Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.
OBJECTIVE
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.


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.
Savander
M
M
Department of Medical Genetics and Folkhälsan Institute of Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Ropponen
A
A
Avela
K
K
Weerasekera
N
N
Cormand
B
B
Hirvioja
M-L
ML
Riikonen
S
S
Ylikorkala
O
O
Lehesjoki
A-E
AE
Williamson
C
C
Aittomäki
K
K
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood; D002780:Cholestasis, Intrahepatic / Q000453:epidemiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D005387:Finland / Q000453:epidemiology; D005799:Genes, Dominant / Q000235:genetics; D018740:Genetic Heterogeneity; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015994:Incidence; D010375:Pedigree; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology / Q000209:etiology*; D011446:Prospective Studies; D000637:Transaminases / Q000097:blood
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; C095122:multidrug resistance protein 3; D000637:Transaminases