Largest genetic study of inflammatory bowel disease provides clues on new drug targets

Genetic variant identified that doubles an individual’s risk of developing ulcerative colitis




Structure of the ADCY7 protein, now implicated in increased risk of ulcerative colitits. DOI 10.1038/ng.3760 and DOI 10.1038/ng.3761

In two studies published today (30 January) in Nature Genetics, researchers from the Wellcome Trust Sanger Institute and their collaborators have identified a genetic variant that doubles an individual’s risk of developing ulcerative colitis, one of the subtypes of a chronic disorder known as Inflammatory Bowel Disease (IBD). (Links to the papers: de Lange KM et al. DOI 10.1038/ng.3760 and Luo Y et al. DOI 10.1038/ng.3761)

They also uncover a further 25 novel genetic associations to IBD risk, including several that implicate genes related to a class of therapeutics that has shown promise in the treatment of this disease.

More than 300,000 people suffer from IBD in the UK. The disorder primarily consists of two subtypes: ulcerative colitis and Crohn’s disease, neither of which currently have a cure. IBD is a debilitating disease in which the body’s own immune system attacks parts of the digestive tract. The exact causes of this disease are unclear.

To understand more about the genetics underlying IBD, researchers studied the genomes of 16,000 UK IBD patients, as well as 10,000 more from a previously published international study, in the largest whole-genome IBD genetic study to date.

From the research, which included 5 per cent of IBD sufferers nationwide, scientists identified a rare genetic variant that doubles the risk of ulcerative colitis. The variant affects a gene known as ADCY7, and is carried by 1 in 200 people in the UK. It is one of the strongest genetic risk factors associated with ulcerative colitis to date and presents a novel drug target for IBD.

In the second study, researchers identified that a family of proteins called integrins play a key role in increasing the risk of IBD. Integrins are transmembrane proteins that act as bridges for interactions between cells from the immune system and the rest of the body. For the inflammation associated with IBD symptoms, drugs targeting some of these interactions have been shown to be effective. This study demonstrated that genetic variants that increase the risk of developing IBD also increase the expression of certain integrins in response to stimulation of the immune system.

“We study genetics because we ultimately want to understand the biology of the disease. From the genetic information we can extract a compelling story about why a particular anti-integrin drug is effective against Inflammatory Bowel Disease, or why others have serious side effects.”

Katrina de Lange, first author from the Wellcome Trust Sanger Institute

These examples of genome wide association studies give scientists a clearer view of IBD biology than they had previously and are helping to reveal the underpinning biology of human inflammatory diseases overall.

Looking to the future, Sanger Institute scientists, with help from the UK IBD BioResource, are aiming to sequence 25,000 genomes of IBD patients in the next five years. The unprecedented scale of this study will hopefully reveal even more details of the biology of this condition.

“Whilst there are challenges in recruiting large numbers of patients to IBD studies and interpreting the resulting volume of data, there are also great opportunities to better understand the role of genetic variation in not only risk of disease but also in treatment and prognosis. The IBD Bioresource will drive recruitment of IBD patients across the UK and allow recall of patients for repeat tests so the function of specific genes behind IBD can be explored.”

Dr Miles Parkes, co-author of the studies and consultant gastroenterologist at Addenbrooke’s Hospital in Cambridge

The results from these studies will be translated into potential treatments by Open Targets, an initiative that takes the outputs of the genetic studies and works with pharmaceutical companies to aid the development of new treatments for diseases including IBD.

“The scale of these collaborations means we are able to spot genetic associations to IBD that we hadn’t seen previously. We hope that by continuing to work together we will be able to translate these findings into better treatments for IBD patients.”

Dr Carl Anderson, a lead author from the Wellcome Trust Sanger Institute 

Notes to Editors

Publications:

Katrina M. de Lange et al. (2017) Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nature Genetics. DOI 10.1038/ng.3760

Yang Luo et al. (2017) Exploring the genetic architecture of inflammatory bowel disease by whole genome sequencing identifies association at ADCY7. Nature Genetics. DOI 10.1038/ng.3761

Funding:

This work was supported by Wellcome and the Medical Research Council.

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