AUTHOR=Lelievre Rebecca , Rakesh Mohan , Hysi Pirro G. , Little Julian , Freeman Ellen E. , Roy-Gagnon Marie-Hélène
TITLE=Effect modification by sex of genetic associations of vitamin C related metabolites in the Canadian Longitudinal study on aging
JOURNAL=Frontiers in Genetics
VOLUME=15
YEAR=2024
URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1411931
DOI=10.3389/fgene.2024.1411931
ISSN=1664-8021
ABSTRACT=Introduction: Vitamin C is an essential nutrient. Sex differences in serum vitamin C concentrations have been observed but are not fully known. Investigation of levels of metabolites may help shed light on how dietary and other environmental exposures interact with molecular processes. O-methylascorbate and ascorbic acid 2-sulfate are two metabolites in the vitamin C metabolic pathway. Past research has found genetic factors that influence the levels of these two metabolites. Therefore, we investigated possible effect modification by sex of genetic variant-metabolite associations and characterized the biological function of these interactions.
Methods: We included individuals of European descent from the Canadian Longitudinal Study on Aging with available genetic and metabolic data (n = 9004). We used linear mixed models to tests for genome-wide associations with O-methylascorbate and ascorbic acid 2-sulfate, with and without a sex interaction. We also investigated the biological function of the important genetic variant-sex interactions found for each metabolite.
Results: Two genome-wide statistically significant (p value < 5 × 10−8) interaction effects and several suggestive (p value < 10–5) interaction effects were found. These suggestive interaction effects were mapped to several genes including HSD11B2, associated with sex hormones, and AGRP, associated with hunger drive. The genes mapped to O-methylascorbate were differently expressed in the testis tissues, and the genes mapped to ascorbic acid 2-sulfate were differently expressed in stomach tissues.
Discussion: By understanding the genetic factors that impact metabolites associated with vitamin C, we can better understand its function in disease risk and the mechanisms behind sex differences in vitamin C concentrations.