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Chromosome 19 Single-Locus and Multilocus Haplotype Associations With Multiple SclerosisEvidence of a New Susceptibility Locus in Caucasian and Chinese Patients
Lisa F. Barcellos, PhD;
Glenys Thomson, PhD;
Mary Carrington, PhD;
John Schafer, MD;
Ann B. Begovich, PhD;
Patricia Lin;
Xu Xian-hao, MD;
Min Bao-quan, MD;
Darlene Marti, MS;
William Klitz, PhD
JAMA. 1997;278(15):1256-1261.
Abstract
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Context.
—Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed.
Objective.
—To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE APOE on chromosome 19q13.2, and MBP(myelin basic protein) on chromosome 18q23.
Design.
—Case-control association testing.
Subjects.
—A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria.
Main Outcome Measures.
— 2 Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods.
Results.
—The HLA effect is due to the class II DR2 haplotype, DRB1*1501-DQA1*0102-DRB1*0602; contributions to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, including D19S178, D19S574, APOE, APOC2, and D19S219, differed between patient and control samples. D19S574 showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). The APOE variation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. Interaction effects between DR2 and chromosome 19q13.2 or MBP in MS susceptibility were not apparent.
Conclusions.
—The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS.
Author Affiliations
From the Department of Integrative Biology, University of California, Berkeley (Drs Barcellos, Thomson, and Klitz and Ms Lin); Department of Human Genetics, Roche Molecular Systems, Inc, Alameda, Calif, and Children's Hospital Oakland Research Institute, Oakland, Calif (Dr Begovich); Intramural Research Support Program, SAIC Frederick, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Md (Dr Carrington and Ms Marti); Department of Neurology, University of California, Davis (Dr Schafer); and Department of Neurology, Beijing Hospital, Beijing, People's Republic of China (Drs Xu and Min).
Footnotes
The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
Reprints: William Klitz, PhD, Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140 (e-mail: wklitz@allele5.biol.berkeley.edu).
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