Gene Study Allows for Environmental Explanation of MS By Crystal Phend, Senior Staff Writer, MedPage Today Published: April 30, 2010 Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Whether a person develops multiple sclerosis isn't entirely up to the genes, according to a study of identical twins. Genetic sequencing in each of three pairs of twins uncovered the same risk-associated gene variants in the one who got multiple sclerosis as in the one who didn't, reported Sergio E. Baranzini, PhD, of the University of California San Francisco, and colleagues. But there were no overall genetic or epigenetic differences in immune cells that might account for why one escaped without the autoimmune disease, they wrote in the April 29 issue of Nature. The implication is that what determines whether a susceptible person develops multiple sclerosis may be environmental, Baranzini said in an interview. These triggers remain unclear, although epidemiologic studies have suggested some weak environmental associations, such as with smoking or Epstein-Barr virus, he noted. "Ideally, one could identify whether an individual is genetically at-risk," Baranzini told MedPage Today. "Then if the environmental factor was known that person could be advised to avoid it." He cautioned, though, that this pilot study could not entirely rule out a genetic role in development of multiple sclerosis, which his group continues to investigate. Nor does the study discount the role genetic inheritance plays in susceptibility to the disease, Baranzini said. A genetic component has been clear from prior studies suggesting a 25% higher risk in one identical twin if the other has multiple sclerosis and lesser degrees of risk for progressively less-closely related family members. Identical twins have been a classic go-to group in studying the relative contribution of nature and nurture. But recent studies have shown that although their genetics start out identical, minor genetic mutations and epigenetic changes to the expression of the genes after birth have been reported as a source of differences between twins, the researchers noted. So Baranzini's group examined genetic, epigenetic, and transcriptomic differences in CD4+ lymphocytes -- T cells involved in the pathophysiology of multiple sclerosis -- in three pairs of identical twins discordant for multiple sclerosis. In one pair of female twins of Ashkenazi Jewish origin, the unaffected twin was confirmed to be without multiple sclerosis by MRI brain imaging and cerebrospinal studies and was beyond the susceptibility age range. The complete genome of this pair was sequenced, but there were no robust differences in gene expression. Rather, the variance in transcript abundance attributable to multiple sclerosis (9.4%) was "within the range of variances obtained by random permutation of multiple sclerosis diagnosis labels" and much lower than the 23.6% day-to-day variation or 57.3% attributable to differences between pairs of twins, the researchers noted. The other two twin pairs in the study -- African-American females and white males -- didn't have their entire genome sequenced but did get analysis of 1 billion single nucleotide polymorphisms (SNPs) representing more than 99% of the genome. This turned up no reproducible differences, suggesting a role of viruses' genomic insertions in T cells from multiple sclerosis-affected compared with unaffected twins. All three sets of twins showed similar genetic risk factors for multiple sclerosis between the affected and unaffected member of the pair. Of 13 common risk variants previously associated with susceptibility to multiple sclerosis, the results were: * For the women of Jewish ancestry, both were homozygous for five, heterozygous for five, and without three of the variants, which together added up to eight-fold elevated risk for development of multiple sclerosis. * For the African-American women, both were homozygous for seven susceptibility variants and heterozygous for two, conferring a 14-fold risk for developing multiple sclerosis. * For the white males, both were homozygous for eight risk alleles and heterozygous for two, which would be expected to produce a 43-fold elevated risk of multiple sclerosis. The 0.3% or fewer mRNA SNP genotypes that differed between co-twins revealed no clear or consistent differences that could account for multiple sclerosis. Analysis of coding SNPs turned up none with an imbalance in homozygous or heterozygous alleles that were shared among the three twin pairs. However, those that did show an allelic imbalance "were significantly closer to transcription-factor-binding sites than random SNPs, providing a new, potential mechanism of action," Baranzini's group wrote. No copy number variants or gains or losses in alleles differed between individuals in any of the pairs of twins. The researchers also looked at epigenetics with genome-scale DNA methylation profiling at nucleotide resolution. But they showed the magnitude of the few epigenetic differences between co-twins "to be at least an order of magnitude less than those between [unrelated] individuals, and about three orders less than those observed between tissues and in malignant transformation," they wrote. The study was supported by grants from Small Ventures USA, A.J. Brass Foundation, Nancy Davis Foundation, National Institutes of Health grants, and National MS Society grants. Baranzini reported being a Harry Weaver Neuroscience Scholar of the National MS Society. The researchers reported no conflicts of interest. Primary source: Nature Source reference: Baranzini SE, "Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis" Nature 2010; 464: 1351-56.