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Genotyping Study Finds MS Risk Variant More Common in Women

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A genotyping study appearing online last night in the journal Neurology suggests multiple sclerosis-associated changes to the major histocompatibility complex gene HLA-DRB1 are more common in women with MS than in men who have the disease.

"Our findings also show women with the HLA gene variant are more likely to transmit the gene variant to other women in their families than to men," corresponding author George Ebers, a clinical neurology researcher at the University of Oxford, said in a statement.

Ebers led a team of investigators from Canada and the UK who identified this female-to-male risk variant pattern by genotyping the HLA-DRB1 in thousands of individuals from more than 1,000 Canadian and European families affected by MS. Based on their findings so far, the researchers speculated that epigenetic modifications in the MHC region might help explain some of the sex-specific inheritance patterns and environmental influences reported for MS.

Past studies suggest that both environmental factors and genetics can up an individual's risk of developing MS, the researchers noted, and a handful of MHC genes have been linked to the autoimmune disease. But, they added, apparent differences in MS genetic patterns have also been detected between men and women.

"There is a general consensus that the incidence and prevalence of MS has been rising with an increased penetrance among women, and an excess monozygotic twins concordance for MS is almost entirely female specific," the team wrote. "Moreover, there is a maternal parent-of-origin effect with [a] higher number of affected mother-daughter pairs and few father-son pairs."

In an effort to explore this in more detail, Ebers and his team used allele-specific PCR amplification to genotype the MHC human leukocyte antigen class II gene HLA-DRB1 in 7,093 individuals from 1,055 MS-affected Canadian and European families, including 2,127 individuals with MS.

"Since HLA genes are the main genetic contributor to MS susceptibility, we hypothesized that gender-discrepant HLA-associated effects are possible," they explained. "By using a large family-based cohort, we were able to address this question."

Overall, they found that the HLA-DRB1*15 version of the gene, which has been previously linked to MS, was 1.4 times more common in MS-affected women than in men with MS.

Of the 1,545 women with MS who were tested, 919 carried the MS-associated HLA-DRB1 variant. On the other hand, the team found that 302 of the 582 men with MS had the risk variant.

Moreover, their results hint that women pass on HLA gene changes to their children more often than men do. And, they say, sex-linked HLA-DRB1*15 inheritance is particularly common when female second degree relatives, such as aunts, carry the risk variant.

"It appears that the less the genetic sharing between individuals, the higher the interaction is between female sex and inheritance of the HLA gene variant," Mayo Clinic researcher Orhun Kantarci said in a statement. Kantarci, who was not involved in the study, wrote an accompanying online editorial in Neurology.

Though more research is needed to get to the bottom of the HLA inheritance patterns and their role in MS, the research team behind the new study speculated that the imbalance in HLA-DRB1*15 inheritance between men and women might be a consequence of a yet unidentified epigenetic mechanism.

"The results here … suggest that the molecular explanation for the increased penetrance of MS among women will have roots in female gender-specific epigenetic modifications of the HLA Class II haplotypes," they wrote.

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