ARTICLE IN PRESS

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ARTICLES
Bilirubin Uridine Diphosphate-glucuronosyltransferase Polymorphism
as a Risk Factor for Prolonged Hyperbilirubinemia in Japanese
Preterm Infants
Takahide Yanagi, MD, Sayuri Nakahara, MD, and Yoshihiro Maruo, MD, PhD

Objective To determine whether a variant of the bilirubin uridine diphosphate-glucuronosyltransferase gene

(UGT1A1*6) is a risk factor for prolonged hyperbilirubinemia in preterm infants.
Study design UGT1A1 genotypes in 46 Japanese preterm infants (<37 weeks of gestation) were compared with
UGT1A1 genotypes in 38 control infants, using polymerase chain reaction-direct sequencing. Prolonged unconjugated
hyperbilirubinemia was defined as serum total bilirubin concentration of >150 µmol/L (8.77 mg/dL) beyond 14 days
of life.
Results In the case group, 41 of 46 infants (89.1%) had a polymorphic variant, c.211G>A, p.G71R (UGT1A1*6).
In the control group, 7 of 38 (18.4%) had UGT1A1*6. The allele frequency of UGT1A1*6 was 0.641 in the pro-
longed hyperbilirubinemia group, which was significantly higher than in the control group (0.092; P < .001). In
total, 39 of 46 infants in the case group were breast fed, and only 10 infants in the control group were breast
fed.
Conclusions These data suggest that UGT1A1*6 is a risk factor for prolonged unconjugated hyperbilirubinemia
in preterm infants in Japan. Given the different rate of breast feeding in this study, additional data are necessary
for drawing a definitive conclusion. (J Pediatr 2017;■■:■■-■■).

yperbilirubinemia in the neonatal period is a common clinical problem that may be associated with genetic factors.1,2

H Bilirubin UDP-glucuronosyltransferase (UGT1A1, EC2.4.1.17) is the only enzyme shown to be responsible for bili-
rubin glucuronidation. Mutations of the gene encoding UGT1A1 (UGT1A1) are known to cause hereditary unconjugated
hyperbilirubinemia, Crigler-Najjar syndrome type I (MIM #21880) and type II (MIM #606785), and Gilbert syndrome (MIM
#143500).3-5 A missense mutation at nucleotide 211 of UGT1A1 (c.211G>A: UGT1A1*6) is one of the most common causes of
Gilbert syndrome in East Asians.6 In previous studies in term infants, we found that UGT1A1*6 is a risk factor for neonatal
hyperbilirubinemia in the early neonatal period7 and a genetic cause of prolonged unconjugated hyperbilirubinemia associ-
ated with breast feeding in the late neonatal period.8,9
In preterm infants, neonatal hyperbilirubinemia is more prevalent, more severe, and has a more protracted course than in
term infants owing to differences in factors influencing bilirubin metabolism, including hepatic and gastrointestinal immatu-
rity, slow postnatal maturation of hepatic bilirubin uptake and conjugation, and delayed initiation of enteral feeding.10,11 It has
not been clarified whether genetic background also affects the prevalence of hyperbilirubinemia in preterm infants. The purpose
of this study was to determine whether a variant of the bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1*6)
is a risk factor for prolonged hyperbilirubinemia in preterm infants.

Methods
This retrospective case-control study used convenience samples from 48 peripheral blood samples that were sent for UGT1A1
genotype analysis from several institutions across Japan to our university for clinical purposes in the course of diagnosis of
prolonged jaundice. Eligible subjects included Japanese preterm infants (<37 weeks of gestation) with prolonged unconjugated
hyperbilirubinemia, with written informed parental consent for enrollment. Exclusion criteria were other causes of hyperbilirubinemia,
such as hemolytic anemia, liver dysfunction, cholestasis, or hypothyroidism, which were confirmed on declaration by each in-
stitution (specific numerical values were not available for all cases). Prolonged hyperbilirubinemia was defined as serum total
bilirubin concentration of >150 µmol/L (8.77 mg/dL) beyond 14 days of life.12
The control group comprised 38 Japanese preterm infants who were admitted
to our neonatal unit and did not show prolonged hyperbilirubinemia beyond 14
days of life. From the Department of Pediatrics, Shiga University of
Medical Science, Otsu, Shiga, Japan
The authors declare no conflicts of interest.

0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights

UGT1A1 Bilirubin uridine diphosphate-glucuronosyl transferase reserved.
http://dx.doi.org10.1016/j.jpeds.2017.07.014

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All of the parents provided written informed consent. This

Table II. Clinical characteristics of infants in the case
study was approved by the ethics committee of Shiga Univer-
group and the control group
sity of Medical Science, Otsu, Shiga, Japan.
Based on our previous study, the UGT1A1*6 allele fre- Case group Control group
n = 46 n = 38 P value
quency in the Japanese general population is 0.16.9 We con-
sider a 2-fold higher allele frequency (0.32) in the case group Gestational age
Range 28w0d-36w6d 28w3d-36w6d
as clinically meaningful compared with that in the control Median 34 w 0 d 34 w 0 d
group. We calculated that with a sample of 40 patients (80 Interquartile range 3.61 w 3.75 w .390 *
alleles), the study would have 80% power to detect 0.16 in- Birth weight (g)
Range 914-2815 916-2880
crease of allele frequency in the control group, with a type I Mean ± SD 2032 ± 462 1843 ± 456 .064†
error of 5%. Sex (male/female) 26/19 (NA 1) 19/19
For sequencing analysis of UGT1A1 polymorphism, genomic Nutrition
Breast fed 39 10
DNA was extracted from the peripheral blood leukocytes of Formula fed 0 14
infants using a blood isolation kit (DNA Quick 2; DS Pharma Mixture 2 (NA 5) 14
Biomedical, Osaka, Japan). Exons, the promoter region, and Direct bilirubin (mg/dL) (NA 8)
Range 0.00-1.40
the phenobarbital-responsive enhancer module of UGT1A1 Mean ± SD 0.67 ± 0.42
were amplified from genomic DNA by polymerase chain re-
NA, data not available.
action. Approximately 100 ng of total genomic DNA was am- *Mann–Whitney test.
plified using pairs of oligonucleotide primers as listed in Table I †Two-sample t test.
(available at www.jpeds.com). Conditions for polymerase chain
reaction were initial denaturation for 2 minutes at 94°C, fol-
lowed by 30 cycles of 1 minute at 94°C, 1 minute at 60°C, and
2 minutes at 72°C with a Minicycler (MJ Research, Inc, Wa- there were no cases of homozygosity for UGT1A1*6 in the
tertown, Massachusetts). A final extension for 10 minutes at control group. The allele frequencies of the UGT1A1*6 was
72°C was performed to ensure complete extension of the poly- 0.641 in the case group and 0.092 in the control group
merase chain reaction products. (c2 = 52.6; P < .001; Tables III and IV).
The sequences of the amplified DNA fragments were de- The distribution of UGT1A1 genotypes was evaluated in sub-
termined directly using a Big Dye Terminator v1.1 Cycle Se- groups consisting of preterm (28-33 weeks of gestation) and
quencing Kit and Genetic Analyzer ABI Prism 3130xl (Applied late preterm (34-36 weeks of gestation) infants. In the case
Biosystems, Carlsbad, California). The used primers are listed group, the allele frequencies of UGT1A1*6 were 0.575 and 0.692
in Table I. in the preterm and late preterm groups, respectively (Table V;
available at www.jpeds.com). In the control group, the allele
Statistical Analyses frequencies of UGT1A1*6 were 0.138 and 0.050 in the preterm
Genotype results were analyzed as the prolonged hyperbili- and late preterm groups, respectively.
rubinemia group vs the control group. A c2 analysis was Maximum serum bilirubin concentrations after 14 days of
conducted on the allele frequency. The highest values of age in the infants with prolonged hyperbilirubinemia were
serum bilirubin concentrations after 14 days of life in the case
group for the different genotypes detected were examined
by ANOVA, and the Tukey’s honestly significant difference
testing was used for pairwise comparison. We performed all
statistical analyses using SPSS (version 22; SPSS, Inc, Chicago, Table III. Distribution of UGT1A1 genotypes in the case
Illinois). group and the control group
Genotypes Case group Control group

Results Allele 1 Allele 2 (n = 46) % (n = 38) %

UGT1A1*6 UGT1A1*6 18 39.3 0 0.0
The clinical characteristics of the infants in the prolonged hy- UGT1A1*6 UGT1A1*1 16 34.7 5 13.2
UGT1A1*6 UGT1A1*60 5 10.8 1 2.6
perbilirubinemia group and the control group are shown in UGT1A1*6 UGT1A1*28 1 2.1 1 2.6
Table II. Gestational age and body weight were not different UGT1A1*6 UGT1A1*7 1 2.1 0 0.0
between the 2 groups. In total, 39 of 46 infants in the case group UGT1A1*60 UGT1A1*63 1 2.1 0 0.0
UGT1A1*60 UGT1A1*1 1 2.1 13 34.2
were fed with breast milk, and only 10 infants in the control UGT1A1*60 UGT1A1*60 0 0.0 1 2.6
group were breast fed. UGT1A1*28 UGT1A1*1 0 0.0 1 2.6
The results of UGT1A1 analysis of all infants are shown in UGT1A1*1 UGT1A1*1 3 6.5 16 42.1
Allele frequency of UGT1A1*6 0.641* 0.092
Table III. In the case group, 41 of 46 infants (89.1%) had (P < .001)
UGT1A1*6. A total of 18 cases were homozygous and the other
UGT1A1*1, wild-type allele; UGT1A1*6, p.G71R; UGT1A1*7, p.Y486D; UGT1A1*28, c.−3279T>G + A
23 were heterozygous. In the control group, 7 of 38 (18.4%) (TA) 7TAA; UGT1A1*60, c.−3279T>G; UGT1A1*63, p.P364L.
had UGT1A1*6. All of these 7 infants were heterozygous and *Significant difference from control group: c2 = 52.6, P < .001.

2 Yanagi, Nakahara, and Maruo

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■■ 2017
Table IV. Allele frequency of UGT1A1 polymorphism in
prolonged jaundice group, control group, and Japanese
general population
Case group Control group
Number Number
of alleles of alleles
(total 92) Frequency (total 76) Frequency
UGT1A1*1 23 0.250 51
UGT1A1*6 58 0.641 7 0.092
UGT1A1*28 1 0.010 2 0.026
UGT1A1*60 7 0.076 16
*Allelic frequency in general Japanese population as determined in a previous study.9
compared among the 5 UGT1A1 genotypes (Figure). ANOVA
and post hoc testing showed a significant difference between
those homozygous for UGT1A1*6 and those heterozygous
UGT1A1*6 (P = .018).
Figure. Differences in serum bilirubin concentration (maximum
value after 14 days of life) depending on genotype in the case
group. ANOVA showed a significant difference among geno-
types (degrees of freedom: 4, 41, F = 3.094, P < .05). Tukey’s
honestly significant difference testing showed significant dif-
ference between those homozygous for UGT1A1*6 and those
heterozygous for it (P = .018). The distribution of bilirubin con-
centration in each genotype is as follows: homozygous for
UGT1A1*6 (n = 18), 19.3 ± 3.5 mg/dL (mean ± SD); heterozy-
gous for UGT1A1*6 and UGT1A1*1 (n = 16), 15.3 ± 3.1; het-
erozygous for UGT1A1*6 and UGT1A1*60 (n = 5), 17.5 ± 2.8;
other genotypes (n = 4, including compound heterozygous for
UGT1A1*6 and UGT1A1*28; UGT1A1*6 and UGT1A1*7;
UGT1A1*60 and UGT1A1*63; and UGT1A1*60 and
UGT1A1*1), 16.6 ± 4.5; and wild type (n = 3), 14.7 ± 5.6.
Bilirubin Uridine Diphosphate-glucuronosyltransferase Polymorphism as a Risk Factor for Prolonged
Hyperbilirubinemia in Japanese Preterm Infants
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ORIGINAL ARTICLES
Discussion
These data suggest that UGT1A1*6 is a risk factor for pro-
General longed unconjugated hyperbilirubinemia in preterm infants.
Japanese
population*
In preterm infants, there are many factors influencing biliru-
bin metabolism, for example, excessive neonatal red cells,
hepatic and gastrointestinal immaturity, slow postnatal matu-
Frequency ration of hepatic bilirubin uptake and conjugation, and delayed
0.671 initiation of enteral feeding.10 These factors may attenuate the
0.151-0.16 impact of genetics on hyperbilirubinemia and genetic back-
0.121-0.15 ground may not be as important in preterm infants as in term
0.210 0.115
infants. In the present study of Japanese preterm infants, the
allele frequency of UGT1A1*6 was 0.641 in the case group,
which was significantly higher than in the control group (0.092).
It was also higher than in the general Japanese population
(range, 0.151-0.160; Table IV).9 Similar to what has been de-
scribed in Japanese term infants,9 the most common geno-
type in the case group was homozygous for UGT1A1*6 (39.3%),
and the second most common was heterozygous for UGT1A1*6
(34.7%). These findings show that the UGT1A1*6 allele is an
important causative factor for prolonged hyperbilirubinemia
in Japanese preterm infants.
UGT1A1*6 is a prevalent polymorphism in East Asia, but
is not found among white, black, or West Asian subjects.5,13
Instead, UGT1A1*28 (c.−3279T>G in the promotor region that
is linked to A[TA]7TAA in the TATA box) is the most common
variant in white, black, and West Asian patients with Gilbert
syndrome. In the present study, we detected only 1 infant with
the UGT1A1*28 allele in the jaundiced group, and this patient
was a compound heterozygote for UGT1A1*6. The allele fre-
quency of UGT1A1*28 in the case group was 0.010, lower than
that in the control group (0.026). In our previous study on
breast milk jaundice in term infants, we did not detect the
UGT1A1*28 allele in the jaundiced group. These findings
suggest that the UGT1A1*28 allele causes hyperbilirubine-
mia in adulthood (Gilbert syndrome), but not during the neo-
natal period. This finding may explain the difference in the
incidence of neonatal hyperbilirubinemia among different
ethnic groups.1
Recent studies have reported that preterm infants are at in-
creased risk for kernicterus (bilirubin encephalopathy).10,14,15
Not only acute but also prolonged unconjugated hyperbiliru-
binemia can cause kernicterus in preterm infants. This problem
is becoming increasingly important, but evidence-based guide-
lines for the management of hyperbilirubinemia in preterm
infants have not yet been optimized.16 It is not known whether
UGT1A1*6 is a risk factor for kernicterus, but if it is, it might
be necessary to take genetics into account for the manage-
ment of jaundice in preterm infants, for example, by apply-
ing a lower threshold for phototherapy and exchange
transfusion for East Asians than for other ethnic groups. The
findings in this study suggest that future studies should evalu-
ate whether UGT1A1*6 is a risk factor for kernicterus in East
Asian preterm infants.
We acknowledge that this study has several limitations. First,
the case and the control groups were recruited from different
3
THE JOURNAL OF PEDIATRICS • www.jpeds.com
institutions. The subjects in the case group were from several
institutions across Japan, and those in the control group were
from our neonatal units. Different policies on phototherapy,
blood transfusion, and nutrition management between insti-
tutions may result in a bias. Information on detailed
management of each infant was not obtained in this study, and
we should take this into account when evaluating the result
of this study.
The second limitation is the different rate of breast feeding
between the 2 groups, which may be a considerable source of
a bias in a case-control study. It is possible that only breast
feeding is a risk factor and that genetic differences are not as-
sociated with prolonged jaundice in preterm infants. It is not
reasonable, however, to assert that compared with the general
Japanese population, the 4-fold higher allele frequency of
UGT1A1*6 in the case group bears no relation to jaundice at
all. We speculate that preterm infants are more likely to develop
prolonged jaundice when breast feeding, an external factor, and
UGT1A1*6, an internal factor, exist together. Formula-fed
infants rarely develop jaundice, even if they have UGT1A1*6.
This speculation would explain the result of our investiga-
tion. Recent research using humanized UGT1 mice showed that
the expression of intestinal UGT1A1, but not hepatic UGT1A1,
correlated with glucuronidation of bilirubin in the neonatal
period.17 Thus, neonatal jaundice and breast milk play an im-
portant role in the suppression of intestinal UGT1A1 expres-
sion. The UGT1A1*6 genotype was not evaluated in these
models, although these findings imply that breast milk sup-
presses intestinal UGT1A1 expression in UGT1A1*6 geno-
type, leading to prolonged jaundice.
Third, our investigation included only a small number of
extremely premature babies. There were no infants with a ges-
tational age of less than 28 weeks in either group. It seems
likely that, with decreasing gestational age, other factors related
to immature metabolism of bilirubin may predominate and
the importance of genetic factors is reduced. In our study,
infants of 28-33 weeks of gestational age in the case group
had a lower UGT1A1*6 allele frequency than infants of 34-
36 weeks of gestational age (0.575 and 0.692, respectively).
The difference in allele frequency between the case and the
control groups is smaller in 28-33 weeks of gestational age
than in 34-36 weeks of gestational age (0.437 and 0.643, re-
spectively). The allele frequency in the case group is, however,
still considerably higher (4-fold) than that in the control group
in infants 28-33 weeks of gestational age (0.575 and 0.138,
respectively), which suggests that genetics has a great impact
even in those groups. The association between genetic factors
and hyperbilirubinemia in more premature infants should be
investigated in the future. ■
Submitted for publication Jan 21, 2017; last revision received May 29, 2017;
accepted Jul 7, 2017
4 Yanagi, Nakahara, and Maruo
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Volume ■■
Reprint requests: Takahide Yanagi, MD, Department of Pediatrics, Shiga
University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192,
Japan. E-mail: tyanagi@belle.shiga-med.ac.jp
References
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4. Aono S, Yamada Y, Keino H, Hanada N, Nakagawa T, Sasaoka Y, et al.
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5. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al.
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Pediatrics 2000;106:E59.
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rubin uridine diphosphate-glucuronosyltransferase variation is a genetic
basis of breast milk jaundice. J Pediatr 2014;165:36-41, e1.
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and outcome. Arch Dis Child Fetal Neonatal Ed 2003;88:F455-8.
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13. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic varia-
tion in bilirubin UPD-glucuronosyltransferase gene promoter and Gil-
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■■ 2017 ORIGINAL ARTICLES

Table I. Lists of primers used for sequence analysis of UGT1A1

Target Tm PCR product
regions Sense primer Anti-sense primer (°C) (bps) Region Primers
gtPBREM 5′-CTGGGGATAAACATGGGATG-3′ 5′-CACCACCACTTCTGGAACCT-3′ 60 605 gtPBREM 5′-TGAGTTTATATAACCTC-3′
TATA box– 5′-AAGTGAACTCCCTGCTACCTT-3′ 5′-GCTTGCTCAGCATATATCTGGG-3′ 60 1104 TATAbox–exon 1 5′-CTATTTCATGTCCCCTCTGC-3′
exon 1 Exon 1 5′-GTCTTTTGTTAGTCTCGGGC-3′
Exon 1 5′-TTGTTGTGCAGTAAGTGGGA-3′
Exon 1 5′-CCATTCTCCTACGTGCCCAG-3′
Exon 1 5′-AAGGGTTGCATACGGGGAATA-3′
Exon 2– 5′-CTCTATCTCAAACACGCATGCC-3′ 5′-TTTTATCATGAATGCCATGACC-3′ 60 1584 Exon 2 5′-GGAAGCTGGAAGTCTGGG-3′
exon 4 Exon 3 5′-CTAGTTAGTATAGCAGAT-3′
Exon 4 5′-CAGCTGTGAAACTCAGAG-3′
Exon 5 5′-GAGGATTGTTCATACCACAGG-3′ 5′-GCACTCTGGGGCTGATTAAT-3′ 60 488 Exon 5 5′-TGCTGACAGTGGCCTTCATC-3′
Exon 5 5′-GGTAGCCATAAGCACAACAT-3′

gtPBREM, phenobarbital responsive enhancer module; PCR, polymerase chain reaction.

Table V. Distribution of UGT1A1 genotypes among

infants in the case group (preterm vs late preterm)
Preterm Late preterm
Genotypes (28-33 weeks) (34-36 weeks)
Allele 1 Allele 2 (n = 20) % (n = 26) %
UGT1A1*6 UGT1A1*6 6 30.0 12 46.1
UGT1A1*6 UGT1A1*1 9 45.0 7 26.9
UGT1A1*6 UGT1A1*60 2 10.0 3 11.5
UGT1A1*6 UGT1A1*28 0 0.0 1 3.8
UGT1A1*6 UGT1A1*7 0 0.0 1 3.8
UGT1A1*60 UGT1A1*63 0 0.0 1 3.8
UGT1A1*60 UGT1A1*1 0 0.0 1 3.8
UGT1A1*1 UGT1A1*1 3 15.0 0 0.0
Allele frequency of UGT1A1*6 0.575 0.692

UGT1A1*1, wild-type allele; UGT1A1*6, p.G71R; UGT1A1*7, p.Y486D; UGT1A1*28, c. –3279T>G+A

(TA) 7TAA; UGT1A1*60, c.–3279T>G; UGT1A1*63, p.P364L.
In the control group, the allele frequencies of UGT1A1*6 were 0.138 and 0.050 in the preterm
and late preterm groups, respectively.

Bilirubin Uridine Diphosphate-glucuronosyltransferase Polymorphism as a Risk Factor for Prolonged 4.e1

Hyperbilirubinemia in Japanese Preterm Infants
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