ABCB4 Gene Variants as Potential Modifiers of Biliary Atresia Outcomes Open Access

Mezina, Anya (2015)

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Biliary atresia (BA), a progressive neonatal cholestatic liver disease, is the leading indication for pediatric liver transplantation in the United States. The Kasai hepatoportoenterostomy is successful in restoring bile drainage and delaying liver transplantation in a subset of patients. Early age at operation is generally associated with improved clinical outcomes, although the optimal age at surgery is contested. African Americans with BA may undergo the Kasai procedure at a later age than white patients. Mutations in the ABCB4 gene, a phospholipid floppase, are associated with severe cholestatic liver disease in children and adults. We performed a case-control study comparing ABCB4 variants between subjects from the Childhood Liver Disease Research and Education Network (ChiLDREN) database who required a liver transplant by age 2 (Early Transplant, ET, n=98) with those who survived with their native liver 4 years after the Kasai with a normal platelet count (Survive with Native Liver, SNL, n=97). Controlling for race, each 1-day delay in age at Kasai increased the odds of ET outcome by 3% (p<0.001). The A934T polymorphism was significantly associated with ET outcome (Trend Test, p=0.044) and was only found in African American subjects. A linked study examining an independent cohort of African American ChiLDREN subjects (n=104) identified 2 heterozygotes for p.A934T. One subject received a liver transplant less than 1 year after Kasai, and 1 survived with his native liver until age 9. A significant difference in survival with native liver at 2 years post-Kasai was not detected until after 120 days of age (p=0.015). A total serum bilirubin ≥ 2 mg/dl at 3 months post-Kasai was a stronger predictor of death or transplant by 2 years after Kasai than age at surgery (OR=12.89, 95% CI: 1.31, 127.26). Heterozygosity for p.A934T may expedite the progression of biliary cirrhosis among African Americans with BA who undergo Kasai. Kasai at an early age may not be an important prognostic determinant of survival with native liver among African Americans. More comprehensive analyses of African Americans with BA, inclusive of patients who forego the Kasai, and functional assays of A934T must be performed to confirm these findings.

Table of Contents

Introduction. 1

Background. 3

Methods. 9

Results. 15

Discussion. 20

References. 31

Tables and Figures. 36

List of Figures

Figure 1 - Pathophysiology of ABCB4-linked disease. 36

Figure 2 - Diagram of subject selection. 37

Figure 3 - Age at Kasai: stratified by race and outcome. 40

Figure 4 - Schematic of ABCB4 gene variants in biliary atresia subjects. 42

Figure 5 - Distribution of age at Kasai for African American subjects. 46

Figure 6 - Kaplan-Meier survival curve for African American subjects. 47

Figure 7 - Kaplan-Meier 2-year survival curves stratified by age at Kasai. 50

Figure 8 - Kaplan-Meier 2-year survival curves comparing age at Kasai. 52

Figure 9 - Kaplan-Meier 2-year survival curves stratified by bilirubin. 54

List of Tables

Table 1 - Univariate analysis of race in biliary atresia subjects. 38

Table 2 - Mean age at Kasai (days) in biliary atresia subjects. 39

Table 3 - Multivariate analysis of race and age at Kasai. 41

Table 4 - ABCB4 genotyping results in biliary atresia subjects. 43

Table 5 - Statistical results for missense variants in ABCB4. 44

Table 6 - Characteristics and outcome measures. 45

Table 7 - Summary statistics for estimated survival. 48

Table 8 - Characteristics of African American subjects with biliary atresia. 49

Table 9 - 2-Year survival analysis stratified by age at Kasai. 51

Table 10 - Univariate analysis of age at Kasai as risk factor for death. 53

Table 11 - Univariate analysis of jaundice clearance and age at Kasai. 55

Table 12 - International data available on age at Kasai. 56

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