria

AU - Taylor, Craig J.

AU - Goodman, Reyna S.

AU - Walsh, Emily

AU - Wolfish, Cara S.

AU - Horton, Roger

AU - Traherne, James

AU - Beck, Stephan

AU - Trowsdale, John

AU - Caillier, Stacy J.

AU - Ivinson, Adrian J.

AU - Green, Todd

AU - Pobywajlo, Susan

AU - Lander, Eric S.

AU - Pericak-Vance, Margaret A

AU - Haines, Jonathan L.

AU - Daly, Mark J.

AU - Oksenberg, Jorge R.

AU - Hauser, Stephen L.

AU - Compston, Alastair

AU - Hafler, David A.

AU - Rioux, John D.

AU - Sawcer, Stephen

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N2 - Objective: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRBl gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. Methods: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DKB1* 1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. Results: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 X 10 -5). Interpretation: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.

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