A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS
Identifieur interne : 000E93 ( Pmc/Curation ); précédent : 000E92; suivant : 000E94A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS
Auteurs : A M. Wills ; S. Cronin ; A. Slowik ; D. Kasperaviciute ; M A. Van Es ; J M. Morahan ; P N. Valdmanis ; V. Meininger ; J. Melki ; C E. Shaw ; G A. Rouleau ; E M. C. Fisher ; P J. Shaw ; K E. Morrison ; R. Pamphlett ; L H. Van Den Berg ; D A. Figlewicz ; P M. Andersen ; A. Al-Chalabi ; O. Hardiman ; S. Purcell ; J E. Landers ; R H. BrownSource :
- Neurology [ 0028-3878 ] ; 2009.
Abstract
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.
We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425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.
The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02–1.16,
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.
= amyotrophic lateral sclerosis;
= confidence interval;
= genome-wide association studies;
= odds ratio;
= sporadic ALS;
= single nucleotide polymorphism.
Url:
DOI: 10.1212/WNL.0b013e3181a18674
PubMed: 19321847
PubMed Central: 2707108
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Morahan</name></author><author><name sortKey="Valdmanis, P N" sort="Valdmanis, P N" uniqKey="Valdmanis P" first="P N." last="Valdmanis">P N. Valdmanis</name></author><author><name sortKey="Meininger, V" sort="Meininger, V" uniqKey="Meininger V" first="V" last="Meininger">V. Meininger</name></author><author><name sortKey="Melki, J" sort="Melki, J" uniqKey="Melki J" first="J" last="Melki">J. Melki</name></author><author><name sortKey="Shaw, C E" sort="Shaw, C E" uniqKey="Shaw C" first="C E." last="Shaw">C E. Shaw</name></author><author><name sortKey="Rouleau, G A" sort="Rouleau, G A" uniqKey="Rouleau G" first="G A." last="Rouleau">G A. Rouleau</name></author><author><name sortKey="Fisher, E M C" sort="Fisher, E M C" uniqKey="Fisher E" first="E M. C." last="Fisher">E M. C. Fisher</name></author><author><name sortKey="Shaw, P J" sort="Shaw, P J" uniqKey="Shaw P" first="P J." last="Shaw">P J. Shaw</name></author><author><name sortKey="Morrison, K E" sort="Morrison, K E" uniqKey="Morrison K" first="K E." last="Morrison">K E. Morrison</name></author><author><name sortKey="Pamphlett, R" sort="Pamphlett, R" uniqKey="Pamphlett R" first="R" last="Pamphlett">R. Pamphlett</name></author><author><name sortKey="Van Den Berg, L H" sort="Van Den Berg, L H" uniqKey="Van Den Berg L" first="L H." last="Van Den Berg">L H. Van Den Berg</name></author><author><name sortKey="Figlewicz, D A" sort="Figlewicz, D A" uniqKey="Figlewicz D" first="D A." last="Figlewicz">D A. Figlewicz</name></author><author><name sortKey="Andersen, P M" sort="Andersen, P M" uniqKey="Andersen P" first="P M." last="Andersen">P M. Andersen</name></author><author><name sortKey="Al Chalabi, A" sort="Al Chalabi, A" uniqKey="Al Chalabi A" first="A" last="Al-Chalabi">A. Al-Chalabi</name></author><author><name sortKey="Hardiman, O" sort="Hardiman, O" uniqKey="Hardiman O" first="O" last="Hardiman">O. Hardiman</name></author><author><name sortKey="Purcell, S" sort="Purcell, S" uniqKey="Purcell S" first="S" last="Purcell">S. Purcell</name></author><author><name sortKey="Landers, J E" sort="Landers, J E" uniqKey="Landers J" first="J E." last="Landers">J E. Landers</name></author><author><name sortKey="Brown, R H" sort="Brown, R H" uniqKey="Brown R" first="R H." last="Brown">R H. Brown</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19321847</idno><idno type="pmc">2707108</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707108</idno><idno type="RBID">PMC:2707108</idno><idno type="doi">10.1212/WNL.0b013e3181a18674</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">001032</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001032</idno><idno type="wicri:Area/Pmc/Curation">000E93</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000E93</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS</title><author><name sortKey="Wills, A M" sort="Wills, A M" uniqKey="Wills A" first="A M." last="Wills">A M. Wills</name></author><author><name sortKey="Cronin, S" sort="Cronin, S" uniqKey="Cronin S" first="S" last="Cronin">S. Cronin</name></author><author><name sortKey="Slowik, A" sort="Slowik, A" uniqKey="Slowik A" first="A" last="Slowik">A. Slowik</name></author><author><name sortKey="Kasperaviciute, D" sort="Kasperaviciute, D" uniqKey="Kasperaviciute D" first="D" last="Kasperaviciute">D. Kasperaviciute</name></author><author><name sortKey="Van Es, M A" sort="Van Es, M A" uniqKey="Van Es M" first="M A." last="Van Es">M A. Van Es</name></author><author><name sortKey="Morahan, J M" sort="Morahan, J M" uniqKey="Morahan J" first="J M." last="Morahan">J M. Morahan</name></author><author><name sortKey="Valdmanis, P N" sort="Valdmanis, P N" uniqKey="Valdmanis P" first="P N." last="Valdmanis">P N. Valdmanis</name></author><author><name sortKey="Meininger, V" sort="Meininger, V" uniqKey="Meininger V" first="V" last="Meininger">V. Meininger</name></author><author><name sortKey="Melki, J" sort="Melki, J" uniqKey="Melki J" first="J" last="Melki">J. Melki</name></author><author><name sortKey="Shaw, C E" sort="Shaw, C E" uniqKey="Shaw C" first="C E." last="Shaw">C E. Shaw</name></author><author><name sortKey="Rouleau, G A" sort="Rouleau, G A" uniqKey="Rouleau G" first="G A." last="Rouleau">G A. Rouleau</name></author><author><name sortKey="Fisher, E M C" sort="Fisher, E M C" uniqKey="Fisher E" first="E M. C." last="Fisher">E M. C. Fisher</name></author><author><name sortKey="Shaw, P J" sort="Shaw, P J" uniqKey="Shaw P" first="P J." last="Shaw">P J. Shaw</name></author><author><name sortKey="Morrison, K E" sort="Morrison, K E" uniqKey="Morrison K" first="K E." last="Morrison">K E. Morrison</name></author><author><name sortKey="Pamphlett, R" sort="Pamphlett, R" uniqKey="Pamphlett R" first="R" last="Pamphlett">R. Pamphlett</name></author><author><name sortKey="Van Den Berg, L H" sort="Van Den Berg, L H" uniqKey="Van Den Berg L" first="L H." last="Van Den Berg">L H. Van Den Berg</name></author><author><name sortKey="Figlewicz, D A" sort="Figlewicz, D A" uniqKey="Figlewicz D" first="D A." last="Figlewicz">D A. Figlewicz</name></author><author><name sortKey="Andersen, P M" sort="Andersen, P M" uniqKey="Andersen P" first="P M." last="Andersen">P M. Andersen</name></author><author><name sortKey="Al Chalabi, A" sort="Al Chalabi, A" uniqKey="Al Chalabi A" first="A" last="Al-Chalabi">A. Al-Chalabi</name></author><author><name sortKey="Hardiman, O" sort="Hardiman, O" uniqKey="Hardiman O" first="O" last="Hardiman">O. Hardiman</name></author><author><name sortKey="Purcell, S" sort="Purcell, S" uniqKey="Purcell S" first="S" last="Purcell">S. Purcell</name></author><author><name sortKey="Landers, J E" sort="Landers, J E" uniqKey="Landers J" first="J E." last="Landers">J E. Landers</name></author><author><name sortKey="Brown, R H" sort="Brown, R H" uniqKey="Brown R" first="R H." last="Brown">R H. Brown</name></author></analytic><series><title level="j">Neurology</title><idno type="ISSN">0028-3878</idno><idno type="eISSN">1526-632X</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background:</title><p>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.</p></sec><sec><title>Methods:</title><p>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.</p></sec><sec><title>Results:</title><p>The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02–1.16, <italic>p</italic> = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07–1.45, <italic>p</italic> = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86–1.10, <italic>p</italic> = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92–1.27, <italic>p</italic> = 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, <italic>p</italic> = 0.22).</p></sec><sec><title>Conclusions:</title><p>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.</p></sec><sec><title>GLOSSARY</title><def-list list-type="abr"><def-item><term><bold>ALS</bold></term><def><p> = amyotrophic lateral sclerosis; </p></def></def-item><def-item><term><bold>CI</bold></term><def><p> = confidence interval; </p></def></def-item><def-item><term><bold>GWAS</bold></term><def><p> = genome-wide association studies; </p></def></def-item><def-item><term><bold>OR</bold></term><def><p> = odds ratio; </p></def></def-item><def-item><term><bold>SALS</bold></term><def><p> = sporadic ALS; </p></def></def-item><def-item><term><bold>SNP</bold></term><def><p> = single nucleotide polymorphism.</p></def></def-item></def-list></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Neurology</journal-id><journal-title>Neurology</journal-title><issn pub-type="ppub">0028-3878</issn><issn pub-type="epub">1526-632X</issn><publisher><publisher-name>American Academy of Neurology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">19321847</article-id><article-id pub-id-type="pmc">2707108</article-id><article-id pub-id-type="publisher-id">znl02509000016</article-id><article-id pub-id-type="doi">10.1212/WNL.0b013e3181a18674</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wills</surname><given-names>A -M.</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Cronin</surname><given-names>S</given-names></name><degrees>PhD, MRCPI</degrees></contrib><contrib contrib-type="author"><name><surname>Slowik</surname><given-names>A</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Kasperaviciute</surname><given-names>D</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Van Es</surname><given-names>M A.</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Morahan</surname><given-names>J M.</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Valdmanis</surname><given-names>P N.</given-names></name><degrees>BSc</degrees></contrib><contrib contrib-type="author"><name><surname>Meininger</surname><given-names>V</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Melki</surname><given-names>J</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>C E.</given-names></name><degrees>MD, FRACP, FRCP</degrees></contrib><contrib contrib-type="author"><name><surname>Rouleau</surname><given-names>G A.</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Fisher</surname><given-names>E M.C.</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>P J.</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Morrison</surname><given-names>K E.</given-names></name><degrees>DPhil</degrees></contrib><contrib contrib-type="author"><name><surname>Pamphlett</surname><given-names>R</given-names></name><degrees>MD, FRACP</degrees></contrib><contrib contrib-type="author"><name><surname>Van den Berg</surname><given-names>L H.</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Figlewicz</surname><given-names>D A.</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Andersen</surname><given-names>P M.</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Al-Chalabi</surname><given-names>A</given-names></name><degrees>PhD, FRCP</degrees></contrib><contrib contrib-type="author"><name><surname>Hardiman</surname><given-names>O</given-names></name><degrees>MD, FRCPI</degrees></contrib><contrib contrib-type="author"><name><surname>Purcell</surname><given-names>S</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Landers</surname><given-names>J E.</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>R H.</given-names><suffix>Jr</suffix></name><degrees>MD, DPhil</degrees></contrib></contrib-group><aff id="N0x20c2ae0N0x2e27190">Authors' affiliations are listed at the end of the article.<break></break>From the Cecil B. Day Neuromuscular Research Laboratory (A.-M.W., J.E.L., R.H.B.), Massachusetts General Hospital, Charlestown; Department of Neurology (S.C., O.H.), Beaumont Hospital, Dublin, Ireland; Department of Neurology (A.S.), Jagiellonian University, Krakow, Poland; Department of Neurodegenerative Disease (D.K., E.M.C.F.), UCL Institute of Neurology, London, UK; Netherlands ALS Center Department of Neurology (M.A.V.E., L.H.V.d.B.), Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands; The Stacey MND Laboratory (J.M.M., R.P.), Department of Pathology, The University of Sydney, Australia; Department of Molecular and Clinical Genetics (J.M.M.), Royal Prince Alfred Hospital, Australia; Center of Excellence in Neuromics (P.N.V., G.A.R.), University of Montreal, CHUM Research Center, and the Department of Medicine, University of Montreal, Canada; Centre Référent SLA (V.M.), Hôpital Salpêtrière, Paris, France; Department of Human Genetics (J.M.), Hadassah University Hospital, Jerusalem, Israel; MRC Centre for Neurodegeneration Research (C.E.S., A.A.-C.), King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, London, UK; Academic Neurology Unit (P.J.S,), Medical School, University of Sheffield, UK; Department of Clinical Neurosciences (K.E.M.), Institute of Biomedical Research, The Medical School, University of Birmingham, UK; University of Michigan (D.A.F.), Ann Arbor, MI and the ALS Society of Canada; Department of Neurology (P.M.A.), Umeå University Hospital, Sweden; Trinity College Institute of Neuroscience (O.H.), Trinity College, Dublin, Ireland; and Center for Human Genetics Research, Richard B. Simches Research Building (S.P.), Massachusetts General Hospital, Boston, MA.<break></break></aff><pub-date pub-type="ppub"><day>7</day><month>7</month><year>2009</year></pub-date><volume>73</volume><issue>1</issue><fpage>16</fpage><lpage>24</lpage><copyright-statement>Copyright © 2009 by AAN Enterprises, Inc.</copyright-statement><abstract><sec><title>Background:</title><p>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.</p></sec><sec><title>Methods:</title><p>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.</p></sec><sec><title>Results:</title><p>The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02–1.16, <italic>p</italic> = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07–1.45, <italic>p</italic> = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86–1.10, <italic>p</italic> = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92–1.27, <italic>p</italic> = 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, <italic>p</italic> = 0.22).</p></sec><sec><title>Conclusions:</title><p>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.</p></sec><sec><title>GLOSSARY</title><def-list list-type="abr"><def-item><term><bold>ALS</bold></term><def><p> = amyotrophic lateral sclerosis; </p></def></def-item><def-item><term><bold>CI</bold></term><def><p> = confidence interval; </p></def></def-item><def-item><term><bold>GWAS</bold></term><def><p> = genome-wide association studies; </p></def></def-item><def-item><term><bold>OR</bold></term><def><p> = odds ratio; </p></def></def-item><def-item><term><bold>SALS</bold></term><def><p> = sporadic ALS; </p></def></def-item><def-item><term><bold>SNP</bold></term><def><p> = single nucleotide polymorphism.</p></def></def-item></def-list></sec></abstract></article-meta><notes><p>Address correspondence and reprint requests to Dr. Wills, CNY 114-3125, 114 16th St, Charlestown, MA 02129 <email>awills@partners.org</email>.</p><p>Supplemental data at <ext-link ext-link-type="uri" xlink:href="www.neurology.org">www.neurology.org</ext-link></p><p>Editorial, page 11.</p><p><italic>e-Pub ahead of print on March 25, 2009, at</italic> <ext-link ext-link-type="uri" xlink:href="www.neurology.org">www.neurology.org</ext-link>.</p><p>Support information is provided at the end of the article.</p><p><italic>Disclosure:</italic> The authors report no disclosures.</p><p><italic>Devices:</italic> GoldenGate assay, Illumina BeadArray station, Infinium II SNP Chip assays, Human Hap550K SNP chips, HumanHap 300K SNP chips (Illumina, San Diego, CA); KASPar PCR system (KBiosciences, Hertfordshire, UK); SNaPshot® assay (Applied Biosystems, Foster City, CA).</p><p>Received September 12, 2008. Accepted in final form January 5, 2009.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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