Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects. Issue 22 (June 2015)

• Record Type: Journal Article
• Authors: Oussalah, Abderrahim; Bosco, Paolo; Anello, Guido; Spada, Rosario; Guéant-Rodriguez, Rosa-Maria; Chery, Céline; Rouyer, Pierre; Josse, Thomas; Romano, Antonino; Elia, Maurizzio; Bronowicki, Jean-Pierre; Guéant, Jean-Louis; Lee., Chaeyoung
• Is Part Of: Medicine. Volume 94:Issue 22(2015)
• Publication Date: 2015-06
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Médecine -- Périodiques; Geneeskunde; Medicine; Periodicals; Periodicals; 610.5
• DOI: 10.1097/MD.0000000000000925
• Languages: English
• ISSNs: 0025-7974

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Abstract</title> <p>Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%–5%) coding variants located in the first exon of the <italic>UGT1A1</italic> gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic <italic>UGT1A1</italic> variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (<italic>P</italic> = 2.34 × 10<sup>−34</sup>, <italic>P</italic> = 7.02 × 10<sup>−34</sup>, and <italic>P</italic> = 8.27 × 10<sup>−34</sup>), as well as unconjugated, and conjugated bilirubin levels. We also identified <italic>UGT1A6</italic> variants in association with total (rs6759892, p.Ser7Ala, <italic>P</italic> = 1.98 × 10<sup>−26</sup>; rs2070959, p.Thr181Ala, <italic>P</italic> = 2.87 × 10<sup>−27</sup>; and rs1105879, p.Arg184Ser, <italic>P</italic> = 3.27 × 10<sup>−29</sup>), unconjugated, and conjugated bilirubin levels. All <italic>UGT1A1</italic> intronic variants (rs887829, rs6742078, and rs4148325) and <italic>UGT1A6</italic> coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The <italic>UGT1A6</italic> variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone–related cholecystectomy (OR, 4.58; 95% CI, 1.58–13.28; <italic>P</italic> = 3.21 × 10<sup>−3</sup>). Using an exome-wide approach we identified coding variants on <italic>UGT1A1</italic> and <italic>UGT1A6</italic> genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. <italic>UGT1A1</italic> intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare <italic>UGT1A1</italic> variants, thereby providing mechanistic explanation to the relationship between <italic>UGT1A1</italic> intronic SNPs and the UGT1A1 enzyme activity. <italic>UGT1A1</italic> and <italic>UGT1A6</italic> variants might be potentially associated with gallstone-related cholecystectomy risk.</p> </sec> </abstract>