Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Abstract

SummaryVariation of a short (TA) n repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDPglucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA) 7 and (TA) 8 )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA) n alleles frequencies were highest in equatorial Africa, (TA) 7, being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA) n . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA) n on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.

Coexistence of Gilbert syndrome with hereditary haemolytic anaemias

“…Discrepancy between our results and some published data may be due to differences between populations/ethnic groups or it may depend on the number of patients involved in the study. In contrast with European populations, a high frequency of the (TA) 7 /(TA) 7 allele was found in some area in Africa, such as Nigeria,12 Cameroon, Ghana, southern Sudan and Ethiopia 6…”

Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert’s syndrome) and respiratory health in the 1946 British birth cohort

“…One theory is that neurotoxicity, induced by very high bilirubin levels in neonates, prevents the alleles causing hyperbilirubinaemia from being more common across populations [42,43]. It should be noted, however, that in certain regions of Equatorial Africa, UGT1A1 promoter alleles that cause Gilbert's syndrome in Europeans are more common than those associated with normal bilirubin levels [43]. Protection from cigarette and other smoke in the environment of adult modern humans may not have had much impact on reproductive Regression coefficients for models including sex, height, and birth region.…”

Синдром Жильбера: Термінологія, Епідеміологія, Генетика, Патогенез (Частина I)

“…Найбільш поширеною доброякісною гіпербілі-рубінемією є СЖ, хоча в середині XX століття даний синдром вважався рідкісним станом. Поширеність мутантного гена в країнах Європи сягає 35-40 % [7], в окремих етнічних групах Африки перевищує 50 % [8], в азіатських країнах виявляється трохи рідше -16-33 % [9]. Гомозиготами є 12 % шотландців, 16 % європейців, 12 % індійців, 8 % єгиптян і 23 % афро-американців [10].…”