Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation.

BACKGROUND: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. METHODS: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. RESULTS: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10-7) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10-11) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25). CONCLUSION: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.

The search for Schizosaccharomyces fission yeasts in environmental metatranscriptomes.

Fission yeast is an important model organism in evolutionary genetics and cell biology research. Nevertheless, most research is limited to a single laboratory strain and knowledge of its natural occurrence is limited, which reduces our understanding of its life history and hinders isolation of new strains from nature. Understanding the natural diversity of fission yeast can provide insight into its genetic and phenotypic diversity and the evolutionary processes that shaped these. Here, we aimed to identify candidate natural habitats of fission yeasts by searching through a large collection of publicly available environmental metatranscriptomic datasets. Using a custom pipeline, we processed over 13,000 NCBI SRA accessions, from a wide range of 34 different environmental categories. Overall, we found a very low abundance of putative yeast transcripts, with most fission yeast signatures coming from the categories of 'food' and 'terrestrial arthropods'. Additionally, a signal could be found in a variety of marine and fresh aquatic habitats. Our results do not provide a conclusive answer on the natural habitat of fission yeasts, but our analysis further narrows the range of locations where fission yeasts naturally occur.

Ambient ultraviolet-B radiation, supplements and other factors interact to impact vitamin D status differently depending on ethnicity: A cross-sectional study.

BACKGROUND & AIMS: Many determinants of vitamin D status have been well-described, yet supplementation guidelines largely follow a one-size-for-all model and deficiency remains common. We hypothesised that accounting accurately for ultraviolet-B (UVB) radiation and considering interactions could advance understanding of vitamin D status. METHODS: Asian, Black, and White participants from the UK Biobank cohort were included (N = 438,978). The Tropospheric Emission Monitoring Internet Service provided UVB data which we linked to participants' place of residence. UVB dose over 135 days prior to blood draw was weighted and added, yielding cumulative and weighted UVB (CW-D-UVB). The association between 25(OH)D and selected variables was assessed in multivariable linear regression models with and without interactions, stratified by ethnicity. Predictors were ranked using standardised ß-coefficients. RESULTS: Median 25(OH)D differed by ethnicity (Asian: 25.4 nmol/L (10.2 ng/mL), Black: 30.6 nmol/L (12.2 ng/mL), White: 47.9 nmol/L (19.2 ng/mL), p-value < 0.001). CW-D-UVB was strongly associated with 25(OH)D in all ethnicities. It was the most important predictor in White (ßAsian = 0.15, ßBlack = 0.20, ßWhite = 0.35), whereas supplementation was in Asian and Black participants (ßAsian = 0.30, ßBlack = 0.24, ßWhite = 0.21). We identified statistically significant interactions between BMI:supplementation (all), CW-D-UVB:sex (Asian and White), and CW-D-UVB:age (Black and White), and in White population between CW-D-UVB and supplementation, BMI, and cholesterol. CONCLUSION: Vitamin D deficiency was widespread, particularly among non-White individuals. UVB was a strong predictor of 25(OH)D and the effect was modified by other factors. Findings suggest that accurately measured ambient-UVB radiation and interactions could improve 25(OH)D prediction models, and support personalised approaches to vitamin D optimisation.

Self-compatibility in yeast is selected for reproductive assurance not population-level compatibility.

In haploid species, sexual reproduction by selfing lacks the common benefits from recombination and is indistinguishable from asexual reproduction at the genetic level. Nevertheless, the evolution of self-compatibility, known as homothallism in organisms with mating types, has occurred hundreds of times in fungi. Two main hypotheses have been proposed for the evolution of homothallism. First, that homothallism offers reproductive assurance, which is especially important when species have an obligatory sexual phase in their lifecycle. Second, that homothallism is associated with population-level compatibility, increasing the chance of outbreeding. Here, we test these hypotheses using the fission yeast Schizosaccharomyces pombe, which is homothallic by mating-type switching, leveraging natural variation for switching efficiency in this species. Combining empirical tests with cellular automaton simulations, we show that homothallism by switching increases mating success of switching genotypes, but does not affect population-level compatibility. Experiments show that outcrossing is actually reduced under homothallism. This reduction in outcrossing is explained by our simulations, which show that due to local mating, gametes that mated through intraclonal selfing are no longer available for outcrossing. Our results suggest that the recurrent evolution of haploid self-compatibility is likely driven by selection for mating assurance, not to increase the potential for outcrossing.

Systematic review on gene-sun exposure interactions in skin cancer.

BACKGROUND: The risk of skin cancer is determined by environmental factors like ultraviolet radiation (UVR), personal habits like time spent outdoors and genetic factors. This review aimed to survey existing studies in gene-environment (GxE) interaction on skin cancer risk, and report on GxE effect estimates. METHODS: We searched Embase, Medline (Ovid) and Web of Science (Core Collection) and included only primary research that reported on GxE on the risk of the three most common types of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. Quality assessment followed the Newcastle-Ottawa Scale. Meta-analysis was not possible because no two studies examined the same interaction. This review was registered on PROSPERO (CRD42021238064). RESULTS: In total 260 records were identified after exclusion of duplicates. Fifteen studies were included in the final synthesis-12 used candidate gene approach. We found some evidence of GxE interactions with sun exposure, notably, with MC1R, CAT and NOS1 genes in melanoma, HAL and IL23A in BCC and HAL and XRCC1 in SCC. CONCLUSION: Sun exposure seems to interact with genes involved in pigmentation, oxidative stress and immunosuppression, indicating that excessive UV exposure might exhaust oxidative defence and repair systems differentially, dependent on genetic make-up. Further research is warranted to better understand skin cancer epidemiology and develop sun exposure recommendations. A genome-wide approach is recommended as it might uncover unknown disease pathways dependent on UV radiation.

Statistical power in vitamin D randomized control trials investigating biomarkers as continuous outcomes.

It has long been suspected that mean vitamin D level and differences among individuals in the population might deteriorate power in vitamin D randomised controlled trials (RCTs). However, standard statistical planning tools cannot accommodate these considerations. Here, to accommodate the large within-person and between-people heterogeneity in naturally fluctuating 25-hydroxyvitamin D (25OHD) concentration, a simulation based approach was used to investigate the power and sample size requirements in vitamin D supplementation RCTs looking at the proportion of regulatory T cells, %Tregs, as a continuous outcome. A range of sample sizes, mean increases in 25OHD in the intervention arm, and population 25OHD heterogeneity were tested. We found that in a population with a mean 25OHD of 50▒nmol/L and moderate heterogeneity in 25OHD (defined as inter-quartile range IQR = 20), sample size of approximately 1000 participants per arm is required to achieve 80% power if 25OHD increased by 10▒nmol/L in the intervention arm, compared to 250, < 100 and < 50 participants per arm if this increase was 20▒nmol/L, 40▒nmol/L or 60▒nmol/L, respectively. Thus we conclude that the increase in 25OHD in the intervention arm and population heterogeneity impact the power of vitamin D RCTs substantially. Sample size determination through simulation is a powerful approach for non-standard trials, and the work presented can easily be adopted to other intervention-outcome pairs.

Gene-Environment Interactions in Vitamin D Status and Sun Exposure: A Systematic Review with Recommendations for Future Research.

Vitamin D is essential for good health. Dermal vitamin D production is dependent on environmental factors such as season and latitude, and personal factors such as time spent outdoors and genetics. Varying heritability of vitamin D status by season has been reported, suggesting that gene-environment interactions (GxE) may play a key role. Thus, understanding GxE might significantly improve our understanding of determinants of vitamin D status. The objective of this review was to survey the existing methods in GxE on vitamin D studies and report on GxE effect estimates. We searched the Embase, Medline (Ovid), and Web of Science (Core Collection) databases. We included only primary research that reported on GxE effects on vitamin D status using 25-hydroxyvitamin D as a biomarker. Sun exposure was the only environmental exposure identified in these studies. The quality assessment followed the Newcastle-Ottawa Scale for cohort studies. Seven studies were included in the final narrative synthesis. We evaluate the limitations and findings of the available GxE in vitamin D research and provide recommendations for future GxE research. The systematic review was registered on PROSPERO (CRD42021238081).

Comprehensive Analysis of Seasonal and Geographical Variation in UVB Radiation Relevant for Vitamin D Production in Europe.

Dermal synthesis, following sun exposure, is the main source of vitamin D. This study characterizes ambient UVB radiation relevant for vitamin D production in Europe. A biological weighing function was applied to data from the Tropospheric Emissions Monitoring Internet Service (TEMIS) for 46 capital cities over an 18-year period (2004-2021) to isolate wavelengths relevant for vitamin D production (D-UVB). Cumulative and weighted D-UVB (CW-D-UVB) were calculated to approximate seasonal vitamin D accumulation and diminution. Monthly 25(OH)D concentration measurements were extracted from published reports. All data were analyzed by location and time. Despite a moderate latitudinal range (35-64° N), we observed large-up to five-fold-regional differences: the highest mean diurnal D-UVB dose of 5.57 kJ/m2 (SD = 3.55 kJ/m2) was observed in Nicosia (Cyprus) and the lowest in Reykjavik (Iceland, 1.16 ± 1.29 kJ/m2). Seasonal differences in diurnal D-UVB dose were even more pronounced, with a median 36-fold difference between annual peak and trough depending on a location (range: 10- to 525-fold). The mean duration of "vitamin D winter" was 126 days but varied widely (4 to 215 days). Monthly CW-D-UVB and 25(OH)D changes were very strongly correlated: the changes in 25(OH)D concentration increased by 12.6 nmol/L for every 100 kJ/m2 increment of CW-D-UVB in population-based studies (r2 = 0.79, p-value = 1.16 × 10-37). Understanding the differences in D-UVB radiation can help understand determinants of vitamin D status and guide region- and season-specific safe and effective sunlight exposure recommendations and vitamin D supplementation guidelines.