HLA Class II Locus and Susceptibility to Podoconiosis
Identifieur interne : 000097 ( PascalFrancis/Checkpoint ); précédent : 000096; suivant : 000098HLA Class II Locus and Susceptibility to Podoconiosis
Auteurs : Fasil Tekola Ayele [États-Unis, Royaume-Uni, Éthiopie] ; Adebowale Adeyemo [États-Unis] ; Chris Finan [Royaume-Uni] ; Elena Hailu [Éthiopie] ; Paul Sinnott [Royaume-Uni] ; Natalia Diaz Burlinson [Royaume-Uni] ; Abraham Aseffa [Éthiopie] ; Charles N. Rotimi [États-Unis] ; Melanie J. Newport [Royaume-Uni] ; Gail Davey [Royaume-Uni]Source :
- The New England journal of medicine [ 0028-4793 ] ; 2012.
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- Pascal (Inist)
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- topic : Médecine.
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Abstract
BACKGROUND Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%). METHODS We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls. RESULTS We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10-9; and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10-8), and suggestive associations (P<1.0×10-5) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis. CONCLUSIONS Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).
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wicri:level="1"><inist:fA14 i1="02"><s1>Brighton and Sus-sex Medical School</s1><s2>Falmer, Brighton</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Brighton and Sus-sex Medical School</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Armauer Hansen Research Institute</s1><s2>Addis Ababa</s2><s3>ETH</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Éthiopie</country><wicri:noRegion>Armauer Hansen Research Institute</wicri:noRegion></affiliation></author><author><name sortKey="Adeyemo, Adebowale" sort="Adeyemo, Adebowale" uniqKey="Adeyemo A" first="Adebowale" last="Adeyemo">Adebowale Adeyemo</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Finan, Chris" sort="Finan, Chris" uniqKey="Finan C" first="Chris" last="Finan">Chris Finan</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Brighton and Sus-sex Medical School</s1><s2>Falmer, Brighton</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Brighton and Sus-sex Medical School</wicri:noRegion></affiliation></author><author><name sortKey="Hailu, Elena" sort="Hailu, Elena" uniqKey="Hailu E" first="Elena" last="Hailu">Elena Hailu</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Armauer Hansen Research Institute</s1><s2>Addis Ababa</s2><s3>ETH</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Éthiopie</country><wicri:noRegion>Armauer Hansen Research Institute</wicri:noRegion></affiliation></author><author><name sortKey="Sinnott, Paul" sort="Sinnott, Paul" uniqKey="Sinnott P" first="Paul" last="Sinnott">Paul Sinnott</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Clinical Transplantation Laboratory, Royal London Hospital</s1><s2>London</s2><s3>GBR</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Diaz Burlinson, Natalia" sort="Diaz Burlinson, Natalia" uniqKey="Diaz Burlinson N" first="Natalia" last="Diaz Burlinson">Natalia Diaz Burlinson</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Clinical Transplantation Laboratory, Royal London Hospital</s1><s2>London</s2><s3>GBR</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Aseffa, Abraham" sort="Aseffa, Abraham" uniqKey="Aseffa A" first="Abraham" last="Aseffa">Abraham Aseffa</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Armauer Hansen Research Institute</s1><s2>Addis Ababa</s2><s3>ETH</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Éthiopie</country><wicri:noRegion>Armauer Hansen Research Institute</wicri:noRegion></affiliation></author><author><name sortKey="Rotimi, Charles N" sort="Rotimi, Charles N" uniqKey="Rotimi C" first="Charles N." last="Rotimi">Charles N. Rotimi</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Newport, Melanie J" sort="Newport, Melanie J" uniqKey="Newport M" first="Melanie J." last="Newport">Melanie J. Newport</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Brighton and Sus-sex Medical School</s1><s2>Falmer, Brighton</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Brighton and Sus-sex Medical School</wicri:noRegion></affiliation></author><author><name sortKey="Davey, Gail" sort="Davey, Gail" uniqKey="Davey G" first="Gail" last="Davey">Gail Davey</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Brighton and Sus-sex Medical School</s1><s2>Falmer, Brighton</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Brighton and Sus-sex Medical School</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">The New England journal of medicine</title><title level="j" type="abbreviated">N. Engl. j. med.</title><idno type="ISSN">0028-4793</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">The New England journal of medicine</title><title level="j" type="abbreviated">N. Engl. j. med.</title><idno type="ISSN">0028-4793</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Class II histocompatibility antigen</term><term>Elephantiasis</term><term>Locus</term><term>Lymphedema</term><term>Medicine</term><term>Podoconiosis</term><term>Predisposition</term><term>Sensitivity</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Lymphoedème</term><term>Antigène histocompatibilité classe II</term><term>Locus</term><term>Eléphantiasis</term><term>Sensibilité</term><term>Prédisposition</term><term>Médecine</term><term>Podoconiose</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Médecine</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">BACKGROUND Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%). METHODS We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls. RESULTS We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10<sup>-9</sup>; and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10<sup>-8</sup>), and suggestive associations (P<1.0×10<sup>-5</sup>) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1<sup>*</sup>0701 (odds ratio, 2.00), DQA1<sup>*</sup>0201 (odds ratio, 1.91), and DQB1<sup>*</sup>0202 (odds ratio, 1.79) and the HLA-DRB1<sup>*</sup>0701-DQB1<sup>*</sup>0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis. CONCLUSIONS Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0028-4793</s0></fA01><fA02 i1="01"><s0>NEJMAG</s0></fA02><fA03 i2="1"><s0>N. Engl. j. med.</s0></fA03><fA05><s2>366</s2></fA05><fA06><s2>13</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>HLA Class II Locus and Susceptibility to Podoconiosis</s1></fA08><fA11 i1="01" i2="1"><s1>TEKOLA AYELE (Fasil)</s1></fA11><fA11 i1="02" i2="1"><s1>ADEYEMO (Adebowale)</s1></fA11><fA11 i1="03" i2="1"><s1>FINAN (Chris)</s1></fA11><fA11 i1="04" i2="1"><s1>HAILU (Elena)</s1></fA11><fA11 i1="05" i2="1"><s1>SINNOTT (Paul)</s1></fA11><fA11 i1="06" i2="1"><s1>DIAZ BURLINSON (Natalia)</s1></fA11><fA11 i1="07" i2="1"><s1>ASEFFA (Abraham)</s1></fA11><fA11 i1="08" i2="1"><s1>ROTIMI (Charles N.)</s1></fA11><fA11 i1="09" i2="1"><s1>NEWPORT (Melanie J.)</s1></fA11><fA11 i1="10" i2="1"><s1>DAVEY (Gail)</s1></fA11><fA14 i1="01"><s1>Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>8 aut.</sZ></fA14><fA14 i1="02"><s1>Brighton and Sus-sex Medical School</s1><s2>Falmer, Brighton</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="03"><s1>Armauer Hansen Research Institute</s1><s2>Addis Ababa</s2><s3>ETH</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="04"><s1>Clinical Transplantation Laboratory, Royal London Hospital</s1><s2>London</s2><s3>GBR</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></fA14><fA20><s1>1200-1208</s1></fA20><fA21><s1>2012</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>6013</s2><s5>354000509745920070</s5></fA43><fA44><s0>0000</s0><s1>© 2012 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>29 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>12-0150841</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>The New England journal of medicine</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>BACKGROUND Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%). METHODS We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls. RESULTS We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10<sup>-9</sup>; and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10<sup>-8</sup>), and suggestive associations (P<1.0×10<sup>-5</sup>) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1<sup>*</sup>0701 (odds ratio, 2.00), DQA1<sup>*</sup>0201 (odds ratio, 1.91), and DQB1<sup>*</sup>0202 (odds ratio, 1.79) and the HLA-DRB1<sup>*</sup>0701-DQB1<sup>*</sup>0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis. CONCLUSIONS Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).</s0></fC01><fC02 i1="01" i2="X"><s0>002B01</s0></fC02><fC02 i1="02" i2="X"><s0>002B12B04</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Lymphoedème</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Lymphedema</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Linfedema</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Antigène histocompatibilité classe II</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Class II histocompatibility antigen</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Antígeno histocompatibilidad clase II</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Locus</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Locus</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Locus</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Eléphantiasis</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Elephantiasis</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Elefantiasis</s0><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Sensibilité</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Sensitivity</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Sensibilidad</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Prédisposition</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Predisposition</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Predisposición</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Médecine</s0><s5>08</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Medicine</s0><s5>08</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Medicina</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Podoconiose</s0><s4>CD</s4><s5>96</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Podoconiosis</s0><s4>CD</s4><s5>96</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Pathologie de l'appareil circulatoire</s0><s5>37</s5></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Cardiovascular disease</s0><s5>37</s5></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Aparato circulatorio patología</s0><s5>37</s5></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Pathologie des vaisseaux lymphatiques</s0><s5>38</s5></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Lymphatic vessel disease</s0><s5>38</s5></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Linfático patología</s0><s5>38</s5></fC07><fN21><s1>114</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist><affiliations><list><country><li>Royaume-Uni</li><li>États-Unis</li><li>Éthiopie</li></country><region><li>Angleterre</li><li>Grand Londres</li><li>Maryland</li></region><settlement><li>Londres</li></settlement></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Tekola Ayele, Fasil" sort="Tekola Ayele, Fasil" uniqKey="Tekola Ayele F" first="Fasil" last="Tekola Ayele">Fasil Tekola Ayele</name></region><name sortKey="Adeyemo, Adebowale" sort="Adeyemo, Adebowale" uniqKey="Adeyemo A" first="Adebowale" last="Adeyemo">Adebowale Adeyemo</name><name sortKey="Rotimi, Charles N" sort="Rotimi, Charles N" uniqKey="Rotimi C" first="Charles N." last="Rotimi">Charles N. Rotimi</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Tekola Ayele, Fasil" sort="Tekola Ayele, Fasil" uniqKey="Tekola Ayele F" first="Fasil" last="Tekola Ayele">Fasil Tekola Ayele</name></noRegion><name sortKey="Davey, Gail" sort="Davey, Gail" uniqKey="Davey G" first="Gail" last="Davey">Gail Davey</name><name sortKey="Diaz Burlinson, Natalia" sort="Diaz Burlinson, Natalia" uniqKey="Diaz Burlinson N" first="Natalia" last="Diaz Burlinson">Natalia Diaz Burlinson</name><name sortKey="Finan, Chris" sort="Finan, Chris" uniqKey="Finan C" first="Chris" last="Finan">Chris Finan</name><name sortKey="Newport, Melanie J" sort="Newport, Melanie J" uniqKey="Newport M" first="Melanie J." last="Newport">Melanie J. Newport</name><name sortKey="Sinnott, Paul" sort="Sinnott, Paul" uniqKey="Sinnott P" first="Paul" last="Sinnott">Paul Sinnott</name></country><country name="Éthiopie"><noRegion><name sortKey="Tekola Ayele, Fasil" sort="Tekola Ayele, Fasil" uniqKey="Tekola Ayele F" first="Fasil" last="Tekola Ayele">Fasil Tekola Ayele</name></noRegion><name sortKey="Aseffa, Abraham" sort="Aseffa, Abraham" uniqKey="Aseffa A" first="Abraham" last="Aseffa">Abraham Aseffa</name><name sortKey="Hailu, Elena" sort="Hailu, Elena" uniqKey="Hailu E" first="Elena" last="Hailu">Elena Hailu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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