title: Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.
abstract: Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen 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 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-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=5.7x10(-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 MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 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 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.
authors.affiliation: Division of Epidemiology, School of Public Health, University of California, Berkeley 94720, USA, and Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, UK. barcello@genepi.berkeley.edu
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Ramsay
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Glenys
authors.initials: G
authors.lastname: Thomson
authors.forename: Farren
authors.initials: F
authors.lastname: Briggs
authors.forename: Bruce C A
authors.initials: BC
authors.lastname: Cree
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.forename: Antonio
authors.initials: A
authors.lastname: Uccelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Savettieri
authors.forename: Robin R
authors.initials: RR
authors.lastname: Lincoln
authors.forename: Carolyn
authors.initials: C
authors.lastname: DeLoa
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D030541:Databases, Genetic; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology*; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains