Vitamin D linked to autoimmune and cancer disease genes, underscoring risks of deficiency

[Guest guest]

Public release date: 23-Aug-2010

Contact: Peggy Calicchia

calicchi@...

Cold Spring Harbor Laboratory

Vitamin D linked to autoimmune and cancer disease genes, underscoring

risks of deficiency

August 24, 2010 – Vitamin D insufficiency is a risk factor for a number

of diseases and thus, is a growing concern worldwide, as approximately

one billion people may be vitamin D deficient. However, the biological

basis for vitamin D deficiency predisposing to disease is poorly

understood. In a report published online today in Genome Research

(www.genome.org), scientists have mapped the molecular interactions of

the vitamin D receptor genome-wide, finding novel connections of vitamin

D with genes related to autoimmune disease and cancer.

Vitamin D deficiency, resulting from either lack of sun exposure or poor

dietary intake, is increasingly being recognized as a risk factor for a

number of serious illnesses, and has been linked with autoimmune

conditions such as multiple sclerosis, type 1 diabetes, and rheumatoid

arthritis. Yet exactly how vitamin D is involved in disease is largely

unknown. Researchers suspect that genetics could be contributing to the

connection.

Vitamin D exerts its effects on genes through the vitamin D receptor

(VDR), which binds to specific locations of the genome to influence gene

expression. An international team of researchers from the United Kingdom

and Canada have now mapped sites of VDR binding, information they can

then use to identify disease-related genes that vitamin D might influence.

Employing a technique called ChIP-seq, Dr. Sreeram Ramagopalan, of the

Wellcome Trust Centre for Human Genetics at Oxford University, and

colleagues isolated fragments of genomic DNA bound to the VDR before and

after treatment of cells with calcitriol, the active form of vitamin D,

and then sequenced the DNA fragments. By mapping the sequences back to

the genome, they identified more than 2,700 sites of VDR binding, a

number that Ramagopalan noted " shows just how important vitamin D is to

humans, and the wide variety of biological pathways that vitamin D plays

a role in. "

In recent years, genome-wide association studies (GWAS) have uncovered

numerous genomic regions harboring genetic variants that confer

increased risk to disease. To identify potential genetic links between

vitamin D and disease, the group analyzed known disease-associated

regions of the genome looking for enrichment of VDR binding in these

intervals.

They found that VDR binding is significantly enriched in genomic regions

associated with several common autoimmune diseases, such as multiple

sclerosis, type 1 diabetes, and Crohn's disease. Importantly, the

analysis revealed a novel role for vitamin D at several disease genes,

information that will be crucial for future investigations. VDR binding

was also enriched in regions associated with cancers such as leukemia

and colorectal cancer, and even common traits such as tanning, height,

and hair color.

Ramagopalan explained that their findings lend significant support to

the hypothesis that vitamin D interacts with genes in the pathogenesis

of these diseases, and underscores the serious risks of vitamin D

deficiency, especially for individuals who may be genetically

predisposed to be sensitive to insufficiency. " Considerations of vitamin

D supplementation as a preventative measure for these diseases are

strongly warranted, " Ramagopalan added.

###

Scientists from the University of Oxford (Oxford, UK), Barts and The

London School of Medicine and Dentistry (London, UK), and Simon Fraser

University (Burnaby, Canada) contributed to this study.

This work was supported by the Multiple Sclerosis Society of Canada

Scientific Research Foundation, the Multiple Sclerosis Society of Great

Britain and Northern Ireland, the Medical Research Council (UK), and the

Wellcome Trust (UK).

Media contacts: Sreeram Ramagopalan, PhD (sreeramr@...; +44

7915 490 167) and Craig Brierley, Senior Media Officer for the Wellcome

Trust, (C.Brierley@...; +44 20 7611 7329), are available for

more information.

Interested reporters may obtain copies of the manuscript from Peggy

Calicchia, Editorial Secretary, Genome Research (calicchi@...;

+1-).

About the article: The manuscript will be published online ahead of

print on August 24, 2010. Its full citation is as follows: Ramagopalan

SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A,

Handunnetthi L, Handel AE, Disanto G, Orton S, CT, Morahan JM,

Giovannoni G, Ponting CP, Ebers GC, Knight JC. A ChIP-seq-defined

genome-wide map of vitamin D receptor binding: Associations with disease

and evolution. Genome Res doi:10.1101/gr.107920.110.

About Genome Research:

Launched in 1995, Genome Research (www.genome.org) is an international,

continuously published, peer-reviewed journal that focuses on research

that provides novel insights into the genome biology of all organisms,

including advances in genomic medicine. Among the topics considered by

the journal are genome structure and function, comparative genomics,

molecular evolution, genome-scale quantitative and population genetics,

proteomics, epigenomics, and systems biology. The journal also features

exciting gene discoveries and reports of cutting-edge computational

biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New

York that conducts research in cancer and other life sciences and has a

variety of educational programs. Its Press, originating in 1933, is the

largest of the Laboratory's five education divisions and is a publisher

of books, journals, and electronic media for scientists, students, and

the general public.

Genome Research issues press releases to highlight significant research

studies that are published in the journal.

http://www.eurekalert.org/pub_releases/2010-08/cshl-vdl081710.php

============

Public release date: 23-Aug-2010

Contact: Craig Brierley

c.brierley@...

44-

Wellcome Trust

Vitamin D found to influence over 200 genes, highlighting links to disease

The extent to which vitamin D deficiency may increase susceptibility to

a wide range of diseases is dramatically highlighted in research

published today. Scientists have mapped the points at which vitamin D

interacts with our DNA – and identified over two hundred genes that it

directly influences. The results are published today in the journal

Genome Research.

It is estimated that one billion people worldwide do not have sufficient

vitamin D. This deficiency is thought to be largely due to insufficient

exposure to the sun and in some cases to poor diet. As well as being a

well-known risk factor for rickets, there is a growing body of evidence

that vitamin D deficiency also increases an individual's susceptibility

to autoimmune conditions such as multiple sclerosis (MS), rheumatoid

arthritis and type 1 diabetes, as well as certain cancers and even dementia.

Now, in a study whose funders include the Medical Research Council

(MRC), the MS Society, the Wellcome Trust and the MS Society of Canada,

researchers at the University of Oxford have shown the extent to which

vitamin D interacts with our DNA. They used new DNA sequencing

technology to create a map of vitamin D receptor binding across the

genome. The vitamin D receptor is a protein activated by vitamin D,

which attaches itself to DNA and thus influences what proteins are made

from our genetic code.

The researchers found 2,776 binding sites for the vitamin D receptor

along the length of the genome. These were unusually concentrated near a

number of genes associated with susceptibility to autoimmune conditions

such as MS, Crohn's disease, systemic lupus erythematosus (or 'lupus')

and rheumatoid arthritis, and to cancers such as chronic lymphocytic

leukaemia and colorectal cancer.

They also showed that vitamin D had a significant effect on the activity

of 229 genes including IRF8, previously associated with MS, and PTPN2,

associated with Crohn's disease and type 1 diabetes.

" Our study shows quite dramatically the wide-ranging influence that

vitamin D exerts over our health, " says Dr s Heger from the MRC

Functional Genomics Unit at Oxford, one of the lead authors of the study.

The first author of the paper, Dr Sreeram Ramagopalan from the Wellcome

Trust Centre for Human Genetics, adds: " There is now evidence supporting

a role for vitamin D in susceptibility to a host of diseases. Vitamin D

supplements during pregnancy and the early years could have a beneficial

effect on a child's health in later life. Some countries such as France

have instituted this as a routine public health measure. "

The main source of vitamin D in the body comes from exposing the skin to

sunlight, although a diet of oily fish can provide some of the vitamin.

Research has previously suggested that lighter skin colour and hair

colour evolved in populations moving to parts of the globe with less sun

to optimise production of vitamin D in the body. A lack of vitamin D can

affect bone development, leading to rickets; in pregnant mothers, poor

bone health can be fatal to both mother and child at birth, hence there

are selective pressures in favour of people who are able to produce

adequate vitamin D.

This new study supports this hypothesis, having found a significant

number of vitamin D receptor binding sites in regions of the genome with

genetic changes more commonly found in people of European and Asian

descent. It is probable that skin lightening as we migrated out of

Africa resulted from the necessity to be able to make more vitamin D and

prevent rickets: vitamin D deficiency led to pelvic contraction

resulting in increased risk of fatality of both mother and unborn child,

effectively ending maternal lineages unable to find ways of increasing

availability of the vitamin.

" Vitamin D status is potentially one of the most powerful selective

pressures on the genome in relatively recent times, " says Professor

Ebers, Action Medical Research Professor of Clinical Neurology

and one of the senior authors of the paper. " Our study appears to

support this interpretation and it may be we have not had enough time to

make all the adaptations we have needed to cope with our northern

circumstances. "

http://www.eurekalert.org/pub_releases/2010-08/wt-vdf081710.php