Heritable modulators of the multiple sclerosis phenotype

Abstract: Studies of families in which more than one case of multiple sclerosis (MS) occurs have demonstrated that shared genetic and/or environmental factors appear to modify clinical features of the disease, including rate of progression and disease course. We undertook in the present project to determine to what extent selected genetic factors constitute heritable determinants of the MS phenotype. We first reviewed the medical records of over 1200 MS patients, cataloguing clinico-demographic data, including disease course, age at onset, results of paraclinical examinations, and degree of disability. In Paper I, we found that carriers of the HLA class II specificity DR15-long known to confer susceptibility to MS-developed MS at an earlier age than noncarriers; that a second HLA class II specificity, DR17, is also positively associated with the risk of MS; that no HLA-DRB1 allele influences course or outcome in MS; and that differences in DR15 positivity rates, after stratification for diagnostic category and examinations results, seem to reflect a gradient of phenocopy contamination, with rates increasing in proportion to the degree of clinical or paraclinical, verification of the MS diagnosis. In Paper II, we show that the "head start" provided by carriage of DR15 is observed, independently, in patients with both bout-onset (BO; i.e., relapsing- remitting or secondary progressive) MS and primary progressive (PP) MS. In Paper III, we examined the possibility-first suggested in a report from Germany-that a rare variant of the CD45-encoding PTPRC gene is associated with nearly full penetrance of MS in a small subset of patients; we found, however, no difference in the occurrence of the variant between Swedish MS patients and controls. In Paper IV, we studied the impact of the Alzheimer-associated APOE gene on disability in MS by comparing genotype frequencies in our cohort's most extreme disability-stratified septiles. We found no significant differences between the benign-MS and severe-MS septiles; however, the risk conferred by the epsilon4 allele rose progressively upon comparison of carriage rates in more narrowly defined antipodal quantiles. In Paper V, we undertook to determine to what extent promoter-exon 1 haplotypes of CTLA4-a gene associated with susceptibility to several autoimmune diseases-influence age at onset, disease severity and disease course in MS. We found that CTLA4 haplotypes had no effect on age at onset or severity, but that deviations in haplotype frequencies could be observed in patients subgrouped by disease course. After subsequent analysis of a second, independent dataset, we confirmed that BOMS patients exhibited the same genotype and phenotype frequencies as controls, but that homozygosity for haplotype 2-a genotype associated with lower expression of CTLA4-conferred a more than two-fold risk of PPMS. In Paper VI, we characterized a consanguineous family of Middle Eastern origin exhibiting multiple cases of MS and performed a genome-wide screen, using microsatellite markers, on five affected and four unaffected family members now residing in Sweden. We found a haplotype spanning 43 centimorgans on the short arm of chromosome 9 for which four of five affected family members were homozygous and all unaffected family members heterozygous; however, the nonparametric logarithm- of -odds score for the region was no higher than a nonsignificant 2.3. Ironically, post-migration disease onset and a tendency towards date-of-onset (rather than age-at-onset) clustering seem to suggest the primacy of environmental factors over heritable ones in the etiology of MS in the kinship.