Genetic Polymorphism at Codon 129 of the Prion Protein Gene Is Not Associated With Multiple Sclerosis

T he endogenous cellular prion protein (PrPC) is an -helical glycophosphatidylinositolanchored sialoglycoprotein highly expressed in neurons, lymphoid cells, and myeloid cells. In humans, the PrP gene (Prnp) is located on chromosome 20p12. Single-nucleotide polymorphisms (SNPs) in Prnp have been shown to determine the susceptibility to inherited, sporadic, and infectious forms of prion diseases. Interestingly, it was also recently shown that the same Prnp129 SNP has a significant effect on the clinical course of numerous nonprion neurodegenerative disorders of the central nervous system (CNS), including early-onset Alzheimer disease, Down syndrome, and Wilson disease. In these studies, methionine/valine (M/V) heterozygosity was associated with less severe clinical disease. Finally, the Prnp129 SNP was also shown to negatively affect long-term memory in adult and senescent healthy individuals. The exact mechanisms by which genetic polymorphisms of Prnp alter CNS function and disease phenotypes are largely unknown. In this study, we investigated the effect of the Prnp129 M/V SNP on disease susceptibility to multiple sclerosis (MS), a human inflammatory neurodegenerative disease of the CNS. To determine whether the Prnp129 M/V SNP plays a role in MS susceptibility, we genotyped 973 families with nuclear MS (n=2998 individuals). Appropriate institutional review boards approved the studies and informed consent was obtained from all participants. The ratio of women to men for affected individuals was 2.9:1, and 91.7% presented with relapsingremitting (67.6%) or secondary progressive (24.1%) MS at the time of study entry. Genotypes were generated by a TaqMan allelic discrimination assay on an ABI7900HT genotyping platform using the Assay-by-Design service from Applied Biosystems (Foster City, California). All family genotypes were examined for mendelian inconsistencies using PedCheck (University of Pittsburgh, Pennsylvania), and any discrepancies were addressed. No deviations from Hardy-Weinberg equilibrium were observed for genotypes in the patient, parent, or combined group (data not shown). Family-based association analysis was performed using the reconstructed-combined transmission disequilibrium test as implemented in SAS Genetics (v.9.1.3; SAS Institute, Cary, North Carolina). There was no evidence of transmission distortion in this data set (P=.5). Families were stratified by sex and by the presence of HLADRB1*1501 in the affected individuals to identify potential genetic interactions. No difference in allelic transmission was observed in either subgroup. The cases from the 973 families with nuclear MS were combined with 490 additional MS cases (total ratio of women to men,2.7:1) ascertained using identical inclusion criteria and compared with 1131 controls (ratio of women to men,1.9:1). There was no statistically significant difference in the frequency of Prnp129 genotypes between patients and controls. Allele frequency distributions were similar in patients with mild (EDSS 3, 15 years after onset) or severe (EDSS 6 within 10 years after onset) MS (data not shown) or when using the Multiple Sclerosis Severity Score as a dependent variable (data not shown). Similarly, no effect of Prpn129 on age of onset was detected. Using the family-based association analysis, we can conclude that an SNP in Prnp129 plays no major role in MS susceptibility. The role of other unlinked polymorphisms or the potential role of Prnp129 in the progression of neuroradiologic or cognitive endpoints of MS cannot be excluded.