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UGT1A1 sequence variants and bilirubin levels in early postnatal life: a quantitative approach.

Hanchard NA, Skierka J, Weaver A, Karon BS, Matern D, Cook W, O'Kane DJ - BMC Med. Genet. (2011)

Bottom Line: These studies have had conflicting results and limited success.We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life.We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic and Foundation, 200 1stSt SW, Rochester, MN 55905, USA. neil.hanchard@green-oxford.com

ABSTRACT

Background: Fundamental to definitively identifying neonates at risk of developing significant hyperbilirubinemia is a better understanding of the genetic factors associated with early bilirubin rise. Previous genetic studies have focused on the UGT1A1 gene, associating common variation in the coding or promoter regions with qualitative assessments of bilirubin (i.e. significantly elevated or not). These studies have had conflicting results and limited success. We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life. We apply this approach to the UGT1A1 gene--exploring the contribution of both rare and common variants to early bilirubin changes.

Methods: We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.

Results: Three novel coding variants were observed, but there was no clear relationship between rare coding variants and bilirubin rise. Adjusted linear regression models fit to evaluate the relationship between changing bilirubin levels and common UGT1A1variants found that among 39 neonates whose bilirubin was resampled within 33 hours, individuals homozygous for the mutant allele of a 3'UTR SNP had significantly smaller changes in bilirubin (P=0.003) than individuals carrying the wild-type allele.

Conclusions: Collectively, rare UGT1A1 coding variants do not appear to play a prominent role in determining early bilirubin levels; however common variants in the 3' UTR of UGT1A1 may modulate the early bilirubin rise. A quantitative approach to evaluating early bilirubin kinetics provides a more robust framework in which to better understand the genetics of neonatal hyperbilirubinemia.

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Related in: MedlinePlus

Change in bilirubin level (between 1st and 2nd bilirubin measurements, mg/dl) by genotype for two UGT1A1 SNPs among neonates who had a repeat bilirubin measured within 33 hours. Figure 1a illustrates the association with SNP rs4148329 - a smaller change is observed for neonates who were homozygous for the mutant allele versus those with wild-type genotypes. This was significant at the P < 0.003 level. A non-significant association with a SNP of comparable minor allele frequency is given in the lower figure (1b) for comparative purposes. In each figure the change in bilirubin for each neonate is given as a diamond; the green lines are the mean values for each genotype and the blue bars show the standard error of the mean.
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Figure 1: Change in bilirubin level (between 1st and 2nd bilirubin measurements, mg/dl) by genotype for two UGT1A1 SNPs among neonates who had a repeat bilirubin measured within 33 hours. Figure 1a illustrates the association with SNP rs4148329 - a smaller change is observed for neonates who were homozygous for the mutant allele versus those with wild-type genotypes. This was significant at the P < 0.003 level. A non-significant association with a SNP of comparable minor allele frequency is given in the lower figure (1b) for comparative purposes. In each figure the change in bilirubin for each neonate is given as a diamond; the green lines are the mean values for each genotype and the blue bars show the standard error of the mean.

Mentions: We thus performed a sub-group analysis in which we focused on those individuals who had their bilirubin re-sampled within 33 hours (N = 39). The first step in this analysis was to graphically evaluate whether there was any visual difference in the mean change in bilirubin between subjects having different genotypes. This approach suggested a lower mean change in bilirubin of subjects having the mutant (TT) genotype at SNP rs4148329 versus persons with the wild-type homozygous or heterozygous genotype (mean change in bilirubin = 1.52 vs. 3.01 or 2.84 mg/dl, for TT vs CT or CC - Figure 1). When we applied our adjusted regression model to this subgroup analysis, this difference was significant under this recessive disease model (i.e. TT vs CT or CC) (difference in adjusted mean change in bilirubin = -1.78 (95% CI -2.90 to -0.66); P = 0.003), and remained significant after accounting for the effects of gestational age (P = 0.002). None of the other eight SNPs showed any evidence of significant differences in mean bilirubin level.


UGT1A1 sequence variants and bilirubin levels in early postnatal life: a quantitative approach.

Hanchard NA, Skierka J, Weaver A, Karon BS, Matern D, Cook W, O'Kane DJ - BMC Med. Genet. (2011)

Change in bilirubin level (between 1st and 2nd bilirubin measurements, mg/dl) by genotype for two UGT1A1 SNPs among neonates who had a repeat bilirubin measured within 33 hours. Figure 1a illustrates the association with SNP rs4148329 - a smaller change is observed for neonates who were homozygous for the mutant allele versus those with wild-type genotypes. This was significant at the P < 0.003 level. A non-significant association with a SNP of comparable minor allele frequency is given in the lower figure (1b) for comparative purposes. In each figure the change in bilirubin for each neonate is given as a diamond; the green lines are the mean values for each genotype and the blue bars show the standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3107779&req=5

Figure 1: Change in bilirubin level (between 1st and 2nd bilirubin measurements, mg/dl) by genotype for two UGT1A1 SNPs among neonates who had a repeat bilirubin measured within 33 hours. Figure 1a illustrates the association with SNP rs4148329 - a smaller change is observed for neonates who were homozygous for the mutant allele versus those with wild-type genotypes. This was significant at the P < 0.003 level. A non-significant association with a SNP of comparable minor allele frequency is given in the lower figure (1b) for comparative purposes. In each figure the change in bilirubin for each neonate is given as a diamond; the green lines are the mean values for each genotype and the blue bars show the standard error of the mean.
Mentions: We thus performed a sub-group analysis in which we focused on those individuals who had their bilirubin re-sampled within 33 hours (N = 39). The first step in this analysis was to graphically evaluate whether there was any visual difference in the mean change in bilirubin between subjects having different genotypes. This approach suggested a lower mean change in bilirubin of subjects having the mutant (TT) genotype at SNP rs4148329 versus persons with the wild-type homozygous or heterozygous genotype (mean change in bilirubin = 1.52 vs. 3.01 or 2.84 mg/dl, for TT vs CT or CC - Figure 1). When we applied our adjusted regression model to this subgroup analysis, this difference was significant under this recessive disease model (i.e. TT vs CT or CC) (difference in adjusted mean change in bilirubin = -1.78 (95% CI -2.90 to -0.66); P = 0.003), and remained significant after accounting for the effects of gestational age (P = 0.002). None of the other eight SNPs showed any evidence of significant differences in mean bilirubin level.

Bottom Line: These studies have had conflicting results and limited success.We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life.We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic and Foundation, 200 1stSt SW, Rochester, MN 55905, USA. neil.hanchard@green-oxford.com

ABSTRACT

Background: Fundamental to definitively identifying neonates at risk of developing significant hyperbilirubinemia is a better understanding of the genetic factors associated with early bilirubin rise. Previous genetic studies have focused on the UGT1A1 gene, associating common variation in the coding or promoter regions with qualitative assessments of bilirubin (i.e. significantly elevated or not). These studies have had conflicting results and limited success. We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life. We apply this approach to the UGT1A1 gene--exploring the contribution of both rare and common variants to early bilirubin changes.

Methods: We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.

Results: Three novel coding variants were observed, but there was no clear relationship between rare coding variants and bilirubin rise. Adjusted linear regression models fit to evaluate the relationship between changing bilirubin levels and common UGT1A1variants found that among 39 neonates whose bilirubin was resampled within 33 hours, individuals homozygous for the mutant allele of a 3'UTR SNP had significantly smaller changes in bilirubin (P=0.003) than individuals carrying the wild-type allele.

Conclusions: Collectively, rare UGT1A1 coding variants do not appear to play a prominent role in determining early bilirubin levels; however common variants in the 3' UTR of UGT1A1 may modulate the early bilirubin rise. A quantitative approach to evaluating early bilirubin kinetics provides a more robust framework in which to better understand the genetics of neonatal hyperbilirubinemia.

Show MeSH
Related in: MedlinePlus