To the Editor: Community Prevalence of Vitamin C Deficiency and Nutrition

We were interested in reading the paper by Carter et al. [1]. In this study, the relatively low serum vitamin C levels in Australians were linked to the average Australian diet. According to the Australian Bureau of Statistics, less than 5% of the population had an inadequate intake of vitamin C based on estimated average requirement (EAR). However, the classical view of vitamin C deficiency (formulated by Szent-Györgyi) as an exclusively nutritional disorder needs to be tailored. In large epidemiological surveys, the correlation between vitamin C intake and vitamin C concentration was shown to be rather weak. Hence, only 17% of the variance in serum vitamin C concentration can be explained by dietary vitamin C intake. Vitamin C status is determined not only by dietary vitamin C content but also by the rate of vitamin C breakdown. Lifestyle (e.g., smoking) and environmental factors, biological factors (e.g., inflammation, iron excess), and pathological conditions (e.g., hemolysis, malabsorption) have a negative effect on vitamin C status.

An increasing number of genetic factors has also been associated with vitamin C metabolism. Several vitamin C affecting polymorphisms show a marked geographical distribution. One of the most thoroughly monitored is the polymorphism of haptoglobin (Hp), which is a plasma protein with three phenotypes Hp 1-1, Hp 2-1, and Hp 2-2. The Hp phenotypes differ in antioxidant capacity, with Hp 2-2 being the worst at binding free hemoglobin and preventing oxidant stress. Hp 2-2 individuals are characterized by persistently lower serum ascorbate concentrations resulting from decreased uptake regardless of dietary intake. A significantly faster depletion of vitamin C in Hp 2-2 subjects is observed compared to Hp 1-1 and Hp 2-1 subjects, both in vivo and in vitro due to increased oxidative turnover and poorer perfusion and stabilization of ascorbate in the presence of redox-active iron [2]. A gene-diet interaction study further revealed that Hp 2-2 individuals were up to 2.8 times more likely to be vitamin C deficient when intake was below the RDA, compared to Hp 1 carriers. Importantly, actual data from an Australian cohort of over 4,200 individuals reported the distribution of Hp phenotypes as follows: Hp 1-1 in ~15%, Hp 2-1 in ~47%, and Hp 2-2 in ~38%. This means that more than one-third of Australians carry the Hp 2-2 phenotype and are therefore potentially more vulnerable to low vitamin C status, regardless of dietary intake. Furthermore, approximately 17.4% of Australians were identified as having at least some Asian ancestry in 2021, which also indicates a high prevalence of the Hp 2-2 phenotype. These direct data reinforce the argument that Australia's population-level risk for vitamin C deficiency cannot be fully understood without accounting for underlying genetic diversity.

Furthermore, in Celtic populations, the HFE C282Y mutation is associated with iron overload, which is linked to an increased catabolism of vitamin C [3]. In the heterogeneous Australian population (Australian census 2021), with many immigrants of Celtic descent (e.g., 9.5% Irish, 8.6% Scottish, and 0.6% Welsh), the prevalence of the HFE C282Y mutation is much higher than in most other countries: 2.1–2.6 million Australians carry one copy of C282Y. According to the Royal Australian College of General Practitioners (RACGP), approximately 1 in 10 individuals of Northern European ancestry are carriers of the C282Y variant.

Glutathione S-transferase P1 (GSTP1) is an enzyme that metabolizes xenobiotics including vitamin C and may have an important role in vitamin C catabolism. Subjects homozygous for the AA genotype of GSTP1 excrete nearly all of their orally administered vitamin C in urine versus the heterozygotes with the GA genotype, who almost always had a significantly lower amount of vitamin C in urine after excretion. This suggests that the homozygous AA genotype has either a higher vitamin C turnover or a lower retention rate than the heterozygous genotype GA [4]. Currently, Australia has no genotype-specific GSTP1 data but population genetic studies from Europe indicate that about 40%–50% of people of European ancestry will have the AA genotype. Given Australia's population composition, we argue that a large proportion of Australians are likely GSTP1 AA carriers which might (at least in part) explain the greater vitamin C turnover and less retention in this group.

Finally, there are multiple single-nucleotide polymorphisms (SNPs) in important genes that interact to affect vitamin C absorption, transport, and catabolism. For example, polymorphisms of the sodium-dependent vitamin C transporters (SLC23A1 and SLC23A2) show differences in plasma concentrations of vitamin C and adverse outcomes in the event of prematurity, highlighting a possible genetic vulnerability in women. Certain SLC23A1 variants are less effective in the intestinal absorption of vitamin C, whereas SLC23A2 variants may affect the dispersion of vitamin C within tissues. One study using polymorphisms in a population of pregnant women with preterm delivery revealed an association between a variant located in intron 2 of SLC23A2 and an increased risk of spontaneous preterm birth of 2.7 fold [5]. While these findings are not directly population-specific, they emphasize the biological relevance of transport-related genetic variation in determining vitamin C adequacy across diverse groups.

While a recommended dietary allowance (RDA) number may be standardized, genetically sensitive subpopulations may have varying demands. Given the high interindividual variability in vitamin C needs, a simple increase in RDA values will not result in an adequate solution for the high community prevalence of vitamin C deficiency. Establishing better-tailored RDA values for individuals at risk for vitamin C deficiency might be more efficient. In future clinical guidelines, individuals with high-risk genotypes may require distinct thresholds for “adequate” vitamin C status and could benefit from genetic screening when an unexplained deficiency is present despite adequate intake.

We support the recommendation by Carter et al. to include vitamin C status screening in general practice guidelines. However, we propose that adding genotypic risk profiling, drawn from the data on Australian Health Surveys and ancestry patterns, would enhance risk stratification and allow for more effective and personalized prevention strategies.

Joris Delanghe: project administration, conceptualization, investigation, writing – original draft. Marc De Buyzere: writing – original draft, methodology, investigation. Marijn Speeckaert: writing – original draft, supervision.

The authors declare no conflicts of interest.