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African Ancestry-Specific Variant Linked to Increased BMI, Obesity

NEW YORK (GenomeWeb) – An international team of researchers has homed in on a variant linked to increased obesity among people of African descent.

While lifestyle and culture affect people's risk of developing obesity, it is also thought to be highly heritable, with some estimates placing its heritability at 60 percent. The prevalence of obesity isn't constant across populations — in the US, African Americans have the highest rates of obesity.

In a new study, a National Human Genome Research Institute-led team conducted a genome-wide association study for body-mass index on some 1,570 people from West Africa and found a novel variant within the SEMA4D gene, which has a role in immune response and other processes. As they reported today in the journal Obesity, the researchers replicated this finding in an additional group of West Africans and African Americans. They also found that higher serum levels of the protein SEMA4D were linked to increased obesity risk.

"By studying people of West Africa, the ancestral home of most African Americans, and replicating our results in a large group of African Americans, we are providing new insights into biological pathways for obesity that have not been previously explored," study co-author Ayo Doumatey from NHGRI said in a statement

She and her colleagues performed a GWAS for BMI on a cohort of 1,570 people from Nigeria, Ghana, and Kenya who were taking part in the African America Diabetes Mellitus study, a genetic epidemiology study of type 2 diabetes. This discovery phase uncovered one variant with genome-wide significance and five loci with suggestive evidence of association.

To validate the significant variant, located within an intron of the SEMA4D gene, the researchers genotyped a further 1,411 West Africans and 9,020 African Americans to again associate it with BMI.

Across all three cohorts, the researchers noted a consistent direct effect of the C allele. They further found that CT heterozygotes had a higher mean BMI, as compared to the TT homozygotes, and that 55.6 percent of the CT heterozygotes were obese, while only 22.9 percent of TT homozygotes were. In particular, they reported that individuals with the C allele were some 4.6 BMI units heavier than carriers of the T allele — a difference of about six pounds.

The lead SNP the researchers uncovered is polymorphic among people of African ancestry, but monomorphic among those of European or Asian descent, according to their analysis of 1000 Genomes Project data. To the researchers, this underscored the need for conducting research among diverse populations.

Circulating SEMA4D protein levels were also higher among obese people, Doumatey and her colleagues reported.

SEMA4D encodes a transmembrane glycoprotein that is expressed by platelets, activated B cells, and resting T cells, among other cell types. It has been linked to cell-cell signaling, immune response, and bone formation, and has been associated with inflammatory and autoimmune disorders like multiple sclerosis and non-alcoholic steatohepatitis, the researchers noted.

In these conditions, SEMA4D has appeared to be up-regulated by the activation and differentiation of T cells and the promotion of T helper 1 cells. In obesity, the researchers added, there's an increased accumulation of T cells, which suggests a possible role for SEMA4D in the condition.

The researchers are planning to replicate this work in additional populations and will pursue cell line and animal model studies to tease out the role of SEMA4D variants in obesity.

"Eventually, we hope to learn how to better prevent or treat obesity," co-author Charles Rotimi from NHGRI said in a statement.