Genetic Spectrum of UGT1A1 in Korean Patients with Unconjugated Hyperbilirubinemia

Jin Ju Kim; M.D.; Joowon Oh; M.D.; Yoonjung Kim; M.D. PhD.; and Kyung-A Lee; M.D. Ph.D.

doi:10.3343/alm.2020.40.3.281

Article

Letter to the Editor

Ann Lab Med 2020; 40(3): 281-283

Published online May 1, 2020 https://doi.org/10.3343/alm.2020.40.3.281

Genetic Spectrum of UGT1A1 in Korean Patients with Unconjugated Hyperbilirubinemia

Jin Ju Kim, M.D.¹, Joowon Oh, M.D.², Yoonjung Kim, M.D. PhD.² , and Kyung-A Lee, M.D. Ph.D.²

¹Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; ²Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Correspondence to: Kyung-A Lee, M.D. PhD.
Department of Laboratory Medicine, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea
Tel: +82-2-2019-3531, Fax: +82-2-2019-4822, E-mail: KAL1119@yuhs.ac

Received: August 7, 2019; Revised: August 29, 2019; Accepted: November 13, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Tables

Go to

CONFLICTS OF INTEREST
ACKNOWLEDGEMENTS
Table
References

Table 1

Variants and frequencies of UGT1A1 detected in patients with hyperbilirubinemia (N=81) and healthy controls

Location	Nucleotide change	Marker allele	Predicted amino acid change	Minor allele frequency (number of heterozygotes/homozygotes)				P^†	dbSNP
				Patients (N = 81)	Controls
				Patients (N = 81)	Chinese [7] (N = 80)	Japanese [8] (N = 71)	Korean^* (N = 1,722)
Promoter	c.-64G > C	^*81	-	0.037 (6/0)	-	-	0.036	0.832	rs873478
Promoter	c.-41_-40dupTA	^*28	-	0.438 (31/20)	0.144 (21/1)	0.113 (12/2)	0.200	< 0.0001	rs34983651
Intron 1	c.864+2T > C	Novel	-	0.006 (1/0)	-	-	0.000	0.045	rs772088902
Exon 1	c.182C > G	Novel	p.Ala61Gly	0.006 (1/0)	-	-	0.000	0.045	rs1273237448
Exon 1	c.211G > A	^*6	p.Gly71Arg	0.315 (31/10)	0.169 (23/2)	0.183 (20/3)	0.173	< 0.0001	rs4148323
Exon 1	c.686C > A	^*27	p.Pro229Gln	0.037 (6/0)	0.013 (2/0)	-	0.014	0.030	rs35350960
Exon 4	c.1091C > T	^*73	p.Pro364Leu	0.031 (5/0)	0.006 (1/0)	-	0.013	0.077	rs34946978
Exon 5	c.1456T > G	^*7	p.Tyr486Asp	0.031 (1/2)	0.000 (0/0)	0.014 (2/0)	0.001	< 0.0001	rs34993780
Exon 5	c.1352C > T	N/A	p.Pro451Leu	0.006 (1/0)	-	-	0.001	0.241	rs114982090

Table 2

Genotyping of UGT1A1 in hyperbilirubinemia patients with clinical data (N=46)

Genotype	Promoter TATA box	Coding region	Patients (N = 46)		Controls [9] (N = 324)
Genotype	Promoter TATA box	Coding region	N	TB (µmol/L) (mean ± SD)	N	TB (µmol/L) (mean ± SD)
1	Wild	Wild	HS (1)	69.08	148	13.34 ± 3.42
2	TA6/7	p.Gly71Arg +/− ; p.Ala61Gly +/−	GS (1)	20.52	-	-
3	Wild	p.Gly71Arg +/+	GS (3)	25.65 ± 2.91	18	23.60 ± 6.16
4	TA6/7	p.Pro229Gln +/−	GS (2)	28.22 ± 1.20	-	-
5	TA7/7	p.Pro229Gln +/+	GS (1)	30.78	-	-
6	TA6/7	Wild	GS (3)	34.54 ± 15.56	49	17.27 ± 5.64
7	TA7/7	p.Pro364Leu +/–	GS (2)	35.91 ± 7.18	-	-
8	Wild	p.Gly71Arg +/–	GS (4)	34.71 ± 12.31	83	15.90 ± 3.25
9	TA6/7	p.Gly71Arg +/–	GS (14)	40.01 ± 24.45	19	24.62 ± 5.13
10	TA7/7	Wild	GS (12)	46.68 ± 17.10	7	33.17 ± 4.10
11	Wild	p.Gly71Arg +/– ; p. Pro364Leu +/–	GS (1)	61.56	-	-
12	Wild	p.Gly71Arg +/– ; p.Tyr486Asp +/+	CNII (1)	75.24	-	-
13	Wild	p.Gly71Arg +/+ ; p.Tyr486Asp +/+	CNII (1)	79.86	-	-

References

Go to

CONFLICTS OF INTEREST
ACKNOWLEDGEMENTS
Table
References

Mackenzie PI, Miners JO, McKinnon RA. Polymorphisms in UDP glucuronosyltransferase genes: functional consequences and clinical relevance. Clin Chem Lab Med 2000;38:889-892.
Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Elferink RO, Chowdhury JR, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994;269:17960-17964.
Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?. Proc Natl Acad Sci 1998;95:8170-8174.
Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136.
Kim SY, Lee SH, Koh H, Lee ST, Ki CS, Kim JW, Chung K. A case of Crigler-Najjar syndrome type 2 diagnosed using genetic mutation analysis. Korean J Pediatr Gastroenterol Nutr 2008;11:219-222.
Ko JS, Chang JY, Moon JS, Yang HR, Seo JK. Molecular analysis of the UGT1A1 gene in Korean patients with Crigler-Najjar syndrome type II. Pediatr Gastroenterol Hepatol Nutr 2014;17:37-40.
Li L, Deng G, Tang Y, Mao Q. Spectrum of UGT1A1 variations in Chinese patients with Crigler-Najjar syndrome type II. PLoS One 2015;10:e0126263.
Takeuchi K, Kobayashi Y, Tamaki S, Ishihara T, Maruo Y, Araki J, et al. Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler–Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol 2004;19:1023-1028.
Ki CS, Lee KA, Lee SY, Kim HJ, Cho SS, Park JH, et al. Haplotype structure of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and its relationship to serum total bilirubin concentration in a male Korean population. Clin Chem 2003;49:2078-2081.
Gantla S, Bakker CTM, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M, et al. Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. Am J Hum Genet 1998;62:585-592.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-424.