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

[Guest guest]

What interests me in this subject is that

PSC seems to occur more in Scandinavia, an

area of the world that does not see a lot of sunlight, and when the sun appears

people are mostly covered in layers of clothes, thus not getting a lot of sun

exposure. Sun exposure raises your vitamin D level.

Regards,

Chaim Boermeester, Israel

From:

[mailto: ] On

Behalf Of Lori

Sent: Sunday, February 08, 2009

16:37

To: ;

Lori

Subject: Lamens terms request: Re:

Genes and environment in multiple sclerosis

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 (AT) Yahoo (DOT) com

www.Lori.FirstWeber.com

From:

<rhodesdavid1 (AT) comcast (DOT) net>

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)

[Guest guest]

Thanks a lot Dave & Arene for your explanations, I really appreciate it very much.

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: Tuesday, February 10, 2009 9:53:34 PMSubject: Lamens terms request: Re: Genes and environment in multiple sclerosis

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.medpaget oday.com/ Neurology/ MultipleSclerosi s/12770The 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: <rhodesdavid1@ ...>> To: @ yahoogroups. com> 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)>