Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy

• Published in: Gut 2003-07, Vol.52 (7), p.1025-1029
• Main Authors: Savander, M, Ropponen, A, Avela, K, Weerasekera, N, Cormand, B, Hirvioja, M-L, Riikonen, S, Ylikorkala, O, Lehesjoki, A-E, Williamson, C, Aittomäki, K
• Format: Article
• Language: English
• Subjects: ABCB11; Adult; ALAT; ASAT; ATP binding cassette subfamily B member 11; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP-Binding Cassette Transporters - genetics; ATP8B1; ATPase class I type 8B; benign recurrent intrahepatic cholestasis; Bile; Bile Acids and Salts - blood; bile salt export pump gene; Biological and medical sciences; BRIC; BSEP; Choledochus; Cholestasis; Cholestasis, Intrahepatic - epidemiology; Cholestasis, Intrahepatic - genetics; Colèdoc; deoxynucleotidetriphosphates; Diseases; dNTPs; Embaràs; familial intrahepatic cholestasis 1 gene; Family Health; Female; FIC1; Finland - epidemiology; gammaglutamyl transferase; Gastroenterology. Liver. Pancreas. Abdomen; Genes; Genes, Dominant - genetics; Genetic aspects; Genetic disorders; Genetic Heterogeneity; Genetic Linkage - genetics; Genotype; Genètica mèdica; Haplotypes - genetics; HBV; HCV; hepatitis B virus; hepatitis C virus; Humans; ICP; Incidence; Inflamació; Inflammation; intrahepatic cholestasis of pregnancy; Jaundice, Obstructive; linkage analysis; Liver; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; LOD score; logarithm of odds score; Malalties del fetge; MDR3; Medical genetics; Medical sciences; multiple drug resistance 3 gene; Mutation; obstetric cholestasis; Other diseases. Semiology; P-glycoprotein 3; PCR; Pedigree; PFIC; PGY3; polymerase chain reaction; Pregnancy; Pregnancy Complications - epidemiology; Pregnancy Complications - etiology; Pregnant women; progressive familial intrahepatic cholestasis; Prospective Studies; Rodents; serum alanine aminotransferase; serum aspartate aminotransferase; Transaminases - blood; γ-GT
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.52.7.1025

Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease. Patients and methods: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3. Results: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families. Conclusions: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.