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

Abstract

Bilirubin has potent antioxidant properties in vitro and raised serum levels have been associated with lower rates of respiratory disease. The enzyme uridine diphosphate glucuronosyltransferase polypeptide 1A1 (UGT1A1) is solely responsible for clearing bilirubin from the blood and homozygosity for seven thymine-adenine (TA) repeats in the TATA box regulatory element of the UGT1A1 gene underlies a mild hereditary unconjugated hyperbilirubinaemia (Gilbert's syndrome). Our aim was to investigate whether this genetic variation is associated with differences in respiratory health. The relationship between the promoter genotype underlying Gilbert's syndrome (UGT1A1 rs8175347 [TA]7/7) and respiratory outcomes assessed at ages 43, 53, and 60-64 were examined in 2190 members of the 1946 British birth cohort. The (TA)7/7 genotype, present in 9% of the cohort, was associated with higher forced expiratory volume (FEV1) and forced vital capacity (FVC). The relationship was strongest for heavy smokers (⩾20 cigarettes per day) at age 53 with mean FEV1 409 ml higher (191 to 627; p<0.001) and mean FVC 530 ml higher (95% CI 262-798; p<0.001) for UGT1A1 (TA)7/7 Gilbert's syndrome participants than for all others, indicating a protection from the pulmonary consequences of heavy smoking. The odds of respiratory disease (chronic obstructive pulmonary disease, self-reported asthma, or prescription of respiratory drugs) were half in those with Gilbert's syndrome genotype (odds ratio 0.49 [95% CI 0.39-0.74]; p<0.001) compared to those without this genotype. Genetically raised unconjugated serum bilirubin is associated with higher adult respiratory function and protection from respiratory disease.