title: Deep sequencing of RYR3 gene identifies rare and common variants associated with increased carotid intima-media thickness (cIMT) in HIV-infected individuals.
abstract: Carotid intima-media thickness (cIMT) is a subclinical measure of atherosclerosis with mounting evidence that higher cIMT confers an increased risk of cardiovascular disease. The ryanodine receptor 3 gene (RYR3) has previously been linked to increased cIMT; however, the causal variants have not yet been localized. Therefore, we sequenced 339,480 bp encompassing 104 exons and 2 kb flanking region of the RYR3 gene in 96 HIV-positive white men from the extremes of the distribution of common cIMT from the Fat Redistribution and Metabolic Changes in HIV infection study (FRAM). We identified 2710 confirmed variants (2414 single-nucleotide polymorphisms (SNPs) and 296 insertion/deletions (indels)), with a mean count of 736 SNPs (ranging from 528 to 1032) and 170 indels (ranging from 128 to 214) distributed in each individual. There were 39 variants in the exons and 15 of these were non-synonymous, of which with only 4 were common variants and the remaining 11 were rare variants, one was a novel SNP. We confirmed that the common variant rs2229116 was significantly associated with cIMT in this design (P<7.9 × 10(-9)), and observed seven other significantly associated SNPs (P<10(-8)). These variants including the private non-synonymous SNPs need to be followed up in a larger sample size and also tested with clinical atherosclerotic outcomes.
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Shendre
authors.affiliation: Department of Medicine, San Francisco VA Medical Center, and University of California, San Francisco, CA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Scherzer
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Rodney T
authors.initials: RT
authors.lastname: Perry
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Department of Medicine, San Francisco VA Medical Center, and University of California, San Francisco, CA, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Grunfeld
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Sadeep
authors.initials: S
authors.lastname: Shrestha
mesh_terms: D000328:Adult; D000483:Alleles; D050197:Atherosclerosis / Q000150:complications / Q000208:ethnology / Q000235:genetics; D059168:Carotid Intima-Media Thickness; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D015658:HIV Infections / Q000150:complications* / Q000208:ethnology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D054643:INDEL Mutation; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel