A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS

Background: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding. Methods: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls. Results: The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02–1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07–1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86–1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92–1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97–1.16, p = 0.22). Conclusions: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.

[1]  Robert A Gross,et al.  Levels of evidence , 2008, Neurology.

[2]  G. Gronseth,et al.  Lost in a jungle of evidence: we need a compass. , 2008, Neurology.

[3]  G. Gronseth,et al.  Invited Article: Practice parameters and technology assessments , 2008, Neurology.

[4]  P. Andersen,et al.  Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden , 2008, Neurology.

[5]  Robert H. Brown,et al.  A common haplotype within the PON1 promoter region is associated with sporadic ALS , 2008, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[6]  Orla Hardiman,et al.  A genome-wide association study of sporadic ALS in a homogenous Irish population. , 2007, Human molecular genetics.

[7]  Frank Baas,et al.  Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis , 2008, Nature Genetics.

[8]  B. Traynor,et al.  Genetics of sporadic amyotrophic lateral sclerosis. , 2007, Human molecular genetics.

[9]  R. Ophoff,et al.  ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study , 2007, The Lancet Neurology.

[10]  K. Shianna,et al.  Large-scale pathways-based association study in amyotrophic lateral sclerosis. , 2007, Brain : a journal of neurology.

[11]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[12]  Kuixing Zhang,et al.  Whole-genome analysis of sporadic amyotrophic lateral sclerosis. , 2007, The New England journal of medicine.

[13]  S. Cronin,et al.  Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis , 2007, Journal of Neurology, Neurosurgery & Psychiatry.

[14]  R. Trent,et al.  A gene-environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis. , 2007, Neurotoxicology.

[15]  Sonja W. Scholz,et al.  Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data , 2007, The Lancet Neurology.

[16]  A. Al-Chalabi,et al.  Amyotrophic lateral sclerosis as a complex genetic disease. , 2006, Biochimica et biophysica acta.

[17]  J. Haines,et al.  Paraoxonase cluster polymorphisms are associated with sporadic ALS , 2006, Neurology.

[18]  M. Małecki,et al.  Paraoxonase gene polymorphisms and sporadic ALS , 2006, Neurology.

[19]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[20]  Robert H. Brown,et al.  Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS) , 2006, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[21]  K. Lunetta,et al.  Polymorphisms in the PON gene cluster are associated with Alzheimer disease. , 2006, Human molecular genetics.

[22]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[23]  J. Witte,et al.  Comparison of missing data approaches in linkage analysis , 2003, BMC Genetics.

[24]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[25]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[26]  P. Durrington,et al.  The paraoxonase gene family and coronary heart disease , 2002, Current opinion in lipidology.

[27]  G. Jarvik,et al.  Effects of 5' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. , 2001, American journal of human genetics.

[28]  M. Swash,et al.  El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[29]  J. Ioannidis,et al.  Quantitative Synthesis in Systematic Reviews , 1997, Annals of Internal Medicine.

[30]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[31]  G. Belle,et al.  Occupational exposures and amyotrophic lateral sclerosis. A population-based case-control study. , 1997, American journal of epidemiology.

[32]  M. Keifer,et al.  The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin , 1996, Nature Genetics.

[33]  B. Brooks,et al.  El escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis , 1994, Journal of the Neurological Sciences.

[34]  A. Motulsky,et al.  Spectrophotometric assays for the enzymatic hydrolysis of the active metabolites of chlorpyrifos and parathion by plasma paraoxonase/arylesterase. , 1989, Analytical biochemistry.

[35]  A. Emery,et al.  The epidemiology of motor neuron disease in Scotland , 1982, Muscle & nerve.

[36]  Mulder Dw.  Clinical limits of amyotrophic lateral sclerosis. , 1982 .

[37]  E. Granieri,et al.  STUDIES ON EPIDEMIOLOGICAL, CLINICAL AND ETIOLOGICAL ASPECTS OF ALS DISEASE IN SARDINIA, SOUTHERN ITALY , 1977, Acta neurologica Scandinavica.

[38]  W. Aldridge.  Serum esterases. II. An enzyme hydrolysing diethyl p-nitrophenyl phosphate (E600) and its identity with the A-esterase of mammalian sera. , 1953, The Biochemical journal.