(TA)n UDP-Glucuronosyltransferase 1A1 Promoter Polymorphism in Nigerian Neonates

Abstract

Nigerian neonates have a high incidence of bilirubin encephalopathy. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is prevalent in this population. (TA) 7 promoter polymorphism in the gene encoding the bilirubin conjugating enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) potentiates hyperbilirubinemia in G-6-PD deficient neonates. We studied (TA) n allele frequency to determine, at least in part, its contribution to the frequency and severity of hyperbilirubinemia. DNA was extracted from umbilical cord blood of sequentially born Nigerian neonates and the (TA) n UGT1A1 promoter sequence determined. The (TA) n allele distribution was compared with reported adults of varying African ancestry and Sephardic Jewish neonates. Among 88 Nigerian neonates, (TA) 6 and (TA) 7 alleles were almost equally distributed (0.46 and 0.43, respectively). Some individuals with (TA) 5 and (TA) 8 sequences were encountered. Allele distribution was similar to that of the African ancestry population but differed from the Sephardic Jewish newborns, in whom the (TA) 6 /(TA) 7 distribution was 0.65/ 0.35. Whereas 45% of Nigerian alleles and 50% of African ancestry alleles, respectively, included a (TA) 7 or (TA) 8 sequence, only 35% of Jewish alleles were (TA) 7 (p Ͻ 0.001), and no (TA) 8 alleles were encountered. The high frequency of (TA) n promoter polymorphism, coupled with G-6-PD deficiency, may contribute to the pathogenesis of extreme neonatal hyperbilirubinemia in Nigeria.

Early Neonatal Bilirubin, Hematocrit, and Glucose-6-Phosphate Dehydrogenase Status

“…6,14 The current study demonstrated a clear association between G6PD deficiency and hyperbilirubinemia even in the absence of exposure to known icterogenic agents. Increased bilirubin production 15 and deficient bilirubin conjugation coupled with uridine diphosphoglucoronate-glucoronosyl transferase promoter polymorphism (Gilbert syndrome) 16,17 have been suggested as part of the possible explanations for this phenomenon.…”

“…4,14 Indeed, the day 0 to 8 hematocrit decline, coupled with impaired bilirubin conjugation, may partly explain the higher rate of increase in TSB among the G6PD-deficient and G6PD-intermediate neonates not exposed to known icterogenic agents. 6,16,17 This is even more so, bearing in mind that a small fall in hematocrit may result in a significant rise in bilirubin, as each gram of hemoglobin broken down produces up to 35 mg of bilirubin. 18 Generally, the prevalence of G6PD deficiency in males reflects the allele frequency of the G6PD gene mutation because the disorder is X linked.…”

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

“…While cancer therapy with irinotecan must be comparatively rare on the African continent, this drug is used to treat people of recent African descent in the United States and Europe. Also the possible implications of UGT1A variation with respect to the HIV treatments that are subsidised for use across Africa, and the negative interaction of low-activity UGT1A1 (TA) n promoter variants, with inherited blood disorders common in parts of Africa, are of considerable clinical importance in Africa itself (Chaar et al, 2005;Kaplan et al, 2008).…”

211 G to A Variation of UDP-Glucuronosyl Transferase 1A1 Gene and Neonatal Breastfeeding Jaundice

“…Recently, homozygous A(TA) 7 TAA variation in promoter region of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia in western people (7)(8)(9)(10)(11)(12)(13)(14). However, in Japanese, Koreans, and Taiwanese studies, the high allele-frequency of Gly71Arg, but not promoter polymorphism, in UGT1A1 gene was found to be responsible for neonatal hyperbilirubinemia (15)(16)(17)(18)(19).…”