Changes in Vitamin D Receptor Gene Tied to Disease Risk, Side Effects

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by Steve Bryson, PhD |

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Variations in the gene that encodes for the vitamin D receptor were associated with the risk of developing Parkinson’s disease — and with side effects from common dopamine-related treatments, a Slovenian study showed.

These findings may help identify people at risk of Parkinson’s as well as those at risk of developing certain side effects from treatment, according to researchers.

“The reported study may support [a] personalized approach to [Parkinson’s] treatment, especially in terms of monitoring vitamin D level and vitamin D supplementation in patients with high risk [vitamin D receptor] genotypes,”  or gene versions, the team wrote.

The study, “Genetic Variability of the Vitamin D Receptor Affects Susceptibility to Parkinson’s Disease and Dopaminergic Treatment Adverse Events,” was published in the journal Frontiers in Aging Neuroscience.

Vitamin D deficiency is common among people with Parkinson’s, but it is still unclear whether low vitamin D contributes to disease development or is a consequence of the condition.

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The vitamin plays an essential role in regulating the activity of genes in many tissues and organs, including the brain. These events are initiated when vitamin D binds to and activates the vitamin D protein receptor (VDR).

Animal models of Parkinson’s indicate that the vitamin D receptor modulates the production of tyrosine hydroxylase, an enzyme that generates dopamine. Dopamine is the nerve cell signaling molecule that is abnormally low in Parkinson’s patients. Most disease treatments are designed to increase dopamine levels.

Genetic analysis of the gene that encodes for the vitamin D receptor found specific single changes in its DNA building blocks — called single nucleotide polymorphism, or SNP — were associated with Parkinson’s risk, disease progression, and cognitive decline. Of note, SNPs are described by changes in the four DNA building blocks: adenine (A), guanine (G), thymine (T), and cytosine (C).

Now, researchers based at the University of Ljubljana, in Slovenia, further investigated the relationship between vitamin D receptor SNPs and Parkinson’s risk. The team also studied whether receptor genetic variability impacts the occurrence of adverse events following treatment with dopamine-increasing (dopaminergic) therapies and influences the daily dose.

A total of 132 men and 99 women with Parkinson’s were involved in the study. These participants ranged in age from 66 to 78, and had a median disease duration of 7.6 years. A group of 125 men and 36 women, ages 52 to 59, were included as a comparison control group.

DNA was extracted from blood samples. The genetic analysis focused on six specific SNPs from regions of the VDR gene that regulate its activity. All were previously associated with Parkinson’s.

Risk analysis showed that those who carried one particular SNP, referred to as VDR rs2228570 T, had a 2.75-times higher relative risk of developing Parkinson’s. In this SNP, the A is changed to a T.

After adjusting for age and sex, the risk of Parkinson’s from this SNP increased to 3.07 times higher. No association was identified for the other investigated SNPs.

The VDR rs4516035 SNP was nominally significantly associated with the dose of dopaminergic therapies needed to control Parkinson’s symptoms adequately. Carriers of at least one VDR rs4516035 C SNP — where T is changed to a C — required higher doses than carriers of the TT version, in which one T occurs in each of the two VDR genes.

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Different gene changes were linked to varying adverse events, or side effects, associated with dopaminergic treatment.

Those who are carriers of VDR rs1544410 GA genotype, or carriers of at least one VDR rs1544410 A allele (gene variant), had a lower risk of developing visual hallucinations.

Patients who carry the VDR rs739837 GG genotype had higher odds of developing orthostatic hypotension — a drop in blood pressure that occurs when standing up. In contrast, those with rs731236 TC and CC genotype and carriers of at least one rs731236 C allele were less likely to develop orthostatic hypotension.

Further, lower odds of experiencing this side effect were found in patients who carried the VDR rs1544410 GA genotype, the AA genotype, and at least one A gene version. Lastly, carriers of the VDR rs731236 TC genotype had lower odds of developing peripheral edema, or swelling in the lower legs or hands.

For motor side effects, carriers of at least one VDR rs2228570 T gene variant were two times more likely to develop motor fluctuations.

With and without adjusting for clinical parameters, statistical analysis found the associations remained significant, except for VDR rs2228570 with motor fluctuations.

“This is the first study that evaluated a comprehensive spectrum of [Parkinson’s disease]-related phenotypes [characteristics] in one cohort of PD [Parkinson’s disease] patients in relation to VDR genetic variability,” the researchers wrote. “Our results may help identify people at risk to develop PD as well as PD patients at risk to develop certain [adverse effects] of dopaminergic treatment.”

The researchers concluded that all patients with genetic variations in the vitamin D receptor would benefit from close monitoring of the level of the vitamin and its supplements.

“Results of the present study should be validated in an independent cohort,” they wrote. “Nevertheless, we believe that these results will contribute to a more personalized treatment strategy in individual [Parkinson’s disease] patients.”