Inflammatory bowel disease (IBD) is a chronic autoimmune disorder – encompassing both Crohn’s disease and ulcerative colitis – that affects more than a million people in the United States. Normally, our immune system works to fight off harmful pathogens that might pass through our digestive tract. In IBD, however, the immune system stays in overdrive and attacks normal intestinal cells. The resulting chronic inflammation causes abdominal cramps, diarrhea, pain and fever, and weight loss.

Most studies of IBD have investigated genetic factors for Crohn’s disease, but a set of articles published this week in Nature Genetics on IBD address two less-explored angles. Two of the studies identify new genetic associations with ulcerative colitis in European and Asian populations. The third study focuses on early-onset IBD (diagnosed prior to age 19), which is typically more severe than adult-onset IBD and is believed to have a stronger genetic component.

In a joint effort, the UK IBD Genetics Consortium and the Wellcome Trust Case Control Consortium 2 identified three genetic variants associated with ulcerative colitis in a group of 4,682 people with the condition and over 10,000 healthy individuals, all of European ancestry. These variants are located in regions of the genome that had not previously been associated with ulcerative colitis .

Each of the three SNPs – rs886774, rs1728785, and rs6017342 – was associated with slightly increased odds of ulcerative colitis. The researchers highlight a number of proteins encoded by genes near these variants that help maintain the lining of the intestine and regulate cell-cell interactions, including HNF4a, E-cadherin, and laminin, though their exact roles in ulcerative colitis are unclear.

(23andMe Complete Edition customers can see their data for SNPs in this post by using the Browse Raw Data feature.** See table at the end of this post.)

The second study, led by Kouichi Asano and Michiaki Kubo of the RIKEN Center for Genomic Medicine in Japan, looked for genetic variants associated with ulcerative colitis in a group of about 1,380 Japanese individuals with the disease and 3,050 individuals without it. Their two strongest associations were SNPs located near genes involved in immune response.

One of these SNPs, rs9263739, is in a region of the genome that encodes antigen-presenting proteins – important for immune system recognition of “self” vs. foreign substances. Antigen-presenting proteins display bits and pieces of proteins or sugars (antigens) from cells and other microorganisms to immune cells that normally ignore “self” antigens but destroy foreign ones. In autoimmune diseases like IBD, the immune system loses the ability to distinguish between the two types of antigens and mistakenly reacts to the body’s own cells.

The other strongly associated SNP, rs1801274, is located in the FCGR2A gene and causes a change to the encoded protein, which is expressed on the surface of several types of immune cells. Previous studies by other groups have shown that this SNP can play a significant role in the development of other autoimmune disorders. The version of the SNP that increased risk for those other disorders, however, is the opposite version compared to the version associated with increased risk for ulcerative colitis in the current Japanese study.

In the third study, a team led by Marcin Imielinski and Hakon Hakonarson of the Children’s Hospital in Philadelphia identified genetic variants associated with early-onset IBD. Almost 3,500 individuals of European ancestry who had been diagnosed with IBD – either Crohn’s disease or ulcerative colitis – before their nineteenth birthday were compared to close to 12,000 individuals free of IBD.

Imielinski’s team identified three SNPs significantly associated with early-onset Crohn’s disease. For two of the SNPs, rs8049439 and rs2412937, the less common version was associated with slightly increased odds of early-onset Crohn’s disease, while the less common version of rs1250550 was associated with slightly decreased odds. They also observed an association between rs4676410 and early-onset ulcerative colitis.

When they conducted a combined analysis of all early-onset IBD cases (Crohn’s and ulcerative colitis), the researchers found that the three genetic variants associated with early-onset Crohn’s disease were associated with early-onset IBD in general.  The effect sizes were similar to those seen when they looked at just Crohn’s disease.  In addition, they identified another SNP associated with early-onset IBD, rs10500264.

Of the four genetic variants associated generally with early-onset IBD, Imielinski and his colleagues consider rs8049439 to be especially important given its proximity to IL27, a gene involved in the immune system. The researchers showed in a small sample that individuals with early-onset Crohn’s disease express the gene at much lower levels than healthy people. IL27 encodes a protein that suppresses inflammatory immune cells in the intestine, so it is possible that lower expression of IL27 contributes to a hyperactive inflammatory response.

Although the biology of IBD is complex, these three studies contribute to a more comprehensive picture of the genetic factors underlying the condition and suggest potential directions for the development of therapeutics.

“This is an evolving story of discovering what genes tell us about the disease,” said Dr. Baldassano from the Children’s Hospital team in a press release. “Pinpointing how specific genes act on biological pathways provides a basis for ultimately personalizing medicine to an individual’s genetic profile.”

* 23andMe does not currently report on rs1728785, so we instead provide information on a perfect proxy for it, rs1170426.

** 23andMe does not currently report on rs886774 or any of its proxy SNPs.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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The exact causes of Crohn’s disease remain a mystery, but scientists do know that genetic factors play an important part. More than 30 variations have been associated with increased risk for the disease, but changes in one gene, NOD2, have been found to be especially critical.  Three different variants in this gene have been associated with significantly increased risk for developing the disease.  It’s estimated that 10-15% of people with Crohn’s disease have two copies of one of these variants.

Because changes in NOD2 are associated with so many cases of Crohn’s disease, medications made to interact with the protein the gene encodes would seem to be obvious candidates for drug development.  But the NOD2 protein doesn’t have the type of function that can be modified by a drug.

A new avenue of drug research may have been opened, however, thanks to a study from Derek Abbott and colleagues at Case Western Reserve University.  In a paper appearing in the August issue of Current Biology, they show for the first time that a protein called ITCH can influence NOD2 biological pathways.  This is important because, in the parlance of pharmaceutical development, ITCH is a  “druggable” target.

NOD2 binds to bacteria that make their way into cells, setting off signals that activate the immune system. Research has shown that the Crohn’s disease-associated NOD2 variants decrease the signals that go through a particular protein called NFkB.  Abbott’s lab found that ITCH also decreases NOD2-dependent NFkB signals.  This is significant because studies have shown that increased NFkB signaling can help slow down the progression of Crohn’s disease.

“The thought is that if you could identify patients with NOD2 polymorphisms who also displayed early gastrointestinal trouble, you could block ITCH to increase NFkB signaling and not let the Crohn’s disease get to the acute stage,” Abbott said in an email.

Abbott and his fellow researchers are in the very early stages of looking for drugs that could be used to inhibit ITCH and possibly be useful in treating Crohn’s disease.  But the road to drug discovery is a long one.  ITCH interacts with many other proteins in cells and it’s not yet clear if blocking it would have unwanted effects on other important biological pathways. However, in the future this research could lead to a valuable drug against Crohn’s disease — at least for the 10 to 15% of patients who have variants that cause decreased NOD2 signaling.

(23andMe customers can check their data for three distinct NOD2 SNPs, as well as nine other Crohn’s disease associated variants, in the Crohn’s Disease Clinical Report.)

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Although the itchy, red rashes that plague people with atopic dermatitis are usually set off by environmental irritants and allergens, the root of the condition (a type of eczema) is thought to be genetic.

A new report, published online this week in the journal Nature Genetics, shows that a DNA variation previously associated with Crohn’s disease may be one of the genetic risk factors for atopic dermatitis.

Researchers analyzed the genetic data of more than 3,500 people with atopic dermatitis and more than 4,900 controls from Germany, Poland and the Czech Republic.  Their results showed that compared to people with two Cs at rs7927894, those with one T have 1.16 times the odds of having atopic dermatitis, while those with two Ts have 1.47 times increased odds.

The researchers estimate that 13% of the population with European ancestry has two Ts at rs7927894.

(23andMe customers can check their data at rs7927894 using the Browse Raw Data feature.  Data for this SNP is available only to those customers who were typed on version 2 of our custom chip – i.e. customers who upgraded from version 1 or who received their data after September 1, 2008.)

A recent report associated rs7927894 with Crohn’s disease.  In that study, each T increased the odds of Crohn’s by 1.16 times.  The authors of the current atopic dermatitis study note that Crohn’s and atopic dermatitis share several features – recurrent bouts of inflammation, cells that fail to form proper barriers (in the intestine and skin, respectively) and deficient immune responses against bacterial infections.  They suggest that the association of rs7927894 with both conditions may explain why there is a high incidence of eczema in people with Crohn’s disease.

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A large international collaboration of researchers has tripled the number of SNPs associated with Crohn’s disease, an inflammatory bowel disease that affects about 500,000 Americans. Their results were published online Sunday in Nature Genetics.

Data from more than 16,000 people with European ancestry – 8,059 from a combination of three previously published reports, a new set of 2,325 patients and 1,809 control subjects, and a group of 1,339 families – identified 21 new SNPs associated with Crohn’s disease and confirmed 11 previously implicated SNPs.

(See the table at the end of this post for SNP details).

Although many of the SNPs described in the report only slightly impact the risk of developing Crohn’s, the findings could be important in helping researchers understand the basic biology of the disease.

“Studies such as this are not about developing diagnostic tests, but about identifying targets for new drug therapies. Crohn’s disease can be a very serious condition, often requiring surgery, and the sooner we can understand the underlying causes, the sooner we will be able to devise new treatments to help our patients,” said study author Dr. Miles Parkes.

Some of the newly identified SNPs are in (or near) genes linked to diseases other than Crohn’s, including type 1 diabetes, arthritis, psoriasis, and asthma. This highlights “the important relationships between different diseases and, as such, may offer valuable insights into the pathways that lead to common symptoms such as inflammation,” said Dr. Mark Walport, director of the Wellcome Trust, one of the funding agencies that supported the study.

The researchers suspect there are many more genetic associations left to find for Crohn’s disease.

“These [SNPs] explain only about a fifth of the genetic risk, which implies that there may be hundreds of genes implicated in the disease, each increasing susceptibility by a small amount,” said the study’s lead author, Jeffrey Barrett.

23andMe customers can check their data for many of the SNPs found by Barrett et al. using Browse Raw Data. Here we list 23 out of the 32 SNPs detailed in the report –six SNPs that are already used in the My Gene Journal (now called Health and Traits) Crohn’s disease article have been omitted, as have three SNPS that are not currently available from 23andMe’s service.

Out of a possible total of 46, 80% of people will have between 17 and 25 copies of the riskier versions of these SNPs. Because there are so many of these SNPs – and because the riskier versions are often more common than their less risky counterparts – even people at the high end of the distribution are not much more likely than average to develop Crohn’s disease.

“Effect” is the increase in odds of developing Crohn’s disease conferred by each copy of the riskier version of a SNP. SNPs where we are providing a proxy for the SNP originally reported in the paper are marked with an asterisk.

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