Having a particular immune system marker greatly increases a person’s risk of developing liver failure in response to a common antibiotic, a new study reports.

Drug-induced liver injury accounts for more than half of the approximately 2,000 cases of acute liver failure in the United States each year.  Most of this is due to acetaminophen (Tylenol®), but a range of other drugs can also present a danger.  One of these, flucloxacillin (also called floxacillin), an antibiotic commonly used to treat staphylococcal infections, leads to liver failure within the first 45 days of treatment in an estimated 8.5 out of every 100,000 people taking the drug.

So far, it has been unknown what makes someone more or less susceptible to flucloxacillin-induced liver damage.  But now an international team of researchers has shown that an immune system variation may be the key.  Their results, published online yesterday in the journal Nature Genetics, show that having one or two Gs at rs2395029 increases the odds of drug-induced liver injury in response to flucloxacillin by at least 45 times compared to having two Ts at this SNP.

A G at rs2395029 indicates the presence of an immune marker known as HLA-B*5701.  This same marker has been linked to hypersensitivity to the HIV drug abacavir, although the researchers say that adverse reactions to flucloxacillin and abacavir may be the result of different biological mechanisms.

(23andMe customers can check their data for rs2395029 using the Browse Raw Data feature.)

HLA-B*5701 is usually found only in people with European ancestry. Approximately 5% of people in this group have one or two copies of the marker.  The authors of the study speculate that because people with Asian and African ancestry rarely carry HLA-B*5701, their risk for drug-induced liver injury in response to flucloxacillin might also be lower, although there is not data for this yet.

The authors conclude that testing for HLA-B*5701 in people suspected of having flucloxacillin drug-induced liver injury could be useful.  If prompt testing were available, they say, alternative drugs such as cloxacillin and dicloxacillin could be substituted for flucloxacillin.  According to their data, an estimated 85% of cases would prove to be HLA-B*5701-positivie.

But, they warn, testing for HLA-B*5701 before administering flucloxacillin would probably not be clinically useful or cost-effective because only one out of every 500 to 1,000 people with the HLA-B*5701 marker is predicted to have liver problems when treated with the drug.

ShareThis

A new report, published online today in the New England Journal of Medicine, shows that several variations in genes related to the immune system are associated with primary biliary cirrhosis (PBC), adding support to the theory that the condition is caused by an autoimmune reaction in which the body’s own defense system turns against itself.

PBC is a chronic disease that slowly destroys bile ducts within the liver.  Inflammation causes bile to remain in the liver, leading to gradual injury and eventual scarring. People with PBC may remain symptom-free for many years after diagnosis, but cirrhosis can eventually lead to life-threatening complications.  Women account for about 90 percent of PBC cases — up to one in 1,000 over 40 are affected by the condition.  Studies have shown that genes influence the risk of developing PBC, but so far only a few genetic variations have been linked to the disease.

Gideon Hirschfield and colleagues analyzed the DNA from a total of 1,031 people with PBC and 2,713 controls, all with European ancestry.  They found associations between several variations in the HLA region of the genome and the condition.  The genes in this region of DNA encode proteins that help the body distinguish between its own tissues and foreign invaders like viruses and bacteria. The strongest association was with rs2856683: each G increased the odds of PBC by 1.75 times compared to having two Ts.

The researchers also identified variations in the IL12A and IL12RB2 genes, which encode proteins involved in immune system signaling.  Each G at rs6441286 in the IL12A gene increased the odds of PBC by 1.54 times.   In the IL12RB2 gene, each A at rs3790567 increased the odds of PBC by 1.51 times.

Several other variations, many also in immune system-related genes, were also associated with PBC, though not as strongly as those detailed above.

According to the authors of the study, their findings will not only help scientists better understand the causes of PBC, but may also aid in the search for treatments.  For instance, the authors suggest drugs that modify signaling by interleukin-12α and its receptor (encoded by the IL12A and IL12RB2 genes, respectively) might be beneficial for patients with PBC.

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