An elaborate statistical analysis of genes from more than 7,000 individuals has identified an amino acid that appears to be a major risk factor for multiple sclerosis, a devastating autoimmune disorder that afflicts 2.5 million people worldwide.
In research published this month in BMC Medical Genetics , scientists from The Rockefeller University and colleagues from the University of Oxford in England and the University of British Columbia in Canada report a binding pocket in a previously implicated gene that may be an attractive research prospect as a potential drug target.
The analysis by biostatistician Knut M. Wittkowski, of Rockefeller's Center for Clinical and Translational Science, is the most sweeping to date of a database containing disease-relevant genes of 13,000 individuals who either have multiple sclerosis or are closely related to someone who does. Wittkowski and colleagues focused on a gene identified about a year ago in the New England Journal of Medicine as the single most important genetic risk factor for multiple sclerosis. The gene, HLA-DRB1 , is part of the major histocompatibility complex, a large cluster of particularly complex genes evolved to help the immune system adaptively respond to foreign invaders that it has never before encountered. How it contributes to the disease remains a mystery, however.
Unlike most human genes, which have only two alleles per locus, HLA-DRB1 has up to four, making traditional statistical analyses problematic. Wittkowski extended a variant of a commonly used method he developed in 2002 with a postdoc from Rockefeller's Laboratory of Statistical Genetics to deal with multi-allelic loci so that it could handle the complexity of HLA-DRB1 . He analyzed 93 locations with genetic variations and found that a single amino acid in the protein that the gene encodes, number 13, is the telltale indicator of susceptibility to multiple sclerosis. Amino acid 13 is at the center of a pocket in the HLA-DRB1 molecule that helps present an invading pathogen to the immune cells that can kill it. The researchers speculate that a mutation in this amino acid could cause the molecule to present healthy tissue for execution, one of the possible ways multiple sclerosis attacks the body.