Genes and environment in multiple sclerosis

[Guest guest]

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-associated 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-dihydroxyvitamin

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)