19 May 2011

'Master switch' gene for obesity and diabetes discovered

Project picks out regulator affecting genes in fat tissue

KLF14 is a master regulator of gene expression in adipose tissue.

KLF14 is a master regulator of gene expression in adipose tissue.

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A team of researchers, led by King's College London and the University of Oxford, have found that a gene linked to type 2 diabetes and cholesterol levels is in fact a 'master regulator' gene, which controls the behaviour of other genes found within fat tissues in the body.

As the amount and distribution of fat plays a key role in susceptibility to metabolic diseases such as obesity, heart disease and diabetes, this study highlights the regulatory gene as a possible target for future treatments to fight these diseases.

Published online on 15 May 2011 in Nature Genetics, the study was one part of a large multi-national collaboration funded by the Wellcome Trust, known as the MuTHER study. It involves researchers from King's College London, University of Oxford, The Wellcome Trust Sanger Institute, and the University of Geneva. DeCODE Genetics also contributed to the results reported in this paper.

It was already known that the KLF14 gene is linked to type 2 diabetes and cholesterol levels but, until now, how it did this and the role it played in controlling other genes located further away on the genome was unknown.

The researchers examined over 20,000 genes in subcutaneous fat biopsies from 800 UK female twin volunteers. They found an association between the KLF14 gene and the expression levels of multiple distant genes found in fat tissue, which means it acts as a master switch to control these genes. This was then confirmed in a further independent sample of 600 subcutaneous fat biopsies from Icelandic subjects.

" This study is an elegant demonstration of how important it is to study gene expression in large well-phenotyped population samples in order to elucidate how sequence variation impacts disease. "

Dr Panos Deloukas

Panos Deloukas from the Wellcome Trust Sanger Institute explained: "This study is an elegant demonstration of how important events in gene regulation - here the control of genes in fat tissue - can be uncovered through large-scale genomics. This is new biological understanding that could be clinically relevant."

These other genes found to be controlled by KLF14 are in fact linked to a range of metabolic traits, including body-mass index (obesity), cholesterol, insulin and glucose levels, highlighting the interconnectedness of metabolic traits.

The KLF14 gene is special in that its activity is inherited from the mother. Each person inherits a set of all genes from both parents. But in this case, the copy of KLF14 from the father is switched off, meaning that the copy from the mother is the active gene - a process called imprinting. Moreover, the ability of KLF14 to control other genes was entirely dependent on the copy of KLF14 inherited from the mother - the copy inherited from the father had no effect.

Professor Tim Spector from the Department of Twin Research at King's, who led the MuTHER project, said: "This is the first major study that shows how small changes in one master regulator gene can cause a cascade of other metabolic effects in other genes. This has great therapeutic potential particularly as by studying large detailed populations such as the twins we hope to find more of these regulators."

Professor Mark McCarthy from the University of Oxford, who co-led the study, said: "KLF14 seems to act as a master switch controlling processes that connect changes in the behaviour of subcutaneous fat to disturbances in muscle and liver that contribute to diabetes and other conditions. We are working hard right now to understand these processes and how we can use this information to improve treatment of these conditions."

Notes to Editors

Publication details

  • Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes.

    Small KS, Hedman AK, Grundberg E, Nica AC, Thorleifsson G, Kong A, Thorsteindottir U, Shin SY, Richards HB, GIANT Consortium, MAGIC Investigators, DIAGRAM Consortium, Soranzo N, Ahmadi KR, Lindgren CM, Stefansson K, Dermitzakis ET, Deloukas P, Spector TD, McCarthy MI and MuTHER Consortium

    Nature genetics 2011;43;6;561-4

Funding

The MuTHER study was funded by the Wellcome Trust: support for the project or participants was received from a National Institutes of Health/Center for Inherited Disease Research (NIH/CIDR) genotyping project, the ENGAGE project grant from the Dept of Health via the National Institute for Health Research (NIHR), ERC the Oxford NIHR Biomedical Research Centre, the Louis-Jeantet Foundation and NIH-NIMH.

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A full list of participants can be found at the Nature website.

Multiple Tissue Human Expression Resource (MuTHER)

The MuTHER study stands for the Multiple Tissue Human Expression Resource study and is a five year program grant funded by the Wellcome Trust. The consortium involves over 30 scientists from the UK and Switzerland. The coordinator is Professor Spector at King's and the other lead PIs are Professor McCarthy at Oxford, Dr Deloukas at the Wellcome Trust Sanger Institute in Hinxton and Professor Demitzakis at University of Geneva. 850 female twins have had skin, fat and blood cells collected as well as hundreds of clinical traits assessed. The overall aim of the study is to use the unique detailed genetic, genomic and phenotypic data generated from the TwinsUK study to understand the mechanisms of how genes influence common age-related and metabolic diseases.
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