Polymorphisms in the vitamin D system and mortality - The Tromsø study

Abstract

Background and objectiveVitamin D deficiency is associated with diabetes, cancer, immunological and cardiovascular diseases as well as increased mortality. It has, however, been difficult to show a causal relation in randomized, controlled trials. Mendelian randomization studies provide another option for testing causality, and results indicate relations between the serum 25hydroxyvitamin D (25(OH)D) level and some diseases, including mortality. We have from the Tromsø Study in 2012 published non-significant relations been vitamin D related single nucleotide polymorphisms (SNPs) and mortality, but have since then genotyped additional subjects, the observation time is longer and new SNPs have been included. Methods Genotyping was performed for SNPs in the NADSYN1, CYP2R1, VDR, CUBILIN and MEGALIN genes in 11 897 subjects who participated in the fourth survey of the Tromsø Study in 1994-1995. Serum 25(OH)D levels were measured in 6733 of these subjects. A genotype score based on SNPs in the NADSYN1 and CYP2R1 genes (related to the serum 25(OH)D level) and serum 25(OH)D percentile groups were created. Mortality data was updated till end of March 2017 and survival analysed with Cox regression adjusted for sex and age. ResultsDuring the observation period 5491 subjects died. The genotype score and the serum 25(OH)D percentile groups were (without Bonferroni correction) significantly related to mortality in favour of high serum 25(OH)D. None of the SNPs in the VDR or MEGALIN genes were related to mortality. However, for the rs12766939 in the CUBILIN gene with the major homozygote as reference, the hazard ratio for mortality for the minor homozygote genotype was 1.17 (1.06 -1.29), P < 0.002. This should be viewed with caution, as rs12766939 was not in Hardy-Weinberg equilibrium. ConclusionOur study confirms a probable causal but weak relation between serum 25(OH)D level and mortality. The relation between rs12766939 and mortality needs confirmation in more homogenous cohorts.

Association between Polymorphisms in Vitamin D Pathway-Related Genes, Vitamin D Status, Muscle Mass and Function: A Systematic Review

“…To extract this detailed information from all included studies caused the rather long duration from the underlying systematic search to reporting the results. However, no conflicting results were found when comparing the outcomes of our study to recently published data [ 121 , 122 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 ]. The focus of recently published data remains in the same gene’s polymorphisms: GC, CYP2R1, VDR, CYP24A1, and CYP27B1.…”

“…Furthermore, it has been shown that C2 myotubes and primary rat muscle fibers express megalin and cubilin receptors, which enable endocytosis of DBP [ 120 ]. Studies on megalin and cubilin published after the search closing date of this systematic review did not reveal new findings [ 121 , 122 ]. In addition to the previously mentioned functional polymorphisms in the GC gene, there are also intron-located SNPs, which were found to be associated with vitamin D status, whereas the underlying mechanism remains unclear.…”

“…The focus of recently published data remains in the same gene’s polymorphisms: GC, CYP2R1, VDR, CYP24A1, and CYP27B1. Except for these genes, Fediriko et al, 2019 and Jorde et al, 2019 identified potentially novel SNPs in vitamin D-related candidate genes (LRP2 and CUBN), but none of those were statistically significant [ 121 , 122 ].…”