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CYP2C9 gene associated with bosentan-induced liver injury
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Variants of the CYP2C9 gene were associated with bosentan-induced liver injury among patients with pulmonary hypertension undergoing therapy with bosentan, according to study data.
“Liver toxicity is a major side effect of bosentan therapy,” the researchers wrote. “We systematically investigated genetic variants of CYP2C9, ABCB11 and NR1H4 as possible genetic risk factors for the development of cholestasis in [pulmonary hypertension] patients during treatment with bosentan.”
Data from 23 patients with pulmonary hypertension were analyzed and compared with data from 25 controls to determine whether the genetic variants of CYP2C9 and ABCB11 could expose patients to bosentan-induced liver injury while undergoing therapy with bosentan. The patients with pulmonary hypertension had elevated levels of alanine aminotransferase or aspartate aminotransferase throughout therapy with bosentan. Various alleles of CYP2C9 and 16 variants of ABCB11 were genotyped and analyzed by researchers.
Logistic regression analysis showed that alleles of CYP2C9 were common in patients with pulmonary hypertension compared with the control group (OR=3.5; 95% CI, 1.01-11.8); alleles CYP2C9*2 and CYP2C9*3 were twice as common among patients with pulmonary hypertension compared with the controls (allele frequency 52% vs. 24%). Variant rs56163822 of the NR1H4 gene and all 16 variants of the ABCB11 gene were not associated with bosentan-induced liver injury.
Further analysis indicated a correlation between AST and ALT ratios before and after bosentan therapy, but they remained unaffected by the various genotypes of the CYP2C9 gene (P=.41 for AST, P=.51 for ALT).
“We conclude that patients carrying the variants CYP2C9*2 and CYP2C9*3 of the CYP2C9 gene are exposed to a significantly higher risk of liver toxicity during treatment with bosentan,” the researchers wrote. “Our results suggest that the examination of CYP2C9 variants in patients with [pulmonary hypertension] may increase safety and efficacy of drug therapy with bosentan. Thus, the systematic investigation of the genetic background of bosentan metabolism represents an important step in the direction of individualized therapy for [pulmonary hypertension].”
Disclosure: Two researchers report receiving speaking and consulting fees from Actelion Pharmaceuticals Deutschland GmbH.