SEMA4D gene variant quadruples obesity risk in individuals of African descent

March 26, 2017 – There is ample evidence that the burden of obesity is not the same across ethnic groups. While diet and lifestyle play a large role in determining body weight, there is also a heritable component. Unfortunately,  most prior studies that have evaluated the role of genes in obesity have looked mostly at people of European or Asian descent, yet there is evidence that in the US, for example, African Americans are having the highest age-adjusted rates of obesity. In a recent study, just published online in the Journal Obesity, a research team led by Guanjie Chen, PhD, of the US National Institutes of Health (NIH) closed the existing gap in genomic research on the etiology of obesity in individuals of African decent.

Body mass index (BMI) > than 31

The researchers performed a genome wide association study (GWAS), which compares the genomes of people with a certain condition, i.e. obesity in this case, and those without it, to find genetic variants linked to obesity.

In a first step, the study included 1570 participants from Nigeria, Ghana, and Kenya, drawn from the African American Diabetes Mellitus Study (AADM). The scientists then replicated their findings in a second analysis, which included 1411 West Africans and 9020 African Americans from the Atherosclerosis Risk in Communities (ARIC) study, Cleveland Family Study, Howard University Family Study, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis(MESA).

Results showed, for the first time, that the SEMA4D gene may be involved in the pathway to obesity. Past studies have implicated the gene in inflammation and autoimmune diseases like multiple sclerosis and nonalcoholic steatohepatitis. The authors noted that the link between SEMA4AD and inflammation was promising, because of the triangular relationship between obesity, inflammation, and metabolic abnormalities like insulin resistance. The GWAS study identified a new genetic variant in the gene, called the C allele, which was significantly associated with BMI (= 2.10 x 10-8). The replication study in West Africans and African Americans similarly showed that the C allele was significantly associated with obesity (= .013 and P  = .017, respectively).

The researchers also tested blood levels of SEMA4D in a subgroup of 1343 individuals from the GWAS study. Results showed that the carriers of the C allelic variant, which was the case in approximately 1% of those studied, had a higher prevalence of obesity and over four times increased odds (see here for Odds ratio) of obesity than those without it (55.6% vs 22.9%; OR, 4.22; < 1 x 10-4). Carriers of this variant had mean body mass indexes (BMI‘s) that were over five points higher than noncarriers (31.9 kg/m2 vs 26.62 kg/m2= .0007). People of European and Asian descent do not appear to carry this C allelic variant, the authors point out, which explains why past studies did not uncover it.

These results highlight the importance of conducting genomic analyses in diverse populations and identifies a novel locus that may drastically improve the understanding of BMI-related physiology. The authors note that the C allele likely does not cause obesity but may be involved in tracking and regulating other genetic elements involved in the condition.


See additional selected information on genes and variants thereof associated with obesity in selectedof ethnicities:

The interesting finding in the Samoan Population is the discovery of the CREBFR gene as a risk factor for obesity occurring in very high frequency (about 50%) in this population.

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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