Vol.:(0123456789) 1 3 Pediatric Surgery International https://doi.org/10.1007/s00383-018-4243-3 ORIGINAL ARTICLE Single nucleotide polymorphisms within Adducin 3 and Adducin 3 antisense RNA1 genes are associated with biliary atresia in Thai infants Wison Laochareonsuk 1  · Piyawan Chiengkriwate 1  · Surasak Sangkhathat 1 Accepted: 28 February 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Background A genome-wide association study in East Asians suggested a genetic association between biliary atresia (BA) and a cluster of variants within the Adducin 3 (ADD3) and ADD3 antisense RNA1 (ADD3-AS1) genes. Another study in Thai neonates reported an association between BA and rs17095355. To validate those fndings, this study aimed to analyze the BA association with single nucleotide polymorphisms (SNPs) and the additive infuence of ADD3 and ADD3-AS1 in Thai neonates. Methods DNAs from 56 BA cases and 166 controls were genotyped for rs2501577, rs11194981, rs12268910 (ADD3) and rs17095355 (ADD3-AS1), using TaqMan PCR. Genotype distributions were compared between the groups, and SNP–SNP interactions were analyzed by combination of allelotypes. Results The risk allele frequencies of rs2501577, rs11194981, and rs17095355 in the BA group were signifcantly higher than in the controls. Univariate analysis showed that recessive variants in the three SNPs were associated with BA risk at ORs of 1.81 (95% CI 1.32–2.50), 1.58 (95% CI 1.14–2.20) and 1.92 (95% CI 1.39–2.66), respectively. SNP–SNP interaction analysis showed that the SNP combination of the two genes rs17095355 and rs2501577 provided an additive increase in BA risk. Conclusion ADD3 and ADD3-AS1 variants increased susceptibility to BA, suggesting that these genes may play an additive role in the pathogenesis of the disease. In addition, these interactions may give a clue to the overexpression of the ADD3 protein in the liver of BA patients. Keywords Biliary atresia · Single nucleotide polymorphism · ADD3 · Genetic association study Introduction Biliary atresia (BA) is an infammatory cholangiopathy of infancy characterized by progressive fbrosclerosis and oblit- eration of extrahepatic and intrahepatic bile ducts [1–3]. If untreated, the obstruction usually leads to biliary cirrhosis, liver failure and death within a few years of birth [4–7]. Estimated incidences of BA range from 1:320 to 1:2000 live births, with the highest incidences in Asians [3, 6, 8]. The etiology and pathogenesis of BA remain unclear; how- ever, putative causes include viral, vascular, immunological, environmental and genetic factors [1, 4, 8, 9]. Regarding genetic components, genome-wide association studies have suggested a genetic association between BA and the region 10q25.1 where the Adducin 3 (ADD3) is situated [10, 11]. ADD3 encodes for Adducin Gamma which forms heter- omeric proteins with Adducin Alpha or Beta. The Adducin is involved in the assembly of the spectrin–actin network [12, 13] that are exclusively present in the extrahepatic biliary epithelium [ 14]. Many single nucleotide poly- morphisms (SNPs) within the vicinity of ADD3, includ- ing rs2501577, rs17095355 and rs11194981, have been reported by recent validation studies in various popula- tions to have an association with BA [15, 16]. rs2501577 and rs11194981 are intron variants on ADD3 while rs17095355 is situated on another transcript, ADD3-AS1, encoding for a long non-coding RNA (lncRNA) which may have infuence on the expression of ADD3 [17, 18]. One study found that knocking down the ADD3 gene pro- duced intrahepatic defects and decreased biliary functions in the liver of developing zebrafshes [19]. Immunohis- tological studies have found the expression of ADD3 * Surasak Sangkhathat surasak.sa@psu.ac.th 1 Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand