Effect modification by sex of genetic associations of vitamin C related metabolites in the Canadian Longitudinal Study on Aging

Vitamin C is an essential dietary factor. There have been observed sex differences in serum vitamin C concentrations but the reason for this is not fully known. To understand how environmental factors like vitamin C intake interact with molecular processes, levels of metabolites can be used. Two metabolites associated with vitamin C are O-methylascorbate and ascorbic acid 2 sulfate. Past research has found there are genetic factors that influence these metabolite levels. Here, we aimed to investigate if there is effect modification by sex of these gene-metabolite associations and characterize the biological function of these interactions. We included individuals of European descent from the Canadian Longitudinal Study on Aging with available genetic and metabolic data (n= 9004). We conducted a genome wide association study with and without a sex interaction using mixed linear models. We also investigated the biological function of the important gene-sex interactions found for each metabolite. Two genome-wide statistically significant (p-value < 5x10-8) interaction effects and several suggestive (p-value < 10-5) interaction effects were found. The suggestive interaction associations were mapped to several genes including HSD11B2, which is associated with sex hormones and AGRP that helps initiate hunger drive. By understanding the genetic factors that impact metabolites associated with vitamin C, we better understand its function in disease risk. In addition, highlighting genetic markers and genes whose effects are modified by sex can help to understand the mechanisms behind sex differences in vitamin C levels and guide further research. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by CIHR operating grant PJT-180615 to Drs Roy-Gagnon and Freeman. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The analysis presented here was approved by the University of Ottawa research ethics board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available from the Canadian Longitudinal Study on Aging (www.clsa-elcv.ca) for researchers who meet the criteria for access to de-identified CLSA data. Code is made available on GitHub (https://github.com/Roy-Gagnon-lab). Summary statistics for the interaction GWAS will be made available on GWAS Catalog (Data are available from the Canadian Longitudinal Study on Aging (www.clsa-elcv.ca) for researchers who meet the criteria for access to de-identified CLSA data. Code is made available on GitHub. Summary statistics for the interaction GWAS will be made available on GWAS Catalog.