Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta‐analysis

Abstract

Abstract. Stender S, Frikke-Schmidt R, Nordestgaard B G, Grande P, Tybjaerg-Hansen A (Rigshospitalet; The Copenhagen General Population Study; Herlev Hospital; The Copenhagen City

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

“…In adult North-European white populations, the UGT1A1*28 genotype is the major known genetic determinant of plasma bilirubin and accounts for 18% of all variations. 26 We suggest that the difference between adult and neonatal findings is in concordance with evidence pointing toward UGT1A1 enzyme expression as being modulated in a developmental manner such that its activity at term birth is ∼1% of adult values, and that it first reaches mature levels by 14 weeks of postnatal life, a process that is believed to be primarily induced by unconjugated bilirubin itself. 13,34,35 Accordingly, it could stand to reason that variations in UGT1A1 activity have no great impact on bilirubin metabolism in the first days of life, but that it could influence the duration of neonatal hyperbilirubinemia.…”

“…The UGT1A1*28 genotype frequencies in our data correspond well with those expected for a white north European population. 15,26 Interpretation Our study diverges from previous studies by being population-based, by containing multiple causes of hyperbilirubinemia (eg, AB0 incompatibility, early discharge, starvation), by its case-control design, and by being to our knowledge the first to directly explore the association between UGT1A1*28 genotypes and extreme hyperbilirubinemia. Most studies find that the UGT1A1*28 allele is unrelated to neonatal hyperbilirubinemia, [27][28][29] but some studies have shown that UGT1A1*28 allele status is associated with increased levels of plasma bilirubin in conjunction with hemolytic factors (AB0 serum incompatibility, spherocytosis, and some variants of glucose-6-phosphate dehydrogenase deficiency).…”

“…For the AB0 incompatible subgroup, the number of cases, and thus statistic power, was more limited, which is reflected in wider confidence intervals. Because of the dose-response relationship between UGT1A1*28 genotypes and UGT1A1 enzyme activity, 15,16,26 in the primary analysis the genotypes were treated as a continuous variable and as a categorical variable in the secondary analysis. Effect estimates were similar for the 2 analytic strategies, but the primary analysis had a higher statistical power and a better precision of estimates.…”

Serum total bilirubin levels and coronary heart disease — Causal association or epiphenomenon?

“…(11,12) Estimates of the association of the genetic variant rs6742078 with CHD were extracted from publicly available data from two genetic consortia, comprising the Coronary Artery Disease Genome wide Replication and Meta-analyses (CARDIoGRAM), (13) The rs6742078 variant has been robustly demonstrated not to be associated with several cardiovascular risk markers that might confound the relationship between serum total bilirubin and CHD risk. (17,18) To further assess the scope for pleiotropic effects, associations of the rs6742078 variant with several cardiometabolic traits were explored using data from published GWASs available from http://csg.sph.umich.edu/locuszoom/.…”

“…(7,8) The rs6742078 variant in the UGT1A1 gene [which has been shown to be in strong linkage disequilibrium with the UGT1A1*28 allele (10)] is well known to robustly and specifically modify levels of circulating serum levels of total bilirubin (explaining up to 20% of the variation in total bilirubin levels (11)) and has been used as an instrument for examining the causal relevance of serum total bilirubin to disease outcomes. (11,12) Stender and colleagues (12) have recently employed a MR approach using this variant as an instrumental variable and suggested a noncausal association between total bilirubin and CHD risk. The authors called for further work to extend these findings.…”