Seeking genes for MS

Molecular genetics has defined the cause of many single gene diseases. Recently, molecular approaches have afforded some success for complex genetic diseases. Complex diseases, such as MS, exhibit familial aggregation, but low penetrance and a high ratio of sporadic to familial cases. Typically, these diseases are polygenic, but the locus and causative alleles are heterogeneous, and there may be interactions between genes and environmental factors. In this issue of Neurology, two studies use a candidate gene approach to address two different hypotheses about the pathogenesis of MS. Mann et al.1 explore whether allelic variants of the glutathione S-transferase supergene family that clear reactive oxygen intermediates (ROI) influence susceptibility or outcome in sporadic MS cases. Their hypothesis is based on evidence that ROI damage myelin and axons, and thereby augment long-term disability. Steckley et al.2 explore whether polymorphic microsatellite or restriction fragment length polymorphisms close to or within genes involved in metabolism of vitamin D are linked to MS susceptibility in families with multiple affected members or whether they are selectively transmitted from heterozygous parents to affected offspring (transmission dysequilibrium). Their hypothesis stems from epidemiologic observations relating MS prevalence with latitude and vitamin D deficiency and favorable effects of vitamin D treatment of experimental allergic encephalomyelitis.

Mann et al. found no association with susceptibility to MS. However, Expanded Disability Status Scale score (EDSS) 6 (needing a cane to walk a distance of about half a block) was reached within 10 years 2.4-fold as often in those with the GSTM3 AA genotype compared with those without this genotype. Using logistic regression, the probability of being in the severely disabled group at 10 years was 5.0-fold greater in the 40 of 179 …