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Fulltext Prevalence of uridine glucuronosyl transferase 1A1 (UGT1A1) mutations in Malay neonates with severe jaundice

Azlin I, Wong FL, Ezham M, Hafiza A, Ainoon O

Malays J Pathol, 2011 Dec;33(2):95-100.
PMID: 22299209 MyJurnal

A number of genetic risk factors have been implicated in the development of neonatal severe hyperbilirubinaemia. This includes mutations in the uridine glucoronosyl transferase 1A1 (UGT1A1) gene which is responsible for unconjugated hyperbilirubinemia in Gilbert's Syndrome. We studied the prevalence of UGT1A1 gene mutations in a group of Malay neonates to determine whether they are risk factors to severe neonatal jaundice. One hundred and twenty-five Malay neonates with severe hyperbilirubinemia were studied. Ninety-eight infants without severe hyperbilirubinaemia were randomly selected from healthy Malay term infants (controls). DNA from EDTA cord blood samples were examined for UGT1A1 mutations nt211G > A and nt247T > C using established Taqman SNP genotyping assays and the UGT1A1*28 variant was detected by the Agilent 2100 bioanalyzer. All samples were also screened for common Malay G6PD variants using established techniques. The frequency of UGT1A1 211G > A mutation is significantly higher in the severely hyperbilirubinemic group (13%) than the control group (4%; p = 0.015) and all the positive cases were heterozygous for the mutation. There was no significant difference in the frequency of UGT1A1*28 mutation between the severely hyperbilirubinemic (3.5%) and the control group (0.01%; p = 0.09). None of the neonates in both groups carried the nt247 T > C mutation. The prevalence of G6PD mutation was significantly higher in the severely jaundiced group than control (9% vs 4%; p = 0.04). In conclusion, nt 211 G > A alleles constitute at least 12% of UGT1A1 mutations underlying unconjugated hyperbilirubinemia and appears to be a significant independent risk factor associated with severe neonatal hyperbilirubinemia in the Malay newborns.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics*
Homozygous variant of UGT1A1 gene mutation and severe neonatal hyperbilirubinemia

Boo NY, Wong FL, Wang MK, Othman A

Pediatr Int, 2009 Aug;51(4):488-93.
PMID: 19674361 DOI: 10.1111/j.1442-200X.2008.02798.x

The aim of the present study was to compare, in a case-control study, the prevalence of nucleotide 211 guanine to adenine (G-->A) mutation of uridine diphosphoglucuronosyl transferase (UGT1A1) gene in Malaysian Chinese newborns with and without severe hyperbilirubinemia (total serum bilirubin >250 micromol/L during first 48 h of life or > or =300 micromol/L thereafter), and to determine whether this mutation was a significant risk factor associated with severe hyperbilirubinemia.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics*
Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population

Yusoff S, Van Rostenberghe H, Yusoff NM, Talib NA, Ramli N, Ismail NZ, et al.

Biol. Neonate, 2006;89(3):171-6.
PMID: 16210851

Gilbert syndrome is caused by defects in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. These mutations differ among different populations and many of them have been found to be genetic risk factors for the development of neonatal jaundice.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics
Fulltext High resolution melting analysis of the NR1I3 genetic variants: Is there an association with neonatal hyperbilirubinemia?

Cheung TP, Van Rostenberghe H, Ismail R, Nawawi NN, Abdullah NA, Ramli N, et al.

Gene, 2015 Dec 1;573(2):198-204.
PMID: 26188155 DOI: 10.1016/j.gene.2015.07.045

Constitutive androstane receptor (CAR) encoded by the nuclear receptor subfamily 1, group I, member 3 (NR1I3) gene regulates the elimination of bilirubin through activating the components of the bilirubin clearance pathway. Hence, NR1I3 genetic variants may affect bilirubin metabolism and result in neonatal hyperbilirubinemia. Thus far, research which investigates the association between NR1I3 variants and neonatal hyperbilirubinemia has not been undertaken in any population. The present study aimed to evaluate the influence of MPJ6_1I3008 (rs10157822), IVS8+116T>G (rs4073054) and 540A>G (rs2307424) on neonatal hyperbilirubinemia development in the Malay population. Buccal swabs were collected from 232 hyperbilirubinemia and 277 control term newborns with gestational age ≥37weeks and birth weight ≥2500g. The NR1I3 variants were genotyped by using high resolution melting (HRM) assays and verified by DNA sequencing. Gender, mode of delivery and birth weight did not differ between hyperbilirubinemia and control groups. The genotypic and allelic frequencies of MPJ6_1I3008, IVS8+116T>G and 540A>G were not significantly different between the groups. However, stratification by gender revealed a significant inverse association between homozygous variant genotype of MPJ6_1I3008 and risk of neonatal hyperbilirubinemia in the females (OR, 0.44; 95% CI, 0.20-0.95; p=0.034). This study demonstrates that the homozygous variant genotype of MPJ6_1I3008 was associated with a significant reduced risk of neonatal hyperbilirubinemia in the females.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics*
Risk factors associated with unconjugated neonatal hyperbilirubinemia in Malaysian neonates

Wong F, Boo N, Othman A

J Trop Pediatr, 2013 Aug;59(4):280-5.
PMID: 23640907 DOI: 10.1093/tropej/fmt023

To investigate the risk factors associated with neonatal hyperbilirubinemia in Malaysian neonates.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics
Fulltext Variants of organic anion transporter polypeptide 2 gene are not risk factors associated with severe neonatal hyperbilirubinemia

Wong FL, Boo NY, Ainoon O, Wang MK

Malays J Pathol, 2009 Dec;31(2):99-104.
PMID: 20514852 MyJurnal

This study aimed to determine the prevalence of four variants of organic anion transporter polypeptide 2 (OATP2) gene, and their association with severe hyperbilirubinemia.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics*
Fulltext The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis

Liu J, Long J, Zhang S, Fang X, Luo Y

J Pediatr (Rio J), 2013 07 11;89(5):434-43.
PMID: 23850112 DOI: 10.1016/j.jped.2013.01.008

OBJECTIVE: To determine whether three variants (388 G>A, 521 T>C, and 463 C>A) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) are associated with neonatal hyperbilirubinemia.
DATA SOURCE: The China National Knowledge Infrastructure and MEDLINE databases were searched. The systematic review with meta-analysis included genetic studies which assessed the association between neonatal hyperbilirubinemia and 388 G>A, 521 T>C, and 463 C>A variants of SLCO1B1 between January of 1980 and December of 2012. Data selection and extraction were performed independently by two reviewers.
SUMMARY OF THE FINDINGS: Ten articles were included in the study. The results revealed that SLCO1B1 388 G>A is associated with an increased risk of neonatal hyperbilirubinemia (OR, 1.39; 95% CI, 1.07-1.82) in Chinese neonates, but not in white, Thai, Latin American, or Malaysian neonates. The SLCO1B1 521 T>C mutation showed a low risk of neonatal hyperbilirubinemia in Chinese neonates, while no significant associations were found in Brazilian, white, Asian, Thai, and Malaysian neonates. There were no significant differences in SLCO1B1 463 C>A between the hyperbilirubinemia and the control group.
CONCLUSION: This study demonstrated that the 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations; the SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics*
Genetic Factors and Delayed TSB Monitoring and Treatment as Risk Factors Associated with Severe Hyperbilirubinemia in Term Neonates Admitted for Phototherapy

Boo NY, Sin S, Chee SC, Mohamed M, Ahluwalia AK, Ling MM, et al.

J Trop Pediatr, 2020 12 01;66(6):569-582.
PMID: 32577754 DOI: 10.1093/tropej/fmaa016

OBJECTIVES: This study aimed to determine whether maternal-fetal blood group isoimmunization, breastfeeding, birth trauma, age when first total serum bilirubin (TSB) was measured, age of admission, and genetic predispositions to hemolysis [due to genetic variants of glucose-6-phosphate dehydrogenase (G6PD) enzyme], and reduced hepatic uptake and/or conjugation of serum bilirubin [due to genetic variants of solute carrier organic anion transporter protein family member 1B1 (SLCO1B1) and uridine diphosphate glucuronosyltransferase family 1 member A1 (UGT1A1)] were significant risk factors associated with severe neonatal hyperbilirubinemia (SNH, TSB ≥ 342µmol/l) in jaundiced term neonates admitted for phototherapy.
METHODS: The inclusion criteria were normal term neonates (gestation ≥ 37 weeks). Parents/care-givers were interviewed to obtain data on demography, clinical problems, feeding practice and age when first TSB was measured. Polymerase chain reaction-restriction fragment length polymorphism method was used to detect common G6PD, UGT1A1 and SLCO1B1 variants on each neonate's dry blood specimens.
RESULTS: Of 1121 jaundiced neonates recruited, 232 had SNH. Logistic regression analysis showed that age (in days) when first TSB was measured [adjusted odds ratio (aOR) = 1.395; 95% confidence interval (CI) 1.094-1.779], age (in days) of admission (aOR = 1.127; 95% CI 1.007-1.260) and genetic mutant UGT1A1 promoter A(TA)7TAA (aOR = 4.900; 95% CI 3.103-7.739), UGT1A1 c.686C>A (aOR = 6.095; 95% CI 1.549-23.985), SLCO1B1 c.388G>A (aOR = 1.807; 95% CI 1.242-2.629) and G6PD variants and/or abnormal G6PD screening test (aOR = 2.077; 95% CI 1.025-4.209) were significantly associated with SNH.
CONCLUSION: Genetic predisposition, and delayed measuring first TSB and commencing phototherapy increased risk of SNH.

Matched MeSH terms: Hyperbilirubinemia, Neonatal/genetics*