Study Provides Insight Into Vitamin D's Link to MS Risk

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.