A good example of liver disease genetic research

[Guest guest]

Dear All;

I think this is a good example of how genetic studies can help

clarify liver diseases. This paper shows that the severe form

of " intrahepatic cholestasis of pregnancy " is associated with

polymorphisms/variants in the ABCB4 gene, which encodes a

phospholipid bile transport protein:

______________

Gut Aug 4 [E pub ahead of print] (2006)

Intrahepatic cholestasis of pregnancy: the severe form is associated

with common variants of the hepatobiliary phospholipid transporter

gene ABCB4.

Hermann E. Wasmuth 1, Glantz 2, Hildegard Keppeler 3, Eva Simon

1, Clemens Bartz 1, Werner Rath 1, Lars-Ake Mattsson 2, Hanns-Ulrich

Marschall 4 and Lammert 3*

1 Aachen University, Germany

2 Sahlgrenska University Hospital, Sweden

3 University of Bonn, Germany

4 Karolinska University Hospital Huddinge, Sweden

* To whom correspondence should be addressed. E-mail:

frank.lammert@....

Accepted 21 June 2006

Abstract

Intrahepatic cholestasis of pregnancy is characterized by

troublesome maternal pruritus, elevated serum bile acid levels, and

increased fetal risk. Mutations of the ABCB4 gene encoding the

hepatobiliary phospholipid transporter have been identified in a

small proportion of patients with cholestasis of pregnancy. In a

recent prospective study of 693 patients with cholestasis of

pregnancy, we determined a cut-off serum bile acid level (>= 40

µmol/l) for increased risk of fetal complications. Here we have

investigated whether common combinations of polymorphisms

(haplotypes) of the genes encoding the hepatobiliary ABC

transporters for phospholipids (ABCB4) and bile acids (ABCB11) were

associated with this severe form of cholestasis of pregnancy. For

genetic analysis, we studied 52 women with bile acid levels >= 40

µmol/l and 52 unaffected women matched for age, parity, and

geographical residence. Gene variants tagging common ABCB4 and

ABCB11 haplotypes were genotyped and haplotype distribution was

compared between cases and controls by permutation testing. In

contrast to ABCB11 haplotypes, ABCB4 haplotypes differed between the

two groups (p = 0.019), demonstrating that the severe form of

cholestasis of pregnancy is associated with ABCB4 gene variants.

Specifically, haplotype ABCB4_5 occurred more frequently in cases,

whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls.

These associations were reflected by different frequencies of at-

risk alleles of the two tagging polymorphisms (c.711A: OR = 2.27, p

= 0.04; del intron5: OR = 14.68, p = 0.012). In conclusion, ABCB4

variants represent genetic risk factors for the severe form of

intrahepatic cholestasis of pregnancy in Sweden.

Keywords: ABC transporter, Haplotype analysis, Intrahepatic

cholestasis of pregnancy, Obstetric cholestasis, Phospholipids

______________

Knowing this, researchers can now test whether these patients might

respond better to " 24-norursodeoxycholic acid " which was shown by

Dr. Trauner's group to be more effective than

ursodeoxycholic acid in preventing and reversing bile-duct injury in

mice that are deficient in this same phospholipid bile transport

protein (Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner

G, Tsybrovskyy O, Zatloukal K, Liu J, Waalkes MP, Cover C, Denk H,

Hofmann AF, Jaeschke H, Trauner M 2006 24-norUrsodeoxycholic acid is

superior to ursodeoxycholic acid in the treatment of sclerosing

cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130: 465-

481).

Sorry for all my posts this evening!

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)