Novel Study Pinpoints Role Sex Plays in the Genetics of IBD
Sex differences in the risk and manifestation of disease are increasingly being explored in the search for effective treatments. Teasing out this variable is often overlooked in complex disease genetics, according to Cedars-Sinai investigators who are researching the role sex plays in genetic mechanisms underlying the development of inflammatory bowel disease (IBD).
In a new study published in the journal IBD, investigators used a novel statistical approach to identify three new regions of the genome associated with developing IBD. They also discovered other areas that were specifically associated with developing IBD in 
only one sex.
“We observed sex differences in the prevalence of specific clinical characteristics. Females were more likely to have Crohn’s disease affecting only the colon. In males, on the other hand, we saw a higher risk for perianal complications in Crohn’s disease as well as more extensive disease in ulcerative colitis,” said Talin Haritunians, PhD, the senior author of the study and a research associate professor of Medicine at Cedars-Sinai.
Haritunians, a research scientist in the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, noted the study was the first international investigation into sex-stratified genetic associations in IBD containing more than 70,000 subjects.
“Most genetic association studies analyze males and females together. Our study highlighted the need to move beyond the 
conventional sex-combined analyses in order to fully appreciate the complex genetic architecture of IBD,” said Dermot McGovern, MD, PhD, a co-author of the study and director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute.
The sex-dimorphic analytic approach used by the investigators identified associations in three new genetic loci (chr9q22, CARMIL1 and UBASH3A) as well as distinct sex-specific patterns of association for several variants, including on chromosome-2 and in the major histocompatibility complex on chromosome-6.
“This is of particular interest given the well-established role of the major histocompatibility complex and HLA locus in IBD and immune-mediated diseases, in general,” said Haritunians.
The investigators say they are continuing the collaboration with the IBD international consortium and are currently expanding the study to include a cohort of more than 100,000 people.
“We plan to also develop sex-specific IBD genetic risk scores to better evaluate the genetic ‘burden’ in males and females,” said Haritunians.
This novel approach to genetic research of sex differences in IBD will also be used in Cedars-Sinai’s large-scale studies of the disease in Black and Hispanic populations, according to the scientists.
“These types of studies are critical if we are to build on our previous success employing genetics to develop new, personalized therapeutics for IBD and using them to treat those most likely to respond well. In other words, getting the right therapy to the right patient at the right time,” said McGovern, who holds the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai.
Funding: This work was supported in part by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grants P01 DK046763 and U01 DK062413), and The Leona M. and Harry B. Helmsley Charitable Trust.
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