Genetic variation at the SLC23A1 locus is associated with circulating concentrations of L-ascorbic acid (vitamin C): evidence from 5 independent studies with >15,000 participants

Abstract

Background: L-ascorbic acid is an essential part of the human diet and has been associated with a wide range of chronic complex diseases, including cardiovascular outcomes. To date, there are no confirmed genetic correlates of circulating concentrations of L-ascorbic acid.

Objective: We aimed to confirm the existence of an association between common variation at the SLC23A1 gene locus and circulating concentrations of L-ascorbic acid.

Design: We used a 2-stage design, which included a discovery cohort (the British Women's Heart and Health Study), a series of follow-up cohorts, and meta-analysis (totaling 15,087 participants) to assess the relation between variation at SLC23A1 and circulating concentrations of L-ascorbic acid.

Results: In the discovery cohort, variation at rs33972313 was associated with a reduction in circulating concentrations of L-ascorbic acid (-4.15 micromol/L; 95% CI: -0.49, -7.81 micromol/L; P = 0.03 reduction per minor allele). Pooled analysis of the relation between rs33972313 and circulating L-ascorbic acid across all studies confirmed this and showed that each additional rare allele was associated with a reduction in circulating concentrations of L-ascorbic acid of -5.98 micromol/L (95% CI: -8.23, -3.73 micromol/L; P = 2.0 x 10(-7) per minor allele).

Conclusions: A genetic variant (rs33972313) in the SLC23A1 vitamin C active transporter locus was identified that is reliably associated with circulating concentrations of L-ascorbic acid in the general population. This finding has implications more generally for the epidemiologic investigation of relations between circulating L-ascorbic acid and health outcomes.

Figure 1

Schematic of genetic variation assessed across the SLC23A1 locus. Variants assessed in discovery cohort, A - rs6596471 (138733487), B - rs6596473 (138738475), C - rs33972313 (138743401), D - rs10063949 (138747425). Open boxes represent 5′ and 3′ untranslated regions, strong bars represent exons. Base positions from Reference Assembly NC_000005.8

Figure 2

Relationship between mean and difference in two repeat measurements of circulating L ascorbic acid (Bland Altman plot) in the British Women’s Heart and Health Study (n = 3592).

Figure 3

Meta-analysis summary of rs33972313 association with circulating vitamin C from discovery and replication studies. X axis represents associated difference in L-ascorbic acid per rare allele at rs33972313 (μmol/L). Sections 1 and 2 show sub-analyses by L-ascorbic assay type. BWHHS n=3425, BRHS n=3740, Ten Towns n=1359, EPIC n=4501, MIDSPAN n=1814. Overall - a meta-analysed pooled estimate of per allele association (random effects).