UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children A retrospective analysis and quantitative correlation
UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children A retrospective analysis and quantitative correlation
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DOI：
10.1097/md.0000000000013576
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发表时间：
2018-12-01
期刊：
影响因子：
1.6
通讯作者：
Wang, Jian-She
中科院分区：
文献类型：
--
作者：
Abuduxikuer, Kuerbanjiang;Fang, Ling-Juan;Wang, Jian-She
目的回顾性分析中国儿童UGT 1A 1基因型与非结合型高胆红素血症（UCH）表型的关系，并与健康对照组进行比较。采用Pfam数据库、SWISS模型和Pymol蛋白质模型对74例UGT 1A 1蛋白质结构域进行分析，包括21例长期未结合高胆红素血症（PUCH）、30例吉尔伯特综合征（GS）、22例Crigler-Najjar综合征II型（CNS-II）和1例Crigler-Najjar综合征I型（CNS-I）。共21个变异体，包括7个新变异体（c. 764T>A/p. L255Q，c. 1112 C>T/p. T371 I，c. 1028C>A/p. S343X，c. 1047delG/p. I350YfsX16，c. 996+ 5G>C/g。6923G>C，c. 287G>A/p. G96E，和c.在多元回归模型中，杂合子A（TA）7 TAA、G71 R/P364 L和Y 486 D/其他突变分别与GS、PUCH和CNS-II的风险增加显著相关。总等位基因数与GS和CNS-II显著相关，随着总等位基因数的增加，GS和CNS-II的优势比（OR）分别增加1.46和4.47倍。仅UGT 1A 1基因功能多态性与PUCH和GS风险增加相关，OR值分别为5.67（95% CI：1.52-21.13）和3.88（95% CI：1.02 - 14.78）。仅突变与GS表型风险显著增加相关（OR：34.00，95%CI：4.65-248.37），但与CNS-II无关。多态性加突变与CNS-II的相关性最强，OR值为64.80（95%CI：7.68-546.41），其次为GS（OR：4.53，95%CI：1.08-19.08）。在中国儿童中，G71 R和P364 L与PUCH独立相关，A（TA）7 TAA与GS相关，Y 486 D或其他致病突变与CNS-II相关。多个等位基因与更严重的表型相关。G71 R + Y 486 D联合变异在中国儿童UCH中很常见。
To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP-glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.We retrospectively reviewed UCH patients, quantitatively analyzed genotype-phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c. 764T>A/p. L255Q, c. 1112C>T/p. T371I, c. 1028C>A/p. S343X, c. 1047delG/p. I350YfsX16, c. 996+ 5G>C/g. 6923G>C, c. 287G>A/p. G96E, and c. 1142G>A/p. S381N) were found. In the multiple regression model, heterozygous A(TA) 7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52-21.13), and 3.88 (95% CI: 1.0214.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65-248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68-546.41), followed by GS (OR: 4.53, 95% CI: 1.08-19.08).We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA) 7TAA is associated with GS, and Y486D or other diseasecausing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+ Y486D is a common occurrence among Chinese children with UCH.