Lamens terms request: Re: Genes and environment in multiple sclerosis

[Guest guest]

Hello

I am not seeing the correlation between Wheat, the HLA-DRB1 gene & Vitamin D defincency as it relates to MS and PSC. It is frustrating being so excited about some great news or a possible break thru and not being able to understand it. It is like reading Chinese, well maybe not that bad, but close. What I think I understand the point to be, is that Vitamin D defincency is most likely the number one cause for PSC and MS? So, could taking enough vitamin D depending upon defincency levels mean a cure or a least remission of MS and PSC.

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

Cell:

1507 E. Sunset Drive

Waukesha, WI 53189

LoriUSA@...

www.Lori.FirstWeber.com

To: Sent: Sunday, February 8, 2009 12:15:31 AMSubject: Genes and environment in multiple sclerosis

Dear All;We've probably all heard the saying that autoimmune disease is determined by both environment and genes. I guess the best example of this is celiac disease, which is triggered by dietary substances (wheat proteins) in patients carrying a certain variant of a gene (HLA-DQB1) in the major histocompatibility complex. Many other autoimmune diseases have been shown to have a genetic component in the major histocompatibility complex region, but few of the environmental factors have been identified, and where they have been identified, their exact interaction with the susceptibility gene has not been worked out. An example of this is multiple sclerosis, where a major susceptibility gene seems to be a certain variant of the HLA-DRB1 gene, and an enviromental susceptibility factor seems to be vitamin D deficiency, but exactly how the two interact with one another has not been

identified.In this paper (which to me represents a major breakthrough! ), the authors show that the particular variant of the multiple sclerosis susceptibility gene (HLA-DRB1*1501) , has a vitamin D response element in its promoter region, and that expression of the susceptibility gene is therefore dependent upon vitamin D:PLoS Genet. 5: e1000369 (2009)Expression of the multiple sclerosis-associate d MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D.Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, Deluca GC, Herrera BM, Chao MJ, Sadovnick AD, Ebers GC, Knight JCWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide

strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non-MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin

immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitam in D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous "VDRE" sequence found in non-MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features

of this disease with major practical implications for studies of disease mechanism and prevention. PMID: 19197344.Best regards to all,Dave (father of (23); PSC 07/03; UC 08/03)