How a Rare CYP2R1 Variant Influences Levels and Multiple Sclerosis Risk
Vitamin D plays a crucial role in maintaining bone health and immune function. Vitamin D insufficiency is widespread and has been linked to several diseases, including multiple sclerosis (MS). Understanding the genetic factors that influence vitamin D levels is essential for developing targeted interventions to prevent related diseases. A recent study published in the American Journal of Human Genetics investigates the impact of low-frequency genetic variants in the CYP2R1 gene on vitamin D levels and the risk of MS.
Key Findings
The study identified a low-frequency synonymous coding variant in the CYP2R1 gene, specifically g.14900931G>A (p.Asp120Asp, rs117913124), which significantly affects vitamin D levels. This variant was found through a meta-analysis of whole-genome sequencing data from the UK10K project and imputed data from genome-wide genotyping of nearly 40,000 individuals.
Vitamin D Levels
The researchers discovered that the A allele of rs117913124 is associated with a substantial decrease in 25-hydroxyvitamin D (25OHD) levels. Carriers of this variant showed a 0.43 standard deviation reduction in 25OHD levels, which is four times larger than the effect of previously identified common variants near CYP2R1. This reduction translates to a significant increase in the risk of vitamin D insufficiency, with heterozygote carriers having an odds ratio (OR) of 2.2 for vitamin D insufficiency compared to non-carriers.
Multiple Sclerosis Risk
The study also explored the impact of the rs117913124 variant on MS risk. Carriers of the A allele were found to have a 40% increased risk of developing MS (OR = 1.4). This effect is considerably larger than that of the previously known common CYP2R1 variant, which had an OR of 1.03. These findings suggest a strong genetic link between vitamin D metabolism and MS susceptibility.
Methodology
The researchers utilized whole-genome sequencing data from 2,619 individuals and deeply imputed genome-wide genotypes from 39,655 individuals. The meta-analysis of summary statistics from 19 cohorts identified the significant impact of the low-frequency variant in CYP2R1. Additionally, the study involved a logistic regression analysis to assess the risk of vitamin D insufficiency and MS in individuals carrying the variant.
Cohorts and Measurements
The study included participants of European descent from various cohorts. Vitamin D levels were measured using different methods across these cohorts, including tandem mass spectrometry, high-performance liquid chromatography, chemiluminescence immunoassay, and electrochemiluminescence immunoassay.
Biological and Clinical Implications
The CYP2R1 gene encodes an enzyme crucial for the 25-hydroxylation of vitamin D in the liver, a necessary step in converting vitamin D to its active form. The identified low-frequency variant likely affects the enzyme's efficiency, leading to lower vitamin D levels in carriers. Given the significant impact on vitamin D levels and the increased risk of MS, these findings highlight the importance of genetic screening for vitamin D-related health risks.
Conclusion
This study sheds light on the substantial effects of low-frequency genetic variations in CYP2R1 on vitamin D levels and MS risk. The identified variant, rs117913124, has a pronounced impact on 25OHD levels and significantly increases the risk of vitamin D insufficiency and MS. These findings underscore the potential for genetic testing to identify individuals at higher risk for these conditions and inform targeted preventive strategies.
Understanding the genetic determinants of vitamin D levels can lead to better public health interventions and personalized medical approaches to mitigate the risk of diseases like MS. Further research into the functional mechanisms of these variants and their interactions with environmental factors will enhance our ability to manage and prevent vitamin D-related health issues.
References
Manousaki, D., et al. (2017). Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. American Journal of Human Genetics, 101(2), 227-238.
