Published online August 1, 2005
PEDIATRICS Vol. 116 No. 2 August 2005, pp. 437-441 (doi:10.1542/peds.2004-1900)
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Hepatitis B

Promoter Polymorphism of the CD14 Endotoxin Receptor Gene Is Associated With Biliary Atresia and Idiopathic Neonatal Cholestasis

Hsiang-Hung Shih, MD*,{ddagger}, Tsun-Mei Lin, PhD§, Jiin-Haur Chuang, MD, Hock-Liew Eng, MD||, Suh-Hang Hank Juo, MD, PhD#, Fu-Chen Huang, MD**, Chao-Long Chen, MD{ddagger}{ddagger} and Huey-Ling Chen, MD, PhD§§

* Department of Pediatrics, Chang-Gung Memorial Hospital at Chiayi, Pu-Tz City, Chiayi Hsien, Taiwan
{ddagger} Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, Taiwan
§ Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
Surgery
|| Pathology
** Pediatrics
{ddagger}{ddagger} Chang-Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan
# Graduate Institute of Medicine; Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
§§ Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

Objective.To investigate whether single-nucleotide polymorphisms in the promoter regions of endotoxin-responsive genes CD14 and tumor necrosis factor-{alpha} (TNF-{alpha}) are associated with biliary atresia (BA) and idiopathic neonatal cholestasis (INC).

Methods.We obtained genomic DNA from 90 patients with established diagnosis of BA and 28 patients with INC. Forty-two adult patients with hepatitis B–related cirrhosis and 143 healthy children served as control populations. The genotypes of CD14/C(–159)T and TNF-{alpha}/G(–308)A (G allele, TNF*1; A allele, TNF*2) were determined by using a restriction enzyme–based assay. Plasma soluble CD14 levels were determined in different disease stages and genotypes of BA.

Results.The frequencies of T allele and T/T homozygosity of the CD14/–159 promoter polymorphism were significantly higher in patients with BA (T allele: 61.7%; T/T genotype: 42.2%) and in patients with INC (T allele: 67.9%; T/T genotype: 53.6%) but not in control populations. Decrease of plasma soluble CD14 from the early stage of BA when the patients received a Kasai operation to the late stage of liver cirrhosis was observed in carriers of the T/T and T/C genotypes but not in carriers of the C/C genotype. The TNF-{alpha}/–308 promoter polymorphisms (TNF*1 and TNF*2) were not associated with BA.

Conclusion.These findings show that the single-nucleotide polymorphism at CD14/–159 is associated with the development of BA and INC. Endotoxin susceptibility may play a role in the pathogenesis of infantile cholestasis.

Key Words: CD14 gene • single nucleotide polymorphism • biliary atresia • neonatal cholestasis • endotoxin susceptibility

Abbreviations: BA, biliary atresia • TNF-{alpha}, tumor necrosis factor-{alpha} • IL, interleukin • LPS, lipopolysaccharide • SNP, single-nucleotide polymorphism • INC, idiopathic neonatal cholestasis • sCD14, soluble CD14

Accepted Nov 23, 2004.