Leprosy is a chronic, disabling disease caused by a bacterium (Mycobacterium leprae) that infects only humans and armadillos. The disease affects the skin and peripheral nerves, leading to sores, numbness in the limbs, muscle weakness, and, in severe cases, disfiguring nodules on the skin. Known since biblical times, leprosy was highly stigmatized until the latter part of the 19^th century, when the Norwegian doctor Gerhard Hansen discovered that it was caused by a microorganism.

Although multi-drug therapy has cured millions of people of leprosy in recent decades, hundreds of thousands of new cases still occur per year, mostly in developing countries. Finding a way to eradicate the disease is therefore considered important for reducing the number of preventable disabilities worldwide.

Because Mycobacterium leprae is specific to humans and cannot be grown in lab dishes, research into factors influencing disease susceptibility and clinical outcomes has been limited. But the host environment as well as the bacterium itself can affect the course of the disease; in other words, human genetic factors may play an important role in determining who is more susceptible to infection. Since leprosy has been shown to cluster in families, scientists suspect that much of the variability in disease susceptibility and symptoms stems from diversity in individual human immune systems rather than differences between and within strains of the bacteria.

In a new study published today in New England Journal of Medicine, a team of researchers reports new human genetic factors associated with susceptibility to leprosy in Asians. Led by Fu-Ren Zhang of the Shangdong Academy of Medical Sciences in China and Jian-Jun Liu of the Genome Institute of Singapore, the scientists tested 93 variants across an estimated 50 genes in 3254 Chinese individuals with leprosy and 5955 Chinese individuals without the condition. Their analysis identified variants in seven of these genes to be significantly associated with leprosy.

“The discovery of these genes is a major breakthrough for research in leprosy and infectious diseases in general, and will be significant in the early diagnosis and development of new treatments,” said Dr. Liu in a press release.

The strongest of the associations were rs602875 in HLA-DR-DQ, rs3764147 in C13orf31, and rs9302752 in NOD2. In addition, some of the genetic variants were more strongly associated with a form of leprosy that results in more severe symptoms, known as the multibacillary form. These included rs9302752 in NOD2 and the variant rs1491938 in LRRK2.

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

Altogether, five of the seven genes identified in the study could be shown to interact biologically in the context of immune response to infection. Two of these five genes, NOD2 and TNFSF15, harbor genetic variants that are also associated with Crohn’s disease (see 23andMe’s report on this condition). Crohn’s manifests some common features with leprosy at the cellular level and other researchers have suggested that mycobacterial infection may be a risk factor for Crohn’s. The findings reported by Zhang and Liu and their colleagues provide additional evidence for shared disease mechanisms between Crohn’s disease and leprosy and may increase the range of treatment options for both conditions.

Variants significantly associated with leprosy in individuals of Asian ancestry

* As reported on the 23andMe website through the Browse Raw Data feature.

** Effect only applicable to the multibacillary form of leprosy. LRRK2 is better known as a susceptibility gene for Parkinson’s disease (see 23andMe’s report on this condition). Interestingly, PARK2, another gene linked to Parkinson’s, was associated with leprosy in earlier studies. The reason for the connection between Parkinson’s and leprosy is unclear, though researchers have speculated that some of the same treatments may be effective for both conditions.

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.

ShareThis

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.

ShareThis

In autoimmune disorders, the immune system — which normally protects us from harmful, foreign substances — goes into overdrive and starts attacking the body’s own cells, causing inflammation and organ damage.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic, widespread inflammation that can result in arthritis, fever, skin rashes, muscle aches, seizures and fatigue, among other symptoms. Some symptoms can even be life-threatening. Between one and seven out of every 10,000 people is affected by SLE. The disease affects women nine times more frequently than men, and tends to be more prevalent and severe in people of non-European descent. The exact causes of SLE are unknown and there is currently no cure.

For several decades now, researchers have probed the genetic underpinnings of this mysterious disease. Two studies published this week in Nature Genetics identify new genetic variants associated with SLE in European and Asian populations.

In the first study, a team led by Vesela Gateva and Robert Graham of Genentech identified ten novel genetic variants associated with SLE in a European group consisting of more than 3,000 people with the disease and 10,000 people without SLE. Half of these variants were previously associated with other autoimmune diseases, but this is the first time they have been associated with SLE. In addition, the researchers confirmed nine variants previously linked to SLE in other studies.

(23andMe customers can see their data for the SNPs currently covered by 23andMe’s service by using the Browse Raw Data feature. See table at the end of this post.)

Of the previously reported autoimmune variants, Gateva and colleagues note that the A version of rs641153, a known risk variant for age-related macular degeneration, seems to be protective against SLE, although additional research will be needed to confirm this effect.

One of the SNPs not previously associated with SLE or any other autoimmune disease, rs7708392, is in the gene that encodes TNIP1.  The TNIP1 protein is known to interact with TNFAIP3, a protein that genetic studies have previously linked to rheumatoid arthritis, psoriasis and type 1 diabetes — all autoimmune disorders — suggesting that the TNIP1-TNFAIP3 association may play a general role in autoimmunity.

(23andMe does not currently report data for rs7708392.)

In the second study, Jian-Wen Han and Xue-Jun Zhang’s team from Anhui Medical University in China identified 21 genetic variants associated with SLE in more than 4,000 Chinese individuals with the disease and 8,200 individuals without autoimmune disorders. About half of the associations confirmed previous reports in European populations, and half represented novel findings.

Interestingly, one of the new variants they identified — rs10036748 — is also in the TNIP1 gene. Here, each copy of a T increased odds of SLE by about 1.24 times. Many other SNPs associated with SLE in the Chinese study were located in or near genes involved in immune response.

The TNIP1-TNFAIP3 connection and association of variants known to be linked to other autoimmune diseases add to growing evidence that common genetic factors contribute to autoimmunity. These findings may help pave the way for novel therapeutics for autoimmune disease that exploit this shared genetic basis.

Novel SNPs associated with SLE in Europeans (Gateva et al. study)

Novel SNPs associated with SLE in Asians (Han et al. study)

ShareThis

No matter what you call it – “flush”, “blush” or “glow” – the red face, nausea and rapid heart beat that many people with Asian ancestry experience when they drink alcohol is more than just a quirk of nature.  Research shows it’s a significant risk factor for esophageal cancer, one of the deadliest malignancies in the world.

In a paper published online yesterday in PLoS Medicine, researchers from the National Institute on Alcohol Abuse and Alcoholism and Japan’s Kurihama Alcohol Center advise physicians that they need to ask their Asian patients about their experiences with alcohol in order to identify and counsel those who are at the highest risk.

In the body, alcohol is first converted into acetaldehyde, a potentially cancer-causing toxin, and then into a harmless substance called acetate.  An enzyme called ALDH2 is responsible for the crucial detoxifying step.  But a genetic variation known as ALDH2*2, most commonly found in people with Asian ancestry, can render the enzyme unable to convert acetaldehyde into acetate.

Having two copies of the ALDH2*2 variation means a person can’t break acetaldehyde down at all.  Even a tiny amount of alcohol leads to a build up of the toxin and extremely unpleasant side effects, causing most of these people to avoid drinking altogether.

People with just one copy of ALDH2*2 flush when they drink alcohol too, but their bodies are able to process some acetaldehyde and their reactions are less severe.  Some of these people build up a tolerance to acetaldehyde, allowing them to drink in substantial quantities. But while these people may think they’ve learned to deal with the annoyance of alcohol flushing, what they’ve really done is train themselves to ignore their bodies’ warning signals.

According to the authors, evidence from several studies has consistently linked alcohol consumption with the risk of esophageal cancer in people with one copy of ALDH2*2.  Depending on the study, the odds of esophageal cancer are raised 3.7 to 18.1 times after taking into account the level of alcohol consumption.  For heavy drinkers with one copy of ALDH2*2 the news is even worse: most studies show their odds of esophageal cancer are increased at least 10-fold.

(23andMe customers can see their data for ALDH2 and learn more about alcohol flushing in the trait report found here.  Customers can also check their data at rs671 using the Browse Raw Data feature.  Each A is a copy of ALDH2*2.)

The authors say that doctors should routinely question Asian patients about their reactions to alcohol and advise those who do flush to keep their drinking to a minimum.  This simple step could have a real impact on esophageal cancer rates.

For example, the authors calculate that if Japanese males with one copy of ALDH2*2 who are moderate to heavy drinkers could be convinced to scale back to only light drinking, 53% of esophageal cancers in this population could be prevented.

“In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in alcohol drinking would translate into a substantial number of lives saved,” the authors write.

Photo: doi:10.1371/journal.pmed.1000050.g001. From: Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A PLoS Medicine Vol. 6, No. 3, e50 doi:10.1371/journal.pmed.1000050

ShareThis

Millions of Americans suffer from the itchy, scaly skin brought on by psoriasis. In mild cases the condition is only a nuisance, but in the most severe cases it can be painful, disfiguring, and disabling.

Although the what of psoriasis is largely understood –immune cells mistakenly attack healthy skin cells, triggering further immune responses that lead to an overproduction of skin cells — – the why is not. Environmental factors, such as infections and injuries, may play a part, but twin studies have suggested that genetics has an even larger role.

Recent studies have started to unravel the genetics of psoriasis, showing that variations in several immune system genes can increase the odds of developing the disease. Now three studies, published online yesterday in the journal Nature Genetics, add to the list of variations associated with psoriasis and expand previous findings among Europeans to an Asian population.

Using data from more than 6,000 psoriasis patients with European ancestry and an equal number of unaffected controls, Rajan Nair and colleagues from the Collaborative Association Study of Psoriasis found seven genetic variations that were significantly associated with increased odds of developing psoriasis. All of these variations were in immune system-related genes, in keeping with previous research.

(Two of the variations identified by Nair et al are equivalent to SNPs already included in the 23andMe Health and Traits Clinical Report on psoriasis. Details of the four of the other five SNPs, and all others discussed here, are included in a table at the end of this post. Data on one SNP, near the TNIP1 gene, is not currently available from 23andMe.)

The second report, authored by Rafael de Cid and colleagues from several institutions in the United States and Europe, found a deletion of about 32,000 DNA bases that increases the odds of psoriasis. Their study used data from about 2,800 psoriasis patients and controls from the U.S., Spain, the Netherlands and Italy.

This deletion compromises two genes, LCE3C and LCE3B, which are part of a larger group of genes called the LCE gene cluster that are involved in the proper development of skin cells. de Cid et al speculate that other LCE genes are usually able to make up for the loss of LCE3C and LCE3B, but not perfectly. The result is skin that can become “leaky” due to injuries, allowing allergens and bacteria to penetrate the protective barrier of the skin. In someone with other risk factors for psoriasis, this could be enough to set off the inflammation characteristic of the disease.

(23andMe customers can use data for a SNP located near the deletion as a proxy for this variation.)

This week’s final Nature Genetics report on psoriasis comes from Xue-Jun Zhang and colleagues, who looked at SNPs in a large group of Han Chinese people (more than 5,000 patients and 6,500 controls) and a smaller group of Chinese Uygurs (539 patients and 824 controls). According to the authors this is the first study of its kind to examine genetic variations linked to psoriasis in the Chinese population.

Zhang et al. found three genetic variations associated with psoriasis in the Chinese population. Two of these – located in the HLA and IL23A genes – were replications of well-established associations in Europeans. The third association was in the LCE gene cluster, supporting the association in this same region found by de Cid in Europeans.

The results of all three studies may help scientists better understand psoriasis, but as Nair et al point out, they are only the beginning of a long road. Researchers will need to look more closely at the regions of the genome identified in these and other studies to find the true causes of the risk increases they have seen. The SNPs found so far are likely to only be signposts pointing the way. Further studies, using larger sample sizes and drawing together the findings of multiple research groups, will also be needed to uncover the many other genetic variations that likely contribute to psoriasis.

*”Effect” is the increase in odds compared to someone with two copies of the non-risk version of each SNP.

Europeans

Chinese

ShareThis