New Gene Variant Linked to Obesity in Africans, Black Americans

Veronica Hackethal, MD

March 24, 2017

Scientists have discovered a new genetic variant linked to obesity in people of African descent. Those who carry a variant in the semaphorin-4D (SEMA4D) gene had body mass indices (BMIs) that were over five points higher than noncarriers, according to the results, published online in Obesity.

While diet and lifestyle play a large role in determining body weight, there is also a heritable component. But most prior studies that have evaluated the role of genes in obesity have looked only at people of European or Asian descent, say the authors of the new study, led by Guanjie Chen, PhD, of the US National Institutes of Health (NIH).

This research is the first genomewide association study (GWAS) to investigate the genetic contributions to obesity in people of African ancestry, who are at increased risk for the condition, they add.  

"The burden of obesity is… not the same across US ethnic groups, with African Americans having the highest age-adjusted rates of obesity," senior author Charles N Rotimi, PhD, notes in an NIH press release.

"We wanted to close this unacceptable gap in genomics research," he added.

Dr Rotimi is chief of the National Human Genome Research Institute's (NHGRI) Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch and director of the Center for Research on Genomics and Global Health (CRGGH) at the NIH.

Gene Variant Quadruples Likelihood of Obesity

The researchers performed a GWAS, which compares the genomes of people with a certain condition and those without it, to find genetic variants linked to obesity.

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).

"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," second author Ayo P Doumatey, PhD, a CRGGH staff scientist, said in the press release.

Results showed, for the first time, that the SEMA4AD 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 link between SEMA4AD and inflammation is "promising," the authors note, because of the triangular relationship between obesity, inflammation, and metabolic abnormalities like insulin resistance.

The GWAS study also identified a new genetic variant in the SEMA4AD gene, called the C allele, which was significantly associated with BMI (P = 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 (P = .013 and P  = .017, respectively).

Researchers also tested blood levels of SEMA4D in a subgroup of 1343 individuals from the GWAS study.

Results showed that those with the C variant — which was approximately 1% of those studied — had a higher prevalence of obesity and over four times increased odds of obesity than those without it (55.6% vs 22.9%; OR, 4.22; P < 1 x 10-4).

Carriers of this variant had mean BMIs that were over five points higher than noncarriers (31.9 kg/m2 vs 26.62 kg/m2; P = .0007).

People of European and Asian descent do not appear to carry this C variant, the authors point out, which explains why past studies did not uncover it.

Such oversight "highlight[s] the importance of conducting genomic analyses in diverse populations and identifies a novel locus that may improve our understanding of BMI-related physiology," they write.

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.

Dr Rotimi and his team now plan to conduct laboratory studies to investigate the function of the variant and test larger populations for it. They also plan larger DNA sequencing studies to look for other genes involved in obesity.

"Eventually, we hope to learn how to better prevent or treat obesity," he concluded.

The study was supported in part by the NIH and National Institutes of Diabetes and Digestive Kidney Diseases (NIDDK). The National Heart, Lung, and Blood (NHLBI) supported genotyping and the Atherosclerosis Risk in Communities (ARIC) study, the Multi-Ethnic Study of Atherosclerosis (MESA), and the MESA SHARe project and Cleveland Family Study were supported by National Heart, Lung, and Blood (NHLBI). The Howard University Family Study (HUFS) was supported by the National Institutes of Health. The Jackson Heart Study was supported by the Jackson State University, Tougaloo College, and the University of Mississippi Medical Center with contracts from NHLBI and the National Institute for Minority Health and Health Disparities. The authors report no relevant financial relationships.

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Obesity. Published online March 13, 2017. Article

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