Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy.
BACKGROUND
Intrahepatic cholestasis of pregnancy is a multifactorial disorder of pregnancy associated with a genetic background.


OBJECTIVE
To evaluate the genetic contribution of ABCB4, MDR3 gene in the development of intrahepatic cholestasis of pregnancy in a large cohort of Italian subjects.


METHODS
This study represents an extension of a previous multicentre-prospective study including three Italian referral centres. In all, we enrolled 96 women at the 3rd trimester of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes by standard procedures. Polymerase chain reaction was used to amplify exon 14, 15 and 16 of MDR3 gene.


RESULTS
We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). MDR3 gene variants in exons 14, 15 and 16 occurred in 7/96 of pregnant mothers with intrahepatic cholestasis of pregnancy (7.2%), and in none of 96 pregnant controls matched for age and parity. All seven patients had normal gamma-glutamyl transpeptidase, normal bilirubin, but high levels of both alanine transferase and serum bile acids. One had cholesterol biliary lithiasis. The outcome of pregnancy was normal in four cases (with vaginal delivery), while there was one fetal distress.


CONCLUSIONS
MDR3 mutations are responsible for the development of intrahepatic cholestasis of pregnancy in only a small percentage of Italian women. Further genetic studies are warranted, however, to clarify the role of different mutations in intrahepatic cholestasis of pregnancy.
Floreani
A
A
Department of Surgical and Gastroenterological Sciences, Padua University, Padova, Italy. Annarosa.floreani@unipd.it
Carderi
I
I
Paternoster
D
D
Soardo
G
G
Azzaroli
F
F
Esposito
W
W
Montagnani
M
M
Marchesoni
D
D
Variola
A
A
Rosa Rizzotto
E
E
Braghin
C
C
Mazzella
G
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D002780:Cholestasis, Intrahepatic / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D018432:Drug Resistance, Multiple; D005091:Exons; D005260:Female; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011248:Pregnancy Complications; D011263:Pregnancy Trimester, Third; D011446:Prospective Studies; D012307:Risk Factors
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D004247:DNA; C095122:multidrug resistance protein 3