Genetic variant c.711A>T in the hepatobiliary phospholipid transporter ABCB4 is associated with significant liver fibrosis.
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY(2020)
摘要
Liver fibrosis is the common consequence of chronic liver diseases (CLD). Recently liver stiffness measurements (LSM) >= 9.1 kPa, as determined by transient elastography (TE), were demonstrated to predict significant fibrosis (stages >= F2) in a population-based setting. The PNPLA3 (adiponutrin) p.I148M polymorphism enhances the risk of liver injury. The aim of our study was to investigate the association between the procholestatic ABCB4 polymorphism c.711A>T and LSM >= 9.1 kPa in humans as well as the interaction between ABCB4 and PNPLA3 in a mouse model of chronic cholestasis. Prospectively, we recruited 712 patients with CLD (278 women, age 50 +/- 13 years) with available TE results; liver biopsy results were available in 165 individuals. The ABCB4 c.711 genotype was determined by PCR-based assays. Pnpla3 expression and liver injury were studied in Abcb4(-/-) mice and wild-type controls. Overall, median LSM in our cohort was 6.7 kPa, and 226 individuals had LSM >= 9.1 kPa. Carriers of the ABCB4 variant c.711A presented more frequently with LSM >= 9.1 kPa (OR = 1.33, P = 0.020) and FIB-4 score >= 2.67 (OR = 1.38, P = 0.040). The presence of the risk allele was associated (P = 0.002) with FIB-4. In a multivariate model, the ABCB4 variant (OR = 1.43, P = 0.047) as well as BMI (P = 0.043, OR = 1.04) and age (OR = 1.02, P < 0.010) were independent risk factors for fibrosis stage >= F2. Abcb4 deficiency in mice led to enhanced liver injury, coupled with a decrease (P = 0.020) of hepatic Pnpla3 expression. To conclude, the procholestatic variant ABCB4 c.711A>T might represent a new genetic risk factor for clinically significant liver fibrosis. Lower expression of Pnpla3 in fibrotic Abcb4(-/-) livers points to the interaction between phospholipid metabolism and PNPLA3 in progressive liver injury.
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关键词
chronic liver diseases,adiponutrin,ATP-binding cassette transporter,fibrosis-4 score,liver fibrosis,single nucleotide polymorphism,transient elastography,phospholipid metabolism
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