Human Molecular Genetics Advance Access published online on August 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl223
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Division of Epidemiology, 140 Warren Hall MC #7360, School of Public Health, University of California, Berkeley, CA 94720, USA; Department of Neurology, University of California, San Francisco, CA 94143, USA; Kaiser Permanente Northern California, Division of Research, 2000 Broadway, Oakland, CA 94612, USA
* To whom correspondence should be addressed. Variation in major histocompatibility complex (MHC) genes on chromosome 6p21.3, specifically the HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1,339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (p=7.8 x 10-31), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4, 13.0, p<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1, 2.9, p=0.03). Strong evidence for under-transmission of DRB1*14 (p=5.7 x 10-6), even after accounting for DRB1*15 (p=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1, 14.4, p<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive (PPMS) families (p=0.0004), similar to relapsing-remitting (RRMS) families, suggests that DRB1 related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2,201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using Expanded Disease Disability Score (EDSS) and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.
Received May 30, 2006
Revised July 12, 2006
Accepted August 3, 2006
Article
Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis
Lisa F. Barcellos 1 *, Stephen Sawcer 2, Patricia P. Ramsay 3, Sergio E. Baranzini 4, Glenys Thomson 5, Farren Briggs 3, Bruce C.A. Cree 4, Ann B. Begovich 6, Pablo Villoslada 7, Xavier Montalban 8, Antonio Ucelli 9, Giovanni Savettieri 10, Robin L. Lincoln 4, Carolyn DeLoa 4, Jonathan L. Haines 11, Margaret A. Pericak-Vance 12, Alastair Compston 2, Stephen L. Hauser 4, and Jorge R. Oksenberg 4
2 University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, BOX 165 Cambridge, CB2 2QQ, UK
3 Division of Epidemiology, 140 Warren Hall MC #7360, School of Public Health, University of California, Berkeley, CA 94720, USA
4 Department of Neurology, University of California, San Francisco, CA 94143, USA
5 Department of Integrative Biology, University of California, Berkeley, CA 94720, USA
6 Celera Diagnostics, Alameda, CA 94502, USA
7 Department of Neurology, University of Navarra, Pamplona, Spain
8 Neuroimmunology Unit, Hospital Vall d'Hebron, Barcelona, Spain
9 Department of Neurology, University of Genova, Genova, Italy
10 Department of Neurology, Ophthalmology, Otolaryngology and Psychiatry, University of Palermo, Palermo, Italy
11 Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232, USA
12 Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
Lisa F. Barcellos, E-mail: barcello{at}genepi.berkeley.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  International MHC and Autoimmunity Genetics Networ, J. D. Rioux, P. Goyette, T. J. Vyse, L. Hammarstrom, M. M. A. Fernando, T. Green, P. L. De Jager, S. Foisy, J. Wang, et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases PNAS, November 3, 2009; 106(44): 18680 - 18685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. De Jager Review: Identifying patient subtypes in multiple sclerosis and tailoring immunotherapy: challenges for the future Therapeutic Advances in Neurological Disorders, November 1, 2009; 2(6): 369 - 377. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Kaushansky, D. M. Altmann, S. Ascough, C. S. David, H. Lassmann, and A. Ben-Nun HLA-DQB1*0602 Determines Disease Susceptibility in a New "Humanized" Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice J. Immunol., September 1, 2009; 183(5): 3531 - 3541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Silva, A Bettencourt, C Pereira, E Santos, C Carvalho, D Mendonca, P. Costa, L Monteiro, and B Martins Protective role of the HLA-A*02 allele in Portuguese patients with multiple sclerosis Multiple Sclerosis, June 1, 2009; 15(6): 771 - 774. [Abstract] [PDF]
|
|
|
|
|
|
M. R. Lincoln, S. V. Ramagopalan, M. J. Chao, B. M. Herrera, G. C. DeLuca, S.-M. Orton, D. A. Dyment, A D. Sadovnick, and G. C. Ebers Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility PNAS, May 5, 2009; 106(18): 7542 - 7547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mangalam, D. Luckey, E. Basal, M. Jackson, M. Smart, M. Rodriguez, and C. David HLA-DQ8 (DQB1*0302)-Restricted Th17 Cells Exacerbate Experimental Autoimmune Encephalomyelitis in HLA-DR3-Transgenic Mice J. Immunol., April 15, 2009; 182(8): 5131 - 5139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. C. Cree, D. E. Reich, O. Khan, P. L. De Jager, I. Nakashima, T. Takahashi, A. Bar-Or, C. Tong, S. L. Hauser, and J. R. Oksenberg Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA Arch Neurol, February 1, 2009; 66(2): 226 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Chao, S. V. Ramagopalan, B. M. Herrera, M. R. Lincoln, D. A. Dyment, A. D. Sadovnick, and G. C. Ebers Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex Hum. Mol. Genet., January 15, 2009; 18(2): 261 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Okuda, R. Srinivasan, J. R. Oksenberg, D. S. Goodin, S. E. Baranzini, A. Beheshtian, E. Waubant, S. S. Zamvil, D. Leppert, P. Qualley, et al. Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures Brain, January 1, 2009; 132(1): 250 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sawcer The complex genetics of multiple sclerosis: pitfalls and prospects Brain, December 1, 2008; 131(12): 3118 - 3131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mangalam, D. Luckey, E. Basal, M. Behrens, M. Rodriguez, and C. David HLA-DQ6 (DQB1*0601)-Restricted T Cells Protect against Experimental Autoimmune Encephalomyelitis in HLA-DR3.DQ6 Double-Transgenic Mice by Generating Anti-Inflammatory IFN-{gamma} J. Immunol., June 1, 2008; 180(11): 7747 - 7756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. De Jager, K. C. Simon, K. L. Munger, J. D. Rioux, D. A. Hafler, and A. Ascherio Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis Neurology, March 25, 2008; 70(13_Part_2): 1113 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Fontaine and L. F. Barcellos Evidence for a complex interaction between HLA-DRB1 and environmental factors in MS Neurology, January 8, 2008; 70(2): 97 - 98. [Full Text] [PDF]
|
|
|
|
|
|
E. Jaros, D. J. Mahad, G. Hudson, D. Birchall, S. J. Sawcer, P. G. Griffiths, J. Sunter, D.A.S. Compston, R. H. Perry, and P. F. Chinnery PRIMARY SPINAL CORD NEURODEGENERATION IN LEBER HEREDITARY OPTIC NEUROPATHY Neurology, July 10, 2007; 69(2): 214 - 216. [Full Text] [PDF]
|
|