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

[Guest guest]

Hi Lori;

Sorry for not explaining this article more clearly. Although Arne has

done a great job of putting it in layman's terms, I thought I would

also point out this news article that may help explain it further:

http://www.medpagetoday.com/Neurology/MultipleSclerosis/12770

The article I posted (and my brief introduction to it) didn't

actually say anything about PSC. I was simply trying to explain that

autoimmune diseases in general seem to involve a genetic factor and

an environmental factor, using celiac disease and multiple sclerosis

as examples.

In the case of celiac disease (one autoimmune disease caused by

intolerance to wheat proteins) wheat proteins are the environmental

factor, and the susceptibility gene is a certian variant of HLA-DQB1.

In the case of multiple sclerosis (another autoimmune disease) it now

appears that vitamin D is the environmental factor, and it directly

interacts with the susceptibility gene ... in the case of multiple

sclerosis this is a certain variant of the HLA-DRB1 gene.

I would love to be able to say what the environmental factor is in

PSC, and which gene it interacts with, but I can't at the moment ...

we don't really know what these are yet! But we can look to other

autoimmune diseases (like celiac disease and multiple sclerosis) for

important clues.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> 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

>  

>

>

>

>

> ________________________________

> From:

> To:

> Sent: Sunday, February 8, 2009 12:15:31 AM

> Subject: 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 JC

>

> Wellcome 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)

>