Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci [IN THESE DAYS OF THIS COVID-19 PANDEMIC, SHOULD WE CONTINUE WITH GEITP?]

[I hadn’t realized the importance of this topic, given today’s pandemic.] 😉 There is a vast amount of medical literature and research — confirming the beneficial effects of vitamin D on the immune system, our ability to fight infections, and to maintain the competence of our innate immunity. Dietary vitamin D and sunlight is generally sufficient. If you wonder whether you are “vitamin D-deficient” or “in the normal range”, it is possible, in any clinic, to get your serum vitamin D level measured. The U.S. Vitamin D Council recommends maintaining serum levels of 40–80 ng/mL, and warns that anything over 100 ng/mL might be harmful. As mentioned below, one can have “beneficial vit D levels”, “vit D-deficiency levels”, and it’s possible to overdose oneself and exhibit “vit D toxicity”.

Most drugs can be viewed the same way: there is a therapeutic range — below which results in therapeutic failure, and above which leads to drug toxicity.


So how does all that — relate to this news item: Former CDC Chief: COVID-19 infection risk may be reduced by Vitamin D?

Please explain this to the unwashed masses.

Regards, JD, Jr.

Dear Dr. Nebert,

I salute you. 👍 I cannot stay focused on my work without looking at the COVID-19 numbers and news every five minutes. 😟 Stay healthy, Ge

From: Dave Eaton
Sent: Monday, March 23, 2020 1:19 PM

I’ve got anti-virus software, so I think my computer and phone are properly immunized from COVID-19 transmission from your GEITP messages 😉 —DE, PhD

Sent: Monday, March 23, 2020 1:15 PM

This topic fits the gene-environment interactions theme of these GEITP pages. The environmental signal is vitamin D; genes respond to this signal, and among other things generate the metabolite 25-hydroxy-vitamin D (25OHD) levels — which can result in numerous health benefits (as well as too much leading to toxicity). 25OHD is a steroid pro-hormone and a fat-soluble metabolite of cholecalciferol, which is predominantly synthesized in our body by exposure to sunlight, or obtained from dietary sources (including fortified foods, supplements, and oily fish). 25OHD plays important roles in: regulating calcium and phosphorus concentrations; influencing cell proliferation, differentiation, and apoptosis; and has immune-modulating effects. Understanding the etiology of low vit D levels could have important public health implications by identifying individuals who would benefit from supplementation. In addition to environmental factors, classical twin studies have shown that 50%–80% of 25OHD level variability is explained by genetic factors — indicating that this is a highly heritable multifactorial trait (reflecting effects of genes, epigenetics, environment, endogenous disease, the microbiome).

Several genome-wide association studies (GWAS) of serum 25OHD have been conducted on Europeans populations, with the largest including 79,366 individuals; these studies have identified six common genetic variants (minor allele frequency [MAF] >5%) that are associated with 25OHD levels; these variants are in or near genes having an established role in vit D synthesis [DHCR7 (7-dehydrocholesterol reductase) and CYP2R1 (cytochrome P450 enzyme)], transportation [GC (GC vit D-binding protein)], and degradation [CYP24A1 (another cytochrome P450 enzyme)] — as well as outside known vit D metabolism pathways [e.g. SEC23A (Sec23 homolog A, coat protein complex II component involved in endoplasmic reticulum (ER)-Golgi protein trafficking; AMDHD1 (amidohydrolase domain-containing 1, enzyme involved in histidine, lysine, phenylalanine, tyrosine, proline, and tryptophan catabolic pathway); and (a MAF <5% variant) at CYP2R1 (another cytochome P450 enzyme)]. Four separate Mendelian randomization (MR; a method of using measured variation in genes of known function to examine causal effects of a variable dose of vit D on disease in observational studies) studies have shown a protective effect of vit D against musculoskeletal disorders, autoimmune diseases such as multiple sclerosis, and cancer. However, despite all GWAS to date, the data suggest that much of the heritability (‘of 25OHD levels in response to vit D dose’) remains to be identified. Therefore authors (see attached article) decided to investigate the genetic architecture (i.e. underlying genetic basis of a phenotypic trait and its variational properties) of 25OHD by substantially increasing the GWAS sample size. Authors set up a GWAS of serum 25OHD levels in 401,460 Caucasian British individuals — combining those data in a meta-analysis with results from a previous GWAS study of 42,274 Europeans. In silico functional follow-up of the GWAS results was carried out to identify enrichment in gene sets, pathways, and expression in tissues — and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the single-nucleotide variant (SNV) heritability of 25OHD was estimated to 16.1%; 138 conditionally independent SNVs were detected (P <6.6 x 10–9), among which 53 had MAFs <5%. These SNV association signals mapped to 69 distinct loci, among which 63 had been previously UNreported. Authors identified enrichment in liver- and lipid-metabolism gene pathways and enriched expression of “25OHD genes” in liver, skin, and gastrointestinal tissues. Interestingly, authors observed partially-shared heritability between 25OHD and socio-economic traits — perhaps mediated by “time spent outdoors”. This extensive GWAS and meta-analysis clearly expands our knowledge about the contribution of “small-effect” genes (outside the vit D canonical metabolic pathway) to the genetic architecture of 25OHD. 😊 DwN Am J Hum Genet 5 Mar 2020; 106: 327–337

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