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Updated: Apr 19, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Variation in the SLC23A1 gene does not influence cardiometabolic outcomes to the extent expected given its
Kaitlin H Wade1, Nita G Forouhi1, Derek G Cook1
1From the Medical Research Council (MRC) Integrative Epidemiology Unit (KHW, DAL, GDS, and NJT) and the School of Social and Community Medicine (KHW, NGF, SR, DAL, GDS, and NJT), University of Bristol, Bristol, United Kingdom; the MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, United Kingdom (NGF, ZY, and NJW); the Division of Community and Health Sciences, St. George's University of London, London, United Kingdom (DGC and PHW); the Robertson Centre for Biostatistics, Glasgow, United Kingdom (PJ and AM); the Department of Primary Care & Population Health (RWM), the Department of Structural and Molecular Biology, University College London (KRB), London, United Kingdom (RWM); the London School of Hygiene and Tropical Medicine, London, United Kingdom (SE); the British Heart Foundation Glasgow Cardiovascular Research Centre, Faculty of Medicine (SP and NS) and General Practice and Primary Care, Division of Community Based Sciences (GW), University of Glasgow, Glasgow, United Kingdom; and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (SC).
Background:
Observational studies showed that circulating L-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation.
Objectives:
We assessed the relation between L-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs33972313) associated with circulating L-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-L-ascorbic acid and L-ascorbic acid-outcome associations.
Design:
A meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737).
Results:
With the use of a meta-analysis of observational estimates, inverse associations were shown between L-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (-0.13-SD change; 95% CI: -0.20-, -0.07-SD change; P = 0.0001) per SD increase in L-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 × 10⁻⁶) increase in L-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected.
Conclusions:
The nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of L-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between L-ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation.
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