BACKGROUND: The paraoxonases, PON1-3, play a major protective role both against environmental toxins and as part of the antioxidant defence system. Recently, non-synonymous coding single nucleotide polymorphisms (SNPs), known to lower serum PON activity, have been associated with sporadic ALS (SALS) in a Polish population. A separate trio based study described a detrimental allele at the PON3 intronic variant INS2+3651 (rs10487132). Association between PON gene cluster variants and SALS requires external validation in an independent dataset. AIMS: To examine the association of the promoter SNPs PON1(-162G>A) and PON1(-108T>C); the non-synonymous functional SNPs PON1(Q192R and L55M) and PON2(C311S and A148G); and the intronic marker PON3(INS2+3651A>G), with SALS in a genetically homogenous population. METHODS: 221 Irish patients with SALS and 202 unrelated control subjects were genotyped using KASPar chemistries. Statistical analyses and haplotype estimations were conducted using Haploview and Unphased software. Multiple permutation testing, as implemented in Unphased, was applied to haplotype p values to correct for multiple hypotheses. RESULTS: Two of the seven SNPs were associated with SALS in the Irish population: PON1(55M) (OR 1.52, p = 0.006) and PON3(INS2+3651 G) (OR 1.36, p = 0.03). Two locus haplotype analysis showed association only when both of these risk alleles were present (OR 1.7, p = 0.005), suggesting a potential effect modification. Low functioning promoter variants were observed to influence this effect when compared with wild-type. CONCLUSIONS: These data provide additional evidence that genetic variation across the paroxanase loci may be common susceptibility factors for SALS.
BACKGROUND: The paraoxonases, PON1-3, play a major protective role both against environmental toxins and as part of the antioxidant defence system. Recently, non-synonymous coding single nucleotide polymorphisms (SNPs), known to lower serum PON activity, have been associated with sporadic ALS (SALS) in a Polish population. A separate trio based study described a detrimental allele at the PON3 intronic variant INS2+3651 (rs10487132). Association between PON gene cluster variants and SALS requires external validation in an independent dataset. AIMS: To examine the association of the promoter SNPs PON1(-162G>A) and PON1(-108T>C); the non-synonymous functional SNPs PON1(Q192R and L55M) and PON2(C311S and A148G); and the intronic marker PON3(INS2+3651A>G), with SALS in a genetically homogenous population. METHODS: 221 Irish patients with SALS and 202 unrelated control subjects were genotyped using KASPar chemistries. Statistical analyses and haplotype estimations were conducted using Haploview and Unphased software. Multiple permutation testing, as implemented in Unphased, was applied to haplotype p values to correct for multiple hypotheses. RESULTS: Two of the seven SNPs were associated with SALS in the Irish population: PON1(55M) (OR 1.52, p = 0.006) and PON3(INS2+3651 G) (OR 1.36, p = 0.03). Two locus haplotype analysis showed association only when both of these risk alleles were present (OR 1.7, p = 0.005), suggesting a potential effect modification. Low functioning promoter variants were observed to influence this effect when compared with wild-type. CONCLUSIONS: These data provide additional evidence that genetic variation across the paroxanase loci may be common susceptibility factors for SALS.
Authors: R D Horner; K G Kamins; J R Feussner; S C Grambow; J Hoff-Lindquist; Y Harati; H Mitsumoto; R Pascuzzi; P S Spencer; R Tim; D Howard; T C Smith; M A K Ryan; C J Coffman; E J Kasarskis Journal: Neurology Date: 2003-09-23 Impact factor: 9.910
Authors: S T Reddy; D J Wadleigh; V Grijalva; C Ng; S Hama; A Gangopadhyay; D M Shih; A J Lusis; M Navab; A M Fogelman Journal: Arterioscler Thromb Vasc Biol Date: 2001-04 Impact factor: 8.311
Authors: C J Ng; D J Wadleigh; A Gangopadhyay; S Hama; V R Grijalva; M Navab; A M Fogelman; S T Reddy Journal: J Biol Chem Date: 2001-09-28 Impact factor: 5.157
Authors: N Martinelli; D Girelli; O Olivieri; C Stranieri; E Trabetti; F Pizzolo; S Friso; I Tenuti; S Cheng; M A Grow; P F Pignatti; R Corrocher Journal: Eur J Clin Invest Date: 2004-01 Impact factor: 4.686
Authors: Nicola Ticozzi; Ashley Lyn LeClerc; Pamela J Keagle; Jonathan D Glass; Anne-Marie Wills; Marka van Blitterswijk; Daryl A Bosco; Ildefonso Rodriguez-Leyva; Cinzia Gellera; Antonia Ratti; Franco Taroni; Diane McKenna-Yasek; Peter C Sapp; Vincenzo Silani; Clement E Furlong; Robert H Brown; John E Landers Journal: Ann Neurol Date: 2010-07 Impact factor: 10.422
Authors: Silke Schmidt; Kelli D Allen; Valerie T Loiacono; Barbara Norman; Catherine L Stanwyck; Kristina M Nord; Christina D Williams; Edward J Kasarskis; Freya Kamel; Valerie McGuire; Lorene M Nelson; Eugene Z Oddone Journal: Neuroepidemiology Date: 2008-04-18 Impact factor: 3.282
Authors: John E Landers; Lijia Shi; Ting-Jan Cho; Jonathan D Glass; Christopher E Shaw; P Nigel Leigh; Frank Diekstra; Meraida Polak; Ildefonso Rodriguez-Leyva; Stephan Niemann; Bryan J Traynor; Diane McKenna-Yasek; Peter C Sapp; Ammar Al-Chalabi; Anne-Marie A Wills; Robert H Brown Journal: Amyotroph Lateral Scler Date: 2008-10