A UGT1A1 variant is associated with serum total bilirubin levels, which are causal for hypertension in African-ancestry individuals

Guanjie Chen,Charles N Rotimi,Ayo P Doumatey,Jie Zhou,Kenneth Ekoru,Daniel Shriner,Amy R Bentley,Adebowale Adeyemo

doi:10.1038/s41525-021-00208-6

Abstract

Serum bilirubin is associated with several clinical outcomes, including hypertension, type 2 diabetes (T2D), and drug metabolism. Here, we describe findings from our genome-wide association studies (GWAS) of serum (TBIL) using a generalized linear mixed model in West Africans (n = 1127), with adjustment for age, sex, body mass index, T2D, significant principal components of population structure, and cryptic relatedness. Genome-wide conditional analysis and CAVIARBF were used to fine map significant loci. The causal effect of TBIL on hypertension was assessed by Mendelian randomization (MR) using the GWAS findings as instrumental variables (IVs) in African Americans (n = 3,067). The SNP rs887829 (UGT1A1) was significantly associated with TBIL levels (effect allele (T) frequency = 0.49, β (SE) = 0.59 (0.04), p = 9.13 × 10−54). Genome-wide conditional analysis and regional fine mapping pointed to rs887829 as a possible causal variant with a posterior inclusion probability of 0.99. The T allele of rs887829 is associated with lower hepatic expression of UGT1A1. Using rs887829 as an IV, two-stage least-squares MR showed a causal effect of bilirubin on hypertension (β = −0.76, 95% CI [−1.52, −0.01], p = 0.0459). Our finding confirms that UGT1A1 influences bilirubin levels. Notably, lower TBIL is causally associated with the increased risk of hypertension.

Highlights

Hyperbilirubinemia has several causes, including hemolysis, cirrhosis, and bile duct obstruction
Using rs887829 as an instrumental variables (IVs), we demonstrate a causal effect of serum total bilirubin (TBIL) on hypertension in African Americans, with lower serum (TBIL) being a causal risk factor for hypertension
The characteristics of participants in the genome-wide association studies (GWAS) and Mendelian randomization (MR) studies are presented in Table 1 and Supplementary Table 1, respectively

Summary

Introduction

Hyperbilirubinemia has several causes, including hemolysis, cirrhosis, and bile duct obstruction. In the absence of liver disease, high circulating bilirubin levels have been associated with the reduced risk of several diseases, including respiratory diseases[1]; oxidative stress-mediated diseases, such as diabetes mellitus, diabetic nephropathy, cancer, and cardiovascular disease[2,3,4,5,6,7,8]; and hypertension[9]. The genetic architecture of circulating bilirubin levels has been studied through genome-wide association studies (GWAS), which have revealed several associated variants in one locus, UGT1A1 UGT1A1 has been found to be a major locus for serum total bilirubin (TBIL) in studies of Han Chinese[20], individuals with European ancestry[21,22], and African Americans[23]

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Results

Conclusion