Multiple Sclerosis more likely if poor vitamin D genes - 22nd study

Created August 2017

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

The American Journal of Human Genetics, Vol 101, # 2, 3 August 2017, Pages 227–238, https://doi.org/10.1016/j.ajhg.2017.06.014

* CYP2R1 gene problem resulted in 1.4X increased risk of Multiple Sclerosis * The CYP2R1 gene works in parallel with the liver to semi-activate vitamin D * A Vitamin D test measures the amount of semi-activated vitamin D in the blood * Another gene, the Vitamin D Receptor (VDR), independently restricts how much Vitamin D actually gets to the cells * A poor VDR is independently associated with 3X ncreased risk of MS * Note: 33+ diseases are strongly associated with the Vitamin D Receptor * Perhaps a 5X increase in chance of getting MS if both CYPR1 and VDR are bad 1. Genetics category listing contains the following {include} 1. # 19+ studies of MS and Genetics     (and 6+ studies with VDR, below) : {category} 1. # 6+ studies of MS and Vitamin D Receptor: {category}

Despoina Manousaki1, 2, 49, Tom Dudding3, 49, Simon Haworth3, 49, Yi-Hsiang Hsu4, 5, 6, 49, Ching-Ti Liu7, 49, Carolina Medina-Gómez8, 9, 10, 49, Trudy Voortman9, 10, 49, Nathalie van der Velde8, 11, 49, Håkan Melhus12, 49,

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10−88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1.

By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78–2.78, p = 1.26 × 10−12).

Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4 , 95% CI = 1.19–1.64, p = 2.63 × 10−5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

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Tags: Genetics Multiple Sclerosis Vit D Receptor