Relationship between UGT1A1 gene mutation and breast milk jaundice
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摘要:
目的 研究UGT1A1基因在汉族新生儿中的分布情况, 探索UGT1A1基因突变对新生儿发生母乳性黄疸的影响。 方法 采用病例对照研究设计, 选取2018年1月-2020年6月南京鼓楼医院集团宿迁医院产科109例母乳性黄疸新生儿为病例组, 另外选取同期109例健康新生儿为对照组, 收集临床资料, 采集外周血, 提取全血DNA, 通过对UGT1A1基因进行PCR扩增及测序, 分析UGT1A1基因多态性与母乳性黄疸以及非结合胆红素浓度峰值的关联。通过前瞻性随访研究, 分析不同基因型母乳性黄疸新生儿黄疸消退情况。 结果 病例组与对照组在性别、出生方式、出生体重、胎龄之间差异均无统计学意义(均P>0.05), UGT1A1*28 7TA/7TA、UGT1A1*63 C/T和UGT1A1*7 T/G在2组之间的频率差异无统计学意义(均P>0.05), UGT1A1*6与新生儿发生母乳性黄疸存在关联(OR=3.561, 95%CI: 2.179~5.822)。UGT1A1*6纯合突变组的血清胆红素浓度高于其他2组(P=0.001)。共随访65例母乳性黄疸新生儿黄疸消退情况, 其中55名新生儿在3个月之内完全消退, 8例UGT1A1*6 G/A突变型新生儿黄疸持续时间超过3个月。 结论 UGT1A1*6突变是本地区汉族人母乳性黄疸发生的危险因素。 Abstract:Objective To study the distribution of UGT1A1 gene in newborns of Han nationality and explore the effect of UGT1A1 gene mutation on the occurrence of breast milk jaundice in newborns. Methods Using the case-control study design, 109 newborns with breast milk jaundice in Suqian Hospital of Nanjing Gulou Hospital Group from January 2018 to June 2020 were selected as the case group, and another 109 healthy newborns in the same period were selected as the control group.Clinical data were collected, peripheral blood was collected, whole blood DNA was extracted, and UGT1A1 gene was amplified and sequenced by PCR.The association of UGT1A1 gene polymorphism with breast milk jaundice and peak concentration of unconjugated bilirubin was analyzed.Through a prospective follow-up study, the regression of jaundice in newborns with different genotypes of breast milk jaundice was analyzed. Results There was no statistically significant difference between the case group and the control group in gender, birth mode, birth weight and gestational age (all P>0.05).There was no statistically significant difference in the frequency of UGT1A1*28 7TA/7TA, UGT1A1*63 C/T and UGT1A1*7 T/G between the two groups (all P>0.05).There was a correlation between UGT1A1*6 and neonatal milk jaundice (OR=3.561, 95%CI: 2.179-5.822).The serum bilirubin concentration of UGT1A1*6 homozygous mutation group was higher than that of the other two groups (P=0.001).A total of 65 cases of neonatal jaundice due to breast milk were followed up.Among them, 55 newborns completely disappeared within three months, and 8 cases of UGT1A1*6G/A mutant neonatal jaundice lasted more than three months. Conclusion UGT1A1*6 mutation is a risk factor for breast milk jaundice in Han nationality in this region. -
Key words:
- Breast-milk jaundice /
- UDP-glucuronosyltransferase 1A1 /
- Gene mutation
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表 1 UGT1A1基因扩增引物序列
Table 1. UGT1A1 gene amplification primer sequence
基因片段 上游引物(5′-3′) 下游引物(5′-3′) TATA盒Exon1 GAAACCTAATAAAGCTCCACCTTC GCCCCAGATATATGCTGAGCAA Exon2 TCATTTAAAGGGACCACGCC GGAACCTTAGATTTGGCTTTTCC Exon3/4 CCTCCCACTCTGTTAAAGAC CTTTGGTCATGGCATTCATG Exon5 GAAACAGGTTTCCTTTCCCAAG TATGTATCGTGCCCCCTCTG 
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表 2 UGT1A1基因启动子及外显子区域测序引物
Table 2. UGT1A1 gene promoter and exon region sequencing primer
基因片段 测序引物
(5′-3′)产物长度
(bp)TATA盒加Exon1 ATTCTTTCCTGCAGCGTGTGATC 480 Exon2 TCATTTAAAGGGACCACGCC 600 Exon3/4 CCTCCCACTCTGTTAAAGAC 710 Exon5 TATGTATCGTGCCCCCTCTG 560
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表 3 2组研究对象一般资料比较
Table 3. Comparison of general data between two groups
组别 例数 性别(例) 出生方式(例) 出生体重
(x±s, g)胎龄
(x±s，d)男 女 顺产 剖宫产 病例组 109 62 47 58 51 3 405±339 278±9 对照组 109 62 47 64 45 3 379±353 279±10 统计量 0.670a 0.555b 0.776b P值 0.413 0.579 0.439 注：a为χ2值，b为t值。
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表 4 2组新生儿UGT1A1基因型频率对比情况[例(%)]
Table 4. Comparison of UGT1A1 genotype frequency between two groups of newborns [cases(%)]
基因型 病例组
(n=109)对照组
(n=109)χ2值 P值 UGT1A1*6 A/A 12(11.01) 4(3.67) 28.011 < 0.001 G/A 49(44.95) 19(17.43) G/G 48(44.04) 86(78.90) UGT1A1*28 A/A 107(98.17) 108(99.08) 0.338 0.561 A/T 2(1.83) 1(0.92) T/T 0 0 UGT1A1*63 C/C 107(98.17) 109(100.00) 2.019 0.155 C/T 2(1.83) 0 T/T 0 0 UGT1A1*7 T/T 106(97.25) 109(100.00) 3.042 0.081 T/G 3(2.75) 0 G/G 0 0
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表 5 UGT1A1*6基因型BMJ患儿临床资料比较
Table 5. Comparison of clinical data of BMJ children with UGT1A1*6 genotype
基因型 例数 胆红素浓度
(x±s, μmol/L)出生方式(例) 出生体重
(x±s, g)胎龄
(x±s, d)性别(例) 顺产 剖腹产 男 女 A/A 8 270.3±45.1 5 3 3 641±240 276±5 4 4 G/A 31 195.2±53.8a 19 12 3 501±360 273±9 18 13 G/G 26 180.3±60.0a 12 14 3 562±319 277±8 14 12 统计量 25.480b 1.498c 5.615b 3.593b 0.209c P值 < 0.001 0.473 0.060 0.166 0.901 注：与基因型A/A比较，aP < 0.05；b为F值，c为χ2值。
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表 6 65例BMJ患儿的黄疸转归情况(例)
Table 6. The prognosis of jaundice in 65 children with BMJ (cases)
UGT1A1基因突变 < 1个月 1~1.5个月 1.5~2个月 2~3个月 3~4个月 >4个月 UGT1A1*6 G/G 7 14 1 4 0 0 UGT1A1*6 G/A 7 11 2 3 7 1 UGT1A1*6 A/A 0 2 0 4 2 0
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