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.

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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.

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Researchers may have identified a genetic reason for why some people are more susceptible to chronic infection with the hepatitis B virus than others.

Whenever a person contracts a virus, the immune system is usually able to clear the infection from the body completely.  But more than 400 million people worldwide have a chronic form of hepatitis B that remains in their livers and puts them at risk for cirrhosis and liver cancer.

Age at infection is one of the most important factors in determining whether hepatitis B will become chronic.  Most people infected with hepatitis B after the age of five are able to fight it off, but the majority of those who are infected as infants or very young children never get rid of the virus. In a new report, scientists show that variations in an immune system protein may also contribute to whether a person will end up with chronic case of hepatitis B. These results, published online today in the journal Nature Genetics, may help scientists understand more about the how hepatitis B causes disease and could someday facilitate the development of new treatments.

Researchers analyzed the DNA of more than 2,000 people with chronic hepatitis B and more than 4,000 controls from Japan and Thailand. Two genetic variations, SNPs rs3077 and rs9277535, showed significant associations with the condition.  For both, each copy of an A reduced the odds of chronic hepatitis B infection by about 40%.

The researchers note that the protective A versions of rs3077 and rs9277535 tend to be found at lower frequencies in areas with high rates of chronic hepatitis B.  While the scientists don’t contend that genetic factors are the sole determinants of disease prevalence, they do suggest that these factors might exert a substantial influence.

(The relationship is strongest for rs3077 – see graphics at the end of this post.  23andMe customers can check their data for rs3077 and rs9277535 using the Browse Raw Data feature.)

The genes in closest proximity to the two identified SNPs, HLA-DPA1 and HLA-DPB1, encode subunits of an immune system protein called HLA-DP.  Upon further analysis, the researchers found that variations in the HLA-DPA1 and HLA-DPB1 genes also affect the odds of chronic hepatitis B infection.

HLA-DP is one of several proteins that help alert the immune system to the presence of infections. The authors of the study suggest that changes in this protein might affect its ability to signal the immune system and could therefore result in a weak, or even completely absent, immune response to hepatitis B infection.  This, in turn, could lead to persistent infection with the virus.  In support of this idea, previous research has shown that some versions of the HLA-DPA1 and HLA-DPB1 genes affect the immune system’s response to the hepatitis B vaccine.

Map Image: PhillipN

Notes:

• Box size is relative to chronic hepatitis infection rate.  Rates were determined by taking the average of the rates given by the authors of this study for each population.  These are only estimates.
• Color indicates the frequency of the A version of rs3077 or rs9277535.  Lighter colors indicate lower frequencies.
• Populations are broad categories: Asian, African, European, Central American
• Subpopulations are HapMap3 populations
• Information can be recategorized by changing order of the population and subpopulation icons at the top of the graphic.

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