title: Linkage analysis conditional on HLA status in a large North American pedigree supports the presence of a multiple sclerosis susceptibility locus on chromosome 12p12.
abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a probable immune-mediated pathogenesis. Strong evidence supports the hypothesis that MS is determined by genetic and environmental factors, but these factors remain largely undefined. The genetic component is suggested by a higher concordance rate in monozygotic (28%) versus dizygotic (5%) twins as well as familial recurrence risk. Several studies have shown association of MS with the histocompatibility leukocyte antigen (HLA) class II region, specifically DR15, DQ6. However, there is no convincing evidence of a common susceptibility locus. We have identified a pedigree of Pennsylvania Dutch extraction, in which MS segregates with an autosomal dominant inheritance pattern. We have collected blood samples from 18 family members, seven of whom show typical signs of MS lesions by magnetic resonance imaging. The 18 individuals were serotyped for HLA class I and II and analyzed by a genome-wide screen for linkage analysis. We have found evidence for suggestive linkage to markers on 12p12 with a maximum multipoint LOD score of 2.71, conditional on the presence of DR15, DQ6. Contingency table analysis showed that all MS affected individuals have both the DR15, DQ6 allele and the 12p12 haplotype whereas the unaffected individuals have either one or neither of these markers (P = 0.00011). Our data suggests that both HLA DR15, DQ6 and a novel locus on chromosome 12p12 may be necessary for development of MS in this family.
authors.affiliation: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark 07103, USA. vitaleem@umdnj.edu
authors.forename: Emilia
authors.initials: E
authors.lastname: Vitale
authors.forename: Stuart
authors.initials: S
authors.lastname: Cook
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.forename: Claudia
authors.initials: C
authors.lastname: Specchia
authors.forename: Kavitha
authors.initials: K
authors.lastname: Subramanian
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: Douglas
authors.initials: D
authors.lastname: Nathanson
authors.forename: Marvin
authors.initials: M
authors.lastname: Schwalb
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Christine
authors.initials: C
authors.lastname: Rohowsky-Kochan
mesh_terms: D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000209:etiology / Q000235:genetics*; D009656:North America; D010375:Pedigree
chemical_list: D006683:HLA-DQ Antigens; C063831:HLA-DQ6 antigen; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen