Definitive Gene Screen Confirms Multiple Sclerosis Suspects

"Our results confirm the strong role of the major histocompatibilitycomplex genes in MS, and provides a definitive statement that no otherregion of the genome harbors a gene with a similar overall influence onMS genetics," said Jonathan Haines, Ph.D, of Vanderbilt University inNashville, Tennessee, who presented on behalf of the InternationalMultiple Sclerosis Genetics Consortium.

"A detailed examination of the major histocompatibility complexis critically important," said Haines, who suggests that this study mayhave profound implications for the future directions of MS geneticsresearch.

The major histocompatibility complex (MHC) is a cluster ofgenes that play a critical role in the recognition of cells in the bodyas belonging to the body, i.e., not intruders such as bacteria or otherpathogens.

When this system of recognition breaks down, the immune systemmay mistakenly launch an attack against cells, as happens in MS.Researchers believe that some genetic variations in MHC genes makepeople more susceptible to whatever environmental causes alsocontribute to MS.

Haines is one of the founders of an international team ofresearchers from many institutions that collected genetic data on 730families with more than one case of MS from Australia, Scandinavia, theUnited Kingdom, and the United States.

Previous studies have implicated the MHC, but also regions onother chromosomes, as harboring genes that increase MS risk. Hainessuggests that these studies failed to include enough subjects.

"This is the largest genetic linkage study on MS, and the firstto be done using the latest technology, which provides very detailedcoverage of the entire human genome," said Haines. "Other genes maystill play an important role in MS, but finding them will require usingnew genomic techniques."

Multiple sclerosis is an enigmatic disease of the nervoussystem and results in the loss of myelin, a substance that normallyinsulates nerve fibers and speeds electrical conduction through thefibers. Patches of inflammation (known as 'plaques') occur throughoutthe brain and spinal cord resulting in the loss of myelin and sometimesthe nerve fibers themselves.

Depending on which nerve fibers are hindered, patients canexperience problems ranging from weakness and clumsiness to numbness,visual disturbances, and even emotional and intellectual alterations.In some patients, MS manifests itself in cycles of relapse andremission and patients may show little sign of the disease betweenattacks.

[Background/Abstract]

A high density screen for linkage in multiple sclerosis
Jonathan L. Haines, Ph.D. (presenting on behalf of the International Multiple Sclerosis Genetics Consortium - IMSGC).
Nashville, TN

This abstract describes the results of what we would considerto be the definitive multiple sclerosis linkage screen. The power ofthe study is so great that it is virtually certain that allsusceptibility loci with effects large enough to be detectable bylinkage have been found. The value of a definitive reliable linkage mapcannot be overemphasized. The results from this study have profoundimplications for the future study of the genetics of this complexdisorder and enable accurate minimum requirements to be determined forfuture studies. This is clearly a critical development in the field.

Ten centimorgan microsatellite map have been the standard toolused for whole genome linkage screening since the mid 1990's and todate 11 screens employing this methodology have been published inmultiple sclerosis. However the scale and quality of the data in thesestudies is limited. In order to establish a definitive linkage map wehave typed 4506 single nucleotide polymorphism markers in a set of 730multiplex families from Australia, Scandinavia, the United Kingdom andthe United States, whichtogether provide 945 affected relative pairs. Highly significantlinkage is observed in the region of the Major HistocompatibilityComplex (lod score 11.7) and suggestive linkage is identified onchromosome 17 and 5. Ordered Sub-set analysis identifies a furtherlocus on chromosome 19. The mean information extraction provided by themarker panel is 79.3% (range 42.4 - 91.3%) and the observed Mendelianinconsistencies suggests that within this data set the genotyping errorrate is just 0.002%. These data have profound implications for thefuture directions of multiple sclerosis genetics research and suggestthat previous efforts in this area are almost all substantiallyunderpowered. In the future association studies will need to include atleast 500-1000 cases.