Gene Variants That Contribute to Skin Color in African Americans Are Associated With Vitamin D Deficiency

Vitamin D deficiency is a known contributor to an individual's risk of developing certain diseases, including cancer and cardiovascular disease (CVD). It's estimated that more than 70% of African Americans are vitamin D deficient, consequently increasing their risk for such diseases.

A new body of work by researchers at City of Hope has adopted a genome-wide association study (GWAS) approach to explore genetic factors that contribute to skin pigmentation in 1,076 African Americans.¹ They have utilized this data to look for specific genetic factors that are associated with vitamin D deficiency in the same population.

Their findings highlight three specific regions, SLC24A5, SLC45A2 and OCA2 in the genes of African Americans that show strong associations with skin color and vitamin D deficiency. The scientists hope that in the future, their work might lead to the development of a precision medicine tool.

This research is the first to identify genetic variants that contribute to pigmentation. Technology Networks interviewed Dr Rick Kittles, associate director of Health Equities at the City of Hope Comprehensive Cancer Center, and professor and director of the Division of Health Equities in the Department of Population Sciences, to learn more about the research and its social and biological significance.

Molly Campbell (MC): How does vitamin D deficiency contribute to being at greater risk of certain diseases such as cancer and cardiovascular disease?

Rick Kittles (RK): The actual mechanism is unknown, but cancer biology work has shown that vitamin D has anti-cancer benefits for certain cancers such as prostate, breast and colon. Vitamin D is a steroid hormone and turns on and off hundreds of genes that play a role in immune response and inflammation. It is likely that vitamin D deficiency leads to unregulated immune surveillance in these tissues.

MC: Can you please discuss the rationale behind the study?

RK: Since the initial stages of vitamin D production occurs in the skin upon exposure to sunlight it is known that darker skinned individuals make less vitamin D than those with lighter skin upon the same UVR exposure. Given this, we believed that genes for skin color may play a role in risk for vitamin D deficiency. We performed a large genetic study to identify genes for skin color in African Americans (AAs) and determine whether these genes play a role in vitamin D deficiency in African Americans.

MC: Please can you briefly outline your study methodology and why you chose this approach?

RK: We performed a genetic association analysis for skin pigmentation in AAs to discover genes for skin color. Since AAs vary greatly in skin color this population would be ideal for finding genes influencing the trait. We then performed genetic analyses to determine if these same genes contribute to risk in vitamin D deficiency. Our risk model included age, UV season, total vitamin D intake, recruitment site, West African Ancestry and also genetic score calculated from vitamin D metabolic pathway gene variants associated with serum 25(OH)D levels (which we published previously).

MC: Can you talk about the three regions, SLC24A5, SLC45A2 and OCA2, that you identified with strong links to skin color and severe vitamin D deficiency?

RK: These three genes are major predictors for skin color. They represent ion channels and transporters that impact PH levels in cells responsible for melanogenesis (production of melanin). Given their importance in skin color, they also play a role in risk for vitamin D deficiency.

MC: This was the first genome-wide association study of skin pigmentation in African Americans. Why is this, in your opinion?

RK: The lack of diversity among biomedical researchers has led to low prioritizing of studies from diverse populations. This also leads to a lack of trust from underrepresented groups and low participation rates from these groups. This is sad, because for a study like skin color and vitamin D deficiency, African Americans contribute so much variation for these traits. Much more than European populations which have been studied exhaustively.

MC: How do you hope to leverage the results of this study?

RK: We intend to continue to develop our risk model for vitamin D deficiency in hopes for some clinical utility. We also will continue the role vitamin D plays in cancer.

MC: Are there any limitations to the study that you would like to highlight?

RK: The only limitation was sample size. If we had a larger sample size, we could have possibly discovered more genetic variants.

MC: In the press release, you say "If we ignore things such as the color of a person's skin, we may be ignoring potential medical issues, thus contributing to health care disparities." Please can you expand on this statement?

RK: There is a growing debate on the utility of race in medical practice. For the most part in the US, race is largely based on skin color and is linked with medicine in a complex and horrible history. In an effort to exorcise the historic demons of race in America, many believe that it is appropriate to simply abandon the use of race and ethnicity in biomedical research and clinical practice. However, I disagree since these variables help capture important epidemiologic information, including social determinants of health such as racism and discrimination, socioeconomic status, and environmental exposures but also their interactions with biology, in this case skin color and vitamin D deficiency.

MC: What are your next steps in this research space?

RK: There is a need to understand how vitamin D deficiency contributes to cancer. We intend to further interrogate the vitamin D signaling pathway in order to find potential mechanism of action and potential therapeutic targets.

Rick Kittles was speaking to Molly Campbell, Science Writer for Technology Networks.

Reference: Batai K, Cui Z, Arora A, et al. Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency. PLOS Genetics. 2021. doi:10.1371/journal.pgen.1009319.