title: A common haplotype within the PON1 promoter region is associated with sporadic ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder of upper and lower motor neurons. Genetic variants in the paraoxonase gene cluster have been associated with susceptibility to sporadic ALS. Because these studies have yielded conflicting results, we have further investigated this association in a larger data set. Twenty SNPs spanning the paraoxonase gene cluster were genotyped on a panel of 597 case and 692 control samples and tested for association with risk of sporadic ALS and with ALS sub-phenotypes. Our study revealed two SNPs, rs987539 and rs2074351, within the paraoxonase gene cluster that are associated with susceptibility to sporadic ALS (uncorrected p=6.47E-04 and 7.87E-04, respectively). None of the 20 SNPs displayed significant associations with age of onset, site of onset or disease survival. Using a sliding window approach, we have also identified a 5-SNP haplotype that is significantly associated with risk of sporadic ALS (p=2.75E-05). We conclude that a common haplotype within the PON1 promoter region is associated with susceptibility to sporadic ALS.
authors.affiliation: Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Lijia
authors.initials: L
authors.lastname: Shi
authors.forename: Ting-Jan
authors.initials: TJ
authors.lastname: Cho
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Frank
authors.initials: F
authors.lastname: Diekstra
authors.forename: Meraida
authors.initials: M
authors.lastname: Polak
authors.forename: Ildefonso
authors.initials: I
authors.lastname: Rodriguez-Leyva
authors.forename: Stephan
authors.initials: S
authors.lastname: Niemann
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Diane
authors.initials: D
authors.lastname: McKenna-Yasek
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Anne-Marie A
authors.initials: AM
authors.lastname: Wills
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000097:blood / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D015810:Linkage Disequilibrium; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D007527:Isoenzymes; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human