Reply: “comment on: The vitamin D–folate hypothesis as an evolutionary model for skin pigmentation: An update and integration of current ideas, nutrients 2018, 10, 554”

We thank Elias and Williams for their interest in our review [...

The vitamin D–folate hypothesis as an evolutionary model for skin pigmentation: An update and integration of current ideas

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Vitamin D is unique in being generated in our skin following ultraviolet radiation (UVR) exposure. Ongoing research into vitamin D must therefore always consider the influence of UVR on vitamin D processes. The close relationship between vitamin D and UVR forms the basis of the “vitamin D–folate hypothesis”, a popular theory for why human skin colour has evolved as an apparent adaption to UVR environments. Vitamin D and folate have disparate sensitivities to UVR; whilst vitamin D may be synthesised following UVR exposure, folate may be degraded. The vitamin D–folate hypothesis proposes that skin pigmentation has evolved as a balancing mechanism, maintaining levels of these vitamins. There are several alternative theories that counter the vitamin D–folate hypothesis. However, there is significant overlap between these theories and the now known actions of vitamin D and folate in the skin. The focus of this review is to present an update on the vitamin D–folate hypothesis by integrating these current theories and discussing new evidence that supports associations between vitamin D and folate genetics, UVR, and skin pigmentation. In light of recent human migrations and seasonality in disease, the need for ongoing research into potential UVR-responsive processes within the body is also discussed

Standard setting in Australian medical schools

Background: Standard setting of assessment is critical in quality assurance of medical programs. The aims of this study were to identify and compare the impact of methods used to establish the passing standard by the 13 medical schools who participated in the 2014 Australian Medical Schools Assessment Collaboration (AMSAC). Methods: A survey was conducted to identify the standard setting procedures used by participating schools. Schools standard setting data was collated for the 49 multiple choice items used for benchmarking by AMSAC in 2014. Analyses were conducted for nine schools by their method of standard setting and key characteristics of 28 panel members from four schools. Results: Substantial differences were identified between AMSAC schools that participated in the study, in both the standard setting methods and how particular techniques were implemented. The correlation between the item standard settings data by school ranged from − 0.116 to 0.632. A trend was identified for panel members to underestimate the difficulty level of hard items and overestimate the difficulty level of easy items for all methods. The median derived cut-score standard across schools was 55% for the 49 benchmarking questions. Although, no significant differences were found according to panel member standard setting experience or clinicians versus scientists, panel members with a high curriculum engagement generally had significantly lower expectations of borderline candidates (p = 0.044). Conclusion: This study used a robust assessment framework to demonstrate that several standard setting techniques are used by Australian medical schools, which in some cases use different techniques for different stages of their program. The implementation of the most common method, the Modified Angoff standard setting approach was found to vary markedly. The method of standard setting used had an impact on the distribution of expected minimally competent student performance by item and overall, with the passing standard varying by up to 10%. This difference can be attributed to the method of standard setting because the ASMSAC items have been shown over time to have consistent performance levels reflecting similar cohort ability. There is a need for more consistency in the method of standard setting used by medical schools in Australia

Environmental UVR Levels and Skin Pigmentation Gene Variants Associated with Folate and Homocysteine Levels in an Elderly Cohort

Ultraviolet radiation (UVR) is a ubiquitous exposure which may contribute to decreased folate levels. Skin pigmentation mediates the biological effect of UVR exposure, but its relationship to folate levels is unexamined. Interactions may exist between UVR and pigmentation genes in determining folate status, which may, in turn, impact homocysteine levels, a potential risk factor for multiple chronic diseases. Therefore, independent and interactive influences of environmental UVR and genetic variants related to skin pigmentation (MC1R-rs1805007, IRF4-rs12203592 and HERC2-rs12913832) on folate (red blood cell (RBC) and serum) and homocysteine levels were examined in an elderly Australian cohort (n = 599). Genotypes were assessed by RT/RFLP-PCR, and UVR exposures were assessed as the accumulated erythemal dose rate accumulated over 4 months (4M-EDR). Multivariate analysis found significant negative associations between 4M-EDR and RBC folate (p < 0.001, β = -0.19), serum folate (p = 0.045, β = -0.08) and homocysteine levels (p < 0.001, β = -0.28). Significant associations between MC1R-rs1805007 and serum folate levels (p = 0.020), and IRF4-rs12203592 and homocysteine levels (p = 0.026) occurred but did not remain significant following corrections with confounders. No interactions between 4M-EDR and pigmentation variants in predicting folate/homocysteine levels were found. UVR levels and skin pigmentation-related variants are potential determinants of folate and homocysteine status, although, associations are mixed and complex, with further studies warranted

Interactions between bitter taste, diet and dysbiosis: Consequences for appetite and obesity

The type 2 family of taste receptors (T2Rs) detect and respond to bitter tastants. These receptors are expressed throughout the gastrointestinal (GI) tract, with location dependant roles. In the oral cavity, T2Rs are involved in the conscious perception of bitter tastants, while in the lower GI tract they have roles in chemoreception and regulation of GI function. Through these diverse roles, these receptors may be involved in modulating appetite and diet, with consequences for weight regulation and obesity. Interestingly, the concentration of T2Rs in the GI tract is greatest in the large intestine, the organ with the densest colonisation of bacteria. The gut microbiome has been the subject of intense research, as a plethora of roles linking microbiota to human health continue to be uncovered. Of particular interest is the microbial signature associated with obesity. Obesity is a leading health concern, and advances in our understanding of this disease are needed. Diet is a known modifiable factor in the development of obesity. However, diet only partially explains disease risk. Changes in microbial energy harvesting by the microbiota plays a role in obesity, and the composition of these energy harvesting populations may be controlled by taste receptors. This review explores T2Rs as a potential link between obesity and the human GI microbiome

Intense Sweeteners, Taste Receptors and the Gut Microbiome: A Metabolic Health Perspective

Intense sweeteners (IS) are often marketed as a healthier alternative to sugars, with the potential to aid in combating the worldwide rise of diabetes and obesity. However, their use has been counterintuitively associated with impaired glucose homeostasis, weight gain and altered gut microbiota. The nature of these associations, and the mechanisms responsible, are yet to be fully elucidated. Differences in their interaction with taste receptors may be a potential explanatory factor. Like sugars, IS stimulate sweet taste receptors, but due to their diverse structures, some are also able to stimulate bitter taste receptors. These receptors are expressed in the oral cavity and extra-orally, including throughout the gastrointestinal tract. They are involved in the modulation of appetite, glucose homeostasis and gut motility. Therefore, taste genotypes resulting in functional receptor changes and altered receptor expression levels may be associated with metabolic conditions. IS and taste receptors may both interact with the gastrointestinal microbiome, and their interactions may potentially explain the relationship between IS use, obesity and metabolic outcomes. While these elements are often studied in isolation, the potential interactions remain unexplored. Here, the current evidence of the relationship between IS use, obesity and metabolic outcomes is presented, and the potential roles for interactions with taste receptors and the gastrointestinal microbiota in modulating these relationships are explored

Distribution of variants in multiple vitamin D-related loci (DHCR7/NADSYN1, GC, CYP2R1, CYP11A1, CYP24A1, VDR, RXRα and RXRγ) vary between European, East-Asian and Sub-Saharan African-ancestry populations

BackgroundThe frequency of vitamin D-associated gene variants appear to reflect changes in long-term ultraviolet B radiation (UVB) environment, indicating interactions exist between the primary determinant of vitamin D status, UVB exposure and genetic disposition. Such interactions could have health implications, where UVB could modulate the impact of vitamin D genetic variants identified as disease risk factors. However, the current understanding of how vitamin D variants differ between populations from disparate UVB environments is limited, with previous work examining a small pool of variants and restricted populations only.MethodsGenotypic data for 46 variants within multiple vitamin D-related loci (DHCR7/NADSYN1, GC, CYP2R1, CYP11A1, CYP27A1, CYP24A1, VDR, RXRα and RXRγ) was collated from 60 sample sets (2633 subjects) with European, East Asian and Sub-Saharan African origin via the NCBI 1000 Genomes Browser and ALFRED (Allele Frequency Database), with the aim to examine for patterns in the distribution of vitamin D-associated variants across these geographic areas.ResultsThe frequency of all examined genetic variants differed between populations of European, East Asian and Sub-Saharan African ancestry. Changes in the distribution of variants in CYP2R1, CYP11A1, CYP24A1, RXRα and RXRγ genes between these populations are novel findings which have not been previously reported. The distribution of several variants reflected changes in the UVB environment of the population’s ancestry. However, multiple variants displayed population-specific patterns in frequency that appears not to relate to UVB changes.ConclusionsThe reported population differences in vitamin D-related variants provides insight into the extent by which activity of the vitamin D system can differ between cohorts due to genetic variance, with potential consequences for future dietary recommendations and disease outcomes

Reduced plasma homocysteine levels in elderly Australians following mandatory folic acid fortification – A comparison of two cross-sectional cohorts

© 2017 Objective In 2009, Australia implemented mandatory folic acid fortification in wheat flour for bread-making. The primary aim was to improve folate status in reproductive-aged women to reduce neural tube defect incidence. However, folic acid consumption has consequently increased in all demographics. Blood folate is inversely associated with homocysteine levels, a risk factor for multiple diseases. Therefore, we assessed the impact of mandatory folic acid fortification on homocysteine levels in elderly Australians. Methods Homocysteine and blood folate levels were compared between two elderly cross-sectional cohorts (pre-versus post-mandatory folic acid fortification). Importantly, dietary habits were assessed to evaluate the confounding influence of altered dietary patterns not related to fortification. Results Post-fortification, plasma homocysteine levels (10.6 vs. 14.5 μmol/L) and hyperhomocysteinemia incidence (27.2% vs 56.3%) were significantly reduced, relative to the pre-fortification subjects. This was associated with increased blood folate (red cell: 1243 vs 1066 nmol/L, serum 28.0 vs 23.9 nmol/L), and increased intake of synthetic folic acid (366.8 vs 231.0 DFE/day) but not natural folate (332.7 vs 323.6 DFE/day). Limited other differences were detected in dietary intake patterns between groups. The positive relationship between homocysteine levels and age was abrogated post-fortification (p = 0.3 vs p = 0.0003). Conclusions A potential off-target benefit of mandatory folic acid fortification in Australia was demonstrated. With many countries still considering the merits and consequences of mandatory fortification policies, it is important to unravel the off-target effects including dietary context

Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels

Elevated homocysteine (Hcy) levels are a risk factor for vascular diseases. Recently, increases in ultraviolet radiation (UVR) have been linked to decreased Hcy levels. This relationship may be mediated by the status of UVR-responsive vitamins, vitamin D and folate, and/or genetic variants influencing their levels; however, this has yet to be examined. Therefore, the independent and interactive influences of environmental UVR, vitamin D and folate levels and related genetic variants on Hcy levels were examined in an elderly Australian cohort (n = 619). Red blood cell folate, 25-hydroxyvitamin D (25(OH)D), and plasma Hcy levels were determined, and genotyping for 21 folate and vitamin D-related variants was performed. Erythemal dose rate accumulated over six-weeks (6W-EDR) and four-months (4M-EDR) prior to clinics were calculated as a measure of environmental UVR. Multivariate analyses found interactions between 6W-EDR and 25(OH)D levels (pinteraction = 0.002), and 4M-EDR and MTHFD1-rs2236225 (pinteraction = 0.006) in predicting Hcy levels. The association between 6W-EDR and Hcy levels was found only in subjects within lower 25(OH)D quartiles (<33.26 ng/mL), with the association between 4M-EDR and Hcy occurring only in subjects carrying the MTHFD1-rs2236225 variant. 4M-EDR, 6W-EDR, and MTHFD1-rs2236225 were also independent predictors of Hcy. Findings highlight nutrient–environment and gene–environment interactions that could influence the risk of Hcy-related outcomes

Salt Taste Genotype, Dietary Habits and Biomarkers of Health: No Associations in an Elderly Cohort

A small amount of emerging research has observed variations between individual sensitivity, preference and intake of salt in the presence of single nucleotide polymorphisms (SNP) on the genes encoding salt taste receptors. Sodium intake is a significant risk factor for common diseases in elderly populations such as hypertension and cardiovascular disease; however, this does not fully explain the risk. Research into the influence of salt taste genetics on diet quality is yet to be undertaken and current research on indicators of health is limited and mixed in the direction of associations. Therefore, a secondary analysis of data from a well-characterised elderly cohort (the cross-sectional Retirement Health and Lifestyle Study, n = 536) was conducted to explore relationships between the salt taste-related SNP TRPV1-rs8065080 (assessed by Taqman genotyping assay), dietary habits and biomarkers of health. Data were analysed with standard least squares regression modelling and Tukey’s HSD post hoc tests. No association was found between the TRPV1-rs8065080 genotype, sodium intake or multiple diet quality indices (assessed by food frequency questionnaire). Sodium-related markers of health including blood pressure and markers of kidney function (urinary creatinine and albumin/creatinine ratio) and general health markers, such as Body Mass Index (BMI), were also not related to TRPV1-rs8065080 genotype. To date, this study is the most comprehensive investigation conducted to determine if the TRPV1-rs8065080 genotype relates to sodium intake and health markers influenced by sodium intake. Although no significant relationships were found, these findings are an important contribution to the limited body of knowledge surround this SNP. In addition to further research across other ages and cultures, the TRPV1-rs8065080 genotype may interact with other ion channels, and so further studies are required to determine if polymorphic variations influence sodium intake, diet and health. View Full-Tex