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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

Pair-wise linkage disequilibrium (LD) across UGT1A1 using common markers (minor allele frequency ≥ 10%). Black boxes indicate pair-wise D' values ≥ 0.9; dark gray boxes indicate D' values > 0.7 but < 0.9; light gray boxes indicate D' values between 0.5 and 0.7; D' values < 0.5 are indicated by a cross. Two 'blocks' of strong LD (D' ≥ 0.9) are seen at the 5' and 3' ends.
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Figure 2: Pair-wise linkage disequilibrium (LD) across UGT1A1 using common markers (minor allele frequency ≥ 10%). Black boxes indicate pair-wise D' values ≥ 0.9; dark gray boxes indicate D' values > 0.7 but < 0.9; light gray boxes indicate D' values between 0.5 and 0.7; D' values < 0.5 are indicated by a cross. Two 'blocks' of strong LD (D' ≥ 0.9) are seen at the 5' and 3' ends.

Mentions: In order to further appraise the contribution of common variants to the rise of bilirubin, we also performed a similar analysis using haplotypes inferred across the UGT1A1 gene. We approached this by first determining pair-wise linkage disequilibrium across the region. This demonstrated two 'blocks' of strong linkage disequilibrium - defined as D' between markers of 0.9 or more- one in the 5' region inclusive of markers between the *60 allele and the TA repeat motif, and another in the 3' region extending from the *76 allele to rs4148329 (Figure 2). We then constructed haplotypes (see Methods) in each of the two regions and repeated our multivariate analysis. For this analysis, haplotypes with frequency less than 10% were not included. The mean change in bilirubin was then analyzed among carriers of each haplotype (without respect to hetero- or homo-zygosity) versus non-carriers of the haplotype under test.


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)

Pair-wise linkage disequilibrium (LD) across UGT1A1 using common markers (minor allele frequency ≥ 10%). Black boxes indicate pair-wise D' values ≥ 0.9; dark gray boxes indicate D' values > 0.7 but < 0.9; light gray boxes indicate D' values between 0.5 and 0.7; D' values < 0.5 are indicated by a cross. Two 'blocks' of strong LD (D' ≥ 0.9) are seen at the 5' and 3' ends.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Pair-wise linkage disequilibrium (LD) across UGT1A1 using common markers (minor allele frequency ≥ 10%). Black boxes indicate pair-wise D' values ≥ 0.9; dark gray boxes indicate D' values > 0.7 but < 0.9; light gray boxes indicate D' values between 0.5 and 0.7; D' values < 0.5 are indicated by a cross. Two 'blocks' of strong LD (D' ≥ 0.9) are seen at the 5' and 3' ends.
Mentions: In order to further appraise the contribution of common variants to the rise of bilirubin, we also performed a similar analysis using haplotypes inferred across the UGT1A1 gene. We approached this by first determining pair-wise linkage disequilibrium across the region. This demonstrated two 'blocks' of strong linkage disequilibrium - defined as D' between markers of 0.9 or more- one in the 5' region inclusive of markers between the *60 allele and the TA repeat motif, and another in the 3' region extending from the *76 allele to rs4148329 (Figure 2). We then constructed haplotypes (see Methods) in each of the two regions and repeated our multivariate analysis. For this analysis, haplotypes with frequency less than 10% were not included. The mean change in bilirubin was then analyzed among carriers of each haplotype (without respect to hetero- or homo-zygosity) versus non-carriers of the haplotype under test.

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