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First comprehensive study of genetic risks for Inflammatory Bowel Disease (IBD) in African-Americans performed.

Crohn’s disease and ulcerative colitis are chronic autoimmune diseases that affect as many as 1.6 million Americans. Patients with Inflammatory Bowel Disease (IBD) have immune systems that attack their own intestines, resulting in inflammation. According to the Crohn’s and Colitis Foundation of America, recent years have seen a steady increase in reported cases of IBD in African-Americans.  Now, researchers at the Johns Hopkins University School of Medicine, Emory University and Cedars-Sinai, state they have performed an in-depth analysis of genetic risk factors of inflammatory bowel disease in African-Americans.  The team hope that it’s the first of many steps to better understand and treat these debilitating diseases.

Previous studies show that IBD genetics have been evaluated in more than 1,000 studies in white and Asian, primarily East Asian, populations. Although the risk is slightly lower than that of white Americans, it has been shown that African-Americans are at significant risk for IBD.  Therefore, the primary goal of the group was to determine whether African-Americans share the same 163 separate genetic variations established in white Americans as IBD genetic risk factors. They go on to add that a secondary goal was to identify novel regions of the genome, known as loci, causing IBD risk in African-Americans.

The researchers also examined in the current study if, within the majority of these IBD genetic loci, there are genetic variations that are of particular risk for causing IBD in African-Americans that are distinct from those identified in whites.  To validate this they also investigated whether there are regions of the genome that cause or protect IBD risk in African-Americans that arise from either their West African or European genetic ancestries.

The current study evaluated more than 1,500 African-American patients with IBD, which included 1,088 with Crohn’s disease and 361 with ulcerative colitis.  The participants were from 35 IBD centers across North America and used 1,797 African-Americans without IBD for comparison.  The results found gene variants within three of the most highly associated regions for Crohn’s disease in whites, namely NOD2, interleukin 23 receptor (IL23R) and a region on chromosome 5 known as 5p15.1, are also important risk factors for Crohn’s disease in African-Americans.

The data findings revealed that in African-Americans, as in whites and Asians, the dominant region for ulcerative colitis genetic risk in is the human leukocyte antigen (HLA) region, a region that is a major determinant of immune regulation and risks for other immune diseases, like celiac disease and type 1 diabetes.  However, the results also show that the specific variant associated with African-Americans in this region is the same as the variant most highly associated with Japanese and Korean ulcerative colitis, and to a lesser degree ulcerative colitis in Europeans. The team note that it is also the same major risk variant in HLA for lupus in African-Americans, whose lupus risk is four times greater than white Americans.

The current study did not find evidence for the major risk variant for European ulcerative colitis as having a role in the African-American population. The lab found evidence for novel variations at a major IBD gene, the interleukin 12 cytokine subunit, IL12B, and for new regions, not previously identified in other IBD studies, of chromosomes 2 and 3, for IBD and ulcerative colitis, respectively.

Next, the researchers identified specific regions of the African-American genome that arise separately from the ancestral West African versus the ancestral European genome that are responsible for a portion of the genetic risk of IBD in the African-American population.  Results showed regions on four of the 22 autosomal (non-sex-linked) chromosomes as causative for IBD. Data findings show that for each of these regions, the IBD risk appears to come from the Caucasian ancestral genome that makes up 20 percent of the African-American genome overall or, conversely, from unique African protective variants as demonstrated in the chromosomal 17 region within immune regulatory genes STAT3 and STAT5.

The group also analyzed cellular pathways that result in IBD development. Results show as in whites, the major pathways were those related to cytokines and chemokines, molecules that transmit inflammatory signals, and cell signaling, known as JAK-STAT. However, the lab observed that the top pathway for ulcerative colitis in African-Americans and fourth of importance to both Crohn’s disease and IBD overall was related to measles infection, a pathway not previously found important to IBD in whites.

Conversely, the team note that not found in IBD in African-Americans was involvement of the Leishmania infection pathway, the second-strongest pathway for IBD in whites. Interestingly, data findings show that African trypanosomiasis infection, the cause of African sleeping sickness, was also found to be a significant and unique pathway for ulcerative colitis in African-Americans.

The lab state that their data shows several gene variants for IBD in whites are key risk factors in African-Americans.  They go on to add that also important are unique African ancestral variants that cause protection against IBD.  The team conclude that in African-Americans, as in whites and Asians, the dominant region for ulcerative colitis genetic risk in is the human leukocyte antigen region, a major determinant of immune regulation.

 

The researchers surmise that the hope for genetic advances is that the medical community will be able to develop new therapies and more precision medicine to managing these chronic and potentially debilitating diseases.  They go on to stress that these benefits should be available to all sections of society.

Source:  Johns Hopkins Medicine

 

First-Ever Comprehensive Study of Genetic Risks for Inflammatory Bowel Disease in African-Americans - healthinnovations

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