title: Associations of mitochondrial haplogroups b4 and e with biliary atresia and differential susceptibility to hydrophobic bile Acid.
abstract: Mitochondrial dysfunction has been implicated in the pathogenesis of biliary atresia (BA). This study aimed to determine whether a specific mitochondrial DNA haplogroup is implicated in the pathogenesis and prognosis of BA. We determined 40 mitochondrial single nucleotide polymorphisms in 15 major mitochondrial haplogroups by the use of 24-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes in 71 patients with BA and in 200 controls in the Taiwanese population of ethnic Chinese background. The haplogroup B4 and E prevalence were significantly lower and higher respectively, in the patients with BA than in the controls (odds ratios, 0.82 [p = 0.007] and 7.36 [p = 0.032] respectively) in multivariate logistic-regression analysis. The 3-year survival rate with native liver was significantly lower in haplogroup E than the other haplogroups (P = 0.037). A cytoplasmic hybrid (cybrid) was obtained from human 143B osteosarcoma cells devoid of mtDNA (ρ(0) cell) and was fused with specific mtDNA bearing E and B4 haplogroups donated by healthy Taiwanese subjects. Chenodeoxycholic acid treatment resulted in significantly lower free radical production, higher mitochondrial membrane potential, more viable cells, and fewer apoptotic cybrid B4 cells than parental 143B and cybrid E cells. Bile acid treatment resulted in a significantly greater protective mitochondrial reaction with significantly higher mitochondrial DNA copy number and mitofusin 1 and 2 concentrations in cybrid B4 and parental cells than in cybrid E cells. The results of the study suggested that the specific mitochondrial DNA haplogroups B4 and E were not only associated with lower and higher prevalence of BA respectively, in the study population, but also with differential susceptibility to hydrophobic bile acid in the cybrid harboring different haplogroups.
authors: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Mao-Meng
authors: MM
authors: Tiao
authors: Chia-Wei
authors: CW
authors: Liou
authors: Li-Tung
authors: LT
authors: Huang
authors: Pei-Wen
authors: PW
authors: Wang
authors: Tsu-Kung
authors: TK
authors: Lin
authors: Jin-Bor
authors: JB
authors: Chen
authors: Yao-Min
authors: YM
authors: Chou
authors: Ying-Hsien
authors: YH
authors: Huang
authors: Hung-Yu
authors: HY
authors: Lin
authors: Chao-Long
authors: CL
authors: Chen
authors: Jiin-Haur
authors: JH
authors: Chuang
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D001647:Bile Acids and Salts / Q000378:metabolism*; D001656:Biliary Atresia / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000145:classification / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007223:Infant; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D015996:Survival Rate
chemical_list: D001647:Bile Acids and Salts; D004272:DNA, Mitochondrial
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