Vitamin B12 status: are genetics a driving factor?

Science Spotlight

Vitamin B12 status: are genetics a driving factor?

From the Reiner Group, Public Health Sciences Division

June 18, 2018

Vitamin B12 is an essential water-soluble vitamin that functions as a required cofactor in two enzymatic reactions. The vitamin B12-dependent enzymes are involved in energy metabolism and DNA synthesis, among other functions, and deficiency of this vitamin can lead to anemia and neurological dysfunction. In the United States, the prevalence of vitamin B12 deficiency is less than 5% in young and middle-aged adults but is between 5 and 10% in the elderly population. However, marginal vitamin B12 status is more common, with an estimated 20% of individuals 60 years and older affected. In addition to age, vitamin B12 status also differs by race/ethnicity, and African Americans have higher circulating levels of B12 compared to Caucasians.

Limited consumption of vitamin B12-containing foods and poor intestinal absorption are major contributors to low plasma levels while recent evidence from genome-wide association studies (GWAS) suggests that genetic factors also contribute to circulating levels of this vitamin. Researchers from Dr. Alex Reiner’s group in the Public Health Sciences Division recently published a paper in the journal Blood that reports results from a GWAS of genetic variants associated with vitamin B12 status in African Americans. The focus on this population was a novel aspect, as none of the previous GWAS of Vitamin B12 status have been performed in populations of African descent.

The authors utilized data from the Jackson Heart Study, a longitudinal epidemiological study of factors associated with cardiovascular disease specifically in African Americans. Dr. Reiner described their study design, “In the current study, we utilized a whole genome sequencing approach and a large African American cohort study from Jackson Mississippi through the National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program to assess genetic determinants of vitamin B12 in a community-based sample of African Americans.” The analyses included plasma vitamin B12 concentration and over twenty-nine million genetic variants from 1,280 participants.

Graphical representation of genetic variants associated with plasma vitamin B12 concentration in African Americans.

Genetic variants of TCN1 (top) and FUT2 (bottom) are significantly associated with plasma vitamin B12 concentration in African Americans. The color dots represent association P-values for genetic variants with vitamin B12 status.

Image provided by Yao Hu

After adjusting for participant age, sex, and genetic ancestry, the authors found significant associations between vitamin B12 levels and thirty-three genetic variants located within two genomic regions (see Figure). One of newly discovered variants was associated with lower levels of circulating vitamin B12 in the study cohort, as explained by Dr. Reiner, “We identified a loss-of-function variant of the transcobalamin B12 transporter gene, TCN1. The TCN1 mutation is prevalent among African descent populations, but not among Europeans.” The impact of this variant on relevant health outcomes that can be altered with low vitamin B12 status, such as certain red blood cell indices and circulating levels of homocysteine, were also explored by the authors. “In a subsequent analysis of two large U.S. electronic health record data sets, we were unable to identify any significant clinical sequelae of African Americans carrying this particular TCN1 mutation, apart from having lower B12 levels,” said Dr. Reiner.

Other significantly associated variants were located within the region of FUT2, a gene that encodes the glycosylation enzyme fucosyltransferase 2 (see Figure). The most highly significant FUT2 variant identified in the current study is specific to African Americans while one of the other FUT2 variants has previously been shown to be associated with vitamin B12 status in Caucasians and Indians.

Taken together with previous work, the results from this study demonstrate that genetic heterogeneity contributes to differences in vitamin B12 status among different races and ethnic groups. These results also suggest that “carrying this particular genetic variant may be benign, and therefore important to exclude from other forms of vitamin B12 deficiency,” noted Dr. Reiner.


This research was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health.

Hu Y, Raffield LM, Polfus LM, Moscati A, Nadkarni G, Preuss MH, Zhong X, Wei Q, Rich SS, Li Y, Wilson JG, Correa A, Loos RJF, Li B, Auer PL, Reiner AP. 2018. A common TCN1 loss-of-function variant is associated with lower vitamin B12 concentration in African Americans. Blood. doi:10.1182/blood-2018-03-841023.