New MS Genetic Risk Factors Found

By Michael Smith, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
July 30, 2007
BOSTON, July 30 -- New genetic contributors to multiple sclerosis have been uncovered for the first time in 35 years, according to researchers here.

Action Points

• Explain to interested that it has long been known that multiple sclerosis has a genetic element, but only the human leucocyte antigen (HLA) gene complex has been conclusively linked to the disease.
• Note that these research reports suggest that variations in two genes outside the HLA complex may also play a role in the pathogenesis of the disease.

In related papers in the New England Journal of Medicine and Nature Genetics, scientists confirmed the importance of the human leucocyte antigen (HLA) gene complex in the pathogenesis of MS and reported two new risk factors:

• Variations in the gene for the alpha chain of interleukin receptor seven (IL7R-alpha), on chromosome five. The protein produced by the gene is also known as CD127.
• Variations in the gene for the alpha subunit of interleukin receptor two (IL2R-alpha), on chromosome 10. The alpha subunit of the receptor is also known as CD25.

Both genes play a role in T-cell-mediated immunity, which makes them plausible candidates for a role in MS.

But the increased risk associated with carrying the risk variants is small, reported David Hafler, M.D., of Harvard, and colleagues in the International Multiple Sclerosis Genetics Consortium.

Writing in the NEJM, Dr. Hafler and colleagues said each of the variants they uncovered in the two genes explained less than 0.2% of the variation in the risk of developing MS.

By contrast, variations in the HLA complex - first linked to MS in 1972 - remain the largest genetic risk factor for the disorder, explaining nearly 50% of the risk, according to Jonathan Haines, Ph.D., of Vanderbilt University Medical Center in Nashville and colleagues in the Multiple Sclerosis Genetics Group.

Dr. Haines and colleagues, reporting in Nature Genetics, said a variation in the IL7R-alpha gene influences the amount of the protein available in the body, hinting that the ups and downs of the alpha chain may be part of the mechanism that leads to MS.

The three papers -- including a second in Nature Genetics by Jan Hillert, M.D., of Karolinska University Hospital in Stockholm, and colleagues -- all report that a single-letter genetic variation in IL7R-alpha is significantly associated with the risk of MS.

The variation - or single nucleotide polymorphism (SNP) -- is dubbed rs6897932.

Dr. Hafler and colleagues and Dr. Haines and colleagues put the significance of the association at about P=2.9×10⁻⁷. The other research group used different statistical methods, but concluded that "all analyses point toward (rs6897932) as being most strongly associated with risk of multiple sclerosis" among a number of SNPs they investigated.

But Dr. Halfer and colleagues also reported that a cluster of SNPs in the HLA gene complex was highly associated with MS (at P=8.94×10⁻⁸¹), confirming the importance of the HLA system.

Also, they said, two SNPs that are usually inherited together in the IL2R-alpha gene were associated with the disease, at (P=2.96×10⁻⁸).

Many of the findings were made using the increasingly popular method of genome-wide association scanning, in which researchers compare the genes of cases and controls, using a panel of many thousand of SNPs to tease out variants linked to the disease in question.

The method has been called "hypothesis-free" because investigators don't have a pre-conceived notion of where in the genome to look for suspected links. Instead, they scan large numbers of cases and controls to see which SNPs are more common among cases.

Recent studies have found previously unsuspected links to heart disease and diabetes, among other disorders. (See Common Genetic Variation Increases Heart Disease Risk)

These new findings "strongly support the dominance of the HLA locus in the genetic background of patients with multiple sclerosis," said Leena Peltonen, M.D., Ph.D., of the University of Helsinki.

But they also support the notion that there are many risk variations for MS outside the HLA complex, she said in an accompanying editorial in the NEJM.

Dr. Peltonen noted that genome-wide scanning -- unlike other studies in other disorders -- did not find any new major risk factors for MS.

And she cautioned that -- by definition -- such a method relies on variations that are common in the population and would miss genetic risk factors that are not widely distributed.

"We need to define the full allelic diversity of the 'suspicious genes' that are initially identified by genome-wide studies," Dr. Peltonen said. Doing so might uncover "rare, high-impact" variants that play an even larger role in the risk of disease, she said.
The International Multiple Sclerosis Genetics Consortium study was supported by the National Multiple Sclerosis Society, the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the Wellcome Trust, the National Center for Research Resources, the Penates Foundation, the Nancy Davis Center Without Walls, and a Jacob Javits Merit Award. The researchers said they had no potential conflicts.

The study by the Multiple Sclerosis Genetics Group was supported by the NIH and the National Multiple Sclerosis Society. The researchers said some members had potential conflicts.

The study by Dr. Hillert and colleagues was supported by the Swedish Research Council, the Norwegian Research Council, the Eastern Norwegian Regional Health Authority, the Danish Multiple Sclerosis Society, the Warwara Larsen Foundation, NeuroproMiSe, the Swedish Society of the Neurologically Disabled, the Bibbi and Nils Jensens Foundation and the Swedish Foundation for Strategic Research, and the Karolinska Institutet. The researchers said they had no potential conflicts.
Additional Multiple Sclerosis Coverage
Primary source: New England Journal of Medicine
Source reference:
Hafler DA et al. "Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study." N Engl J Med 2007;357.
Additional source: New England Journal of Medicine
Source reference:
Leena Peltonen. "Old Suspects Found Guilty - The First Genome Profile of Multiple Sclerosis." N Engl J Med 2007;357.
Additional source: Nature Genetics
Source reference:
Gregory SG et al. "Interleukin 7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis." Nature Genetics 2007; doi:10.1038/ng2103.


http://www.medpagetoday.com/Neurology/MultipleSclerosis/dh/6287