title: Targeted deep resequencing ofALOX5andALOX5APin patients with diabetes and association of rare variants with leukotriene pathways.
abstract: The aim of the present study was to investigate a possible association between the accumulation of rare coding variants in the genes for arachidonate 5-lipoxygenase (ALOX5) and ALOX5-activating protein (ALOX5AP), and corresponding production of leukotrienes (LTs) in patients with type 2 diabetes mellitus (T2DM) receiving acetylsalicylic therapy. Twenty exons and corresponding introns of the selected genes were resequenced in 303 DNA samples from patients with T2DM using pooled polymerase chain reaction amplification and next-generation sequencing, using an Illumina HiSeq 2000 sequencing system. The observed non-synonymous variants were further confirmed by individual genotyping of DNA samples comprising of all individuals from the original discovery pools. The association between the investigated phenotypes was based on LTB4and LTE4concentrations, and the accumulation of rare missense variants (genetic burden) in investigated genes was evaluated using statistical collapsing tests. A total of 10 exonic variants were identified for each resequenced gene, including 5 missense and 5 synonymous variants. The rare missense variants did not exhibit statistically significant differences in the accumulation pattern between the patients with low and high LTs concentrations. As the present study only included patients with T2DM, it is unclear whether the absence of observed association between the accumulation of rare missense variants in investigated genes and LT production is associated with diabetic populations only or may also be applied to other populations.
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw 02-097, Poland; Perioperative Genomics Laboratory, Penn State University, College of Medicine, Hershey, PA 17033, USA.
authors.forename: Marek
authors.initials: M
authors.lastname: Postula
authors.affiliation: Perioperative Genomics Laboratory, Penn State University, College of Medicine, Hershey, PA 17033, USA.
authors.forename: Piotr Kazimierz
authors.initials: PK
authors.lastname: Janicki
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw 02-097, Poland; Department of Cardiology and Hypertension, Central Clinical Hospital, The Ministry of the Interior, Warsaw 02-507, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Rosiak
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw 02-097, Poland.
authors.forename: Ceren
authors.initials: C
authors.lastname: Eyileten
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw 02-097, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zaremba
authors.affiliation: Department of Cardiology, Medical University of Warsaw, Warsaw 02-091, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kaplon-Cieslicka
authors.affiliation: Perioperative Genomics Laboratory, Penn State University, College of Medicine, Hershey, PA 17033, USA.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Sugino
authors.affiliation: Department of Cardiology and Hypertension, Central Clinical Hospital, The Ministry of the Interior, Warsaw 02-507, Poland; Department of Applied Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw 02-106, Poland.
authors.forename: Dariusz Artur
authors.initials: DA
authors.lastname: Kosior
authors.affiliation: Department of Cardiology, Medical University of Warsaw, Warsaw 02-091, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Opolski
authors.affiliation: Department of Cardiology, Medical University of Warsaw, Warsaw 02-091, Poland.
authors.forename: Krzysztof Jerzy
authors.initials: KJ
authors.lastname: Filipiak
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw 02-097, Poland.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Mirowska-Guzel
keywords: acetylsalicylic acid; diabetes mellitus; genetic polymorphism; leukotrienes; next-generation sequencing