A functional promoter variant in IL12B predisposes to cerebral malaria
The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by th...
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| Veröffentlicht in: | Human molecular genetics 2008-07, Vol.17 (14), p.2190-2195 |
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| creator | Marquet, Sandrine Doumbo, Ogobara Cabantous, Sandrine Poudiougou, Belco Argiro, Laurent Safeukui, Innocent Konate, Salimata Sissoko, Sibiri Chevereau, Estelle Traore, Abdoulaye Keita, Mamadou M. Chevillard, Christophe Abel, Laurent Dessein, Alain J. |
| description | The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-γ. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49–2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-γ and IL-12 levels in CM, support a protective role for the Th1 pathway in CM. |
| doi_str_mv | 10.1093/hmg/ddn118 |
| format | Article |
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We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-γ. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49–2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-γ and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddn118</identifier><identifier>PMID: 18413324</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Biological and medical sciences ; Child ; Cohort Studies ; Fundamental and applied biological sciences. Psychology ; Genetic Predisposition to Disease ; Genetics of eukaryotes. Biological and molecular evolution ; Heterozygote ; Human protozoal diseases ; Humans ; Infectious diseases ; Interleukin-12 Subunit p35 - genetics ; Interleukin-12 Subunit p40 - genetics ; Life Sciences ; Malaria ; Malaria, Cerebral - genetics ; Medical sciences ; Microbiology and Parasitology ; Molecular and cellular biology ; Odds Ratio ; Parasitic diseases ; Polymorphism, Genetic ; Promoter Regions, Genetic ; Protozoal diseases ; Receptors, Interleukin-12 - genetics ; STAT4 Transcription Factor - genetics</subject><ispartof>Human molecular genetics, 2008-07, Vol.17 (14), p.2190-2195</ispartof><rights>The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2008</rights><rights>2008 INIST-CNRS</rights><rights>The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-84dbf622183091a22ec394efc0c18f828f4dfb59e51b8d1905ddc28aab09011e3</citedby><cites>FETCH-LOGICAL-c511t-84dbf622183091a22ec394efc0c18f828f4dfb59e51b8d1905ddc28aab09011e3</cites><orcidid>0000-0001-7011-6496 ; 0000-0001-7016-6493 ; 0000-0002-5269-8813</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20484066$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18413324$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://amu.hal.science/hal-01592703$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Marquet, Sandrine</creatorcontrib><creatorcontrib>Doumbo, Ogobara</creatorcontrib><creatorcontrib>Cabantous, Sandrine</creatorcontrib><creatorcontrib>Poudiougou, Belco</creatorcontrib><creatorcontrib>Argiro, Laurent</creatorcontrib><creatorcontrib>Safeukui, Innocent</creatorcontrib><creatorcontrib>Konate, Salimata</creatorcontrib><creatorcontrib>Sissoko, Sibiri</creatorcontrib><creatorcontrib>Chevereau, Estelle</creatorcontrib><creatorcontrib>Traore, Abdoulaye</creatorcontrib><creatorcontrib>Keita, Mamadou M.</creatorcontrib><creatorcontrib>Chevillard, Christophe</creatorcontrib><creatorcontrib>Abel, Laurent</creatorcontrib><creatorcontrib>Dessein, Alain J.</creatorcontrib><title>A functional promoter variant in IL12B predisposes to cerebral malaria</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-γ. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49–2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-γ and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.</description><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Cohort Studies</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Heterozygote</subject><subject>Human protozoal diseases</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Interleukin-12 Subunit p35 - genetics</subject><subject>Interleukin-12 Subunit p40 - genetics</subject><subject>Life Sciences</subject><subject>Malaria</subject><subject>Malaria, Cerebral - genetics</subject><subject>Medical sciences</subject><subject>Microbiology and Parasitology</subject><subject>Molecular and cellular biology</subject><subject>Odds Ratio</subject><subject>Parasitic diseases</subject><subject>Polymorphism, Genetic</subject><subject>Promoter Regions, Genetic</subject><subject>Protozoal diseases</subject><subject>Receptors, Interleukin-12 - genetics</subject><subject>STAT4 Transcription Factor - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c-L1DAUB_Agiju7evEPkCIoKNR9L0nT5Djuus7CiBcF8RLSJHW7ts2YtIv-92boMAse9BR4-byXH19CniG8RVDs_Gb4fu7ciCgfkBVyASUFyR6SFSjBS6FAnJDTlG4BUHBWPyYnKDkyRvmKXK2Ldh7t1IXR9MUuhiFMPhZ3JnZmnIpuLK63SN_lHe-6tAvJp2IKhfXRNzF3DKbf0yfkUWv65J8e1jPy5er954tNuf304fpivS1thTiVkrumFZSiZKDQUOotU9y3FizKVlLZctc2lfIVNtKhgso5S6UxDShA9OyMvF7m3phe72I3mPhbB9PpzXqr9zXAStEa2B1m-2qx-VU_Z58mPXTJ-r43ow9z0kJRoWoJ_4UUFMWK8gxf_AVvwxzzx2WDiEoxqTJ6syAbQ0rRt8d7Iuh9XjrnpZe8Mn5-mDg3g3f39BBQBi8PwCRr-jaa0Xbp6ChwyUGIexfm3b8PLBfXpcn_OkoTf2hRs7rSm6_fNHxEVV8yppH9AS4ptqk</recordid><startdate>20080715</startdate><enddate>20080715</enddate><creator>Marquet, Sandrine</creator><creator>Doumbo, Ogobara</creator><creator>Cabantous, Sandrine</creator><creator>Poudiougou, Belco</creator><creator>Argiro, Laurent</creator><creator>Safeukui, Innocent</creator><creator>Konate, Salimata</creator><creator>Sissoko, Sibiri</creator><creator>Chevereau, Estelle</creator><creator>Traore, Abdoulaye</creator><creator>Keita, Mamadou M.</creator><creator>Chevillard, Christophe</creator><creator>Abel, Laurent</creator><creator>Dessein, Alain J.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><general>Oxford University Press (OUP)</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>M7N</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0001-7011-6496</orcidid><orcidid>https://orcid.org/0000-0001-7016-6493</orcidid><orcidid>https://orcid.org/0000-0002-5269-8813</orcidid></search><sort><creationdate>20080715</creationdate><title>A functional promoter variant in IL12B predisposes to cerebral malaria</title><author>Marquet, Sandrine ; Doumbo, Ogobara ; Cabantous, Sandrine ; Poudiougou, Belco ; Argiro, Laurent ; Safeukui, Innocent ; Konate, Salimata ; Sissoko, Sibiri ; Chevereau, Estelle ; Traore, Abdoulaye ; Keita, Mamadou M. ; Chevillard, Christophe ; Abel, Laurent ; Dessein, Alain J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-84dbf622183091a22ec394efc0c18f828f4dfb59e51b8d1905ddc28aab09011e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Cohort Studies</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Heterozygote</topic><topic>Human protozoal diseases</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Interleukin-12 Subunit p35 - genetics</topic><topic>Interleukin-12 Subunit p40 - genetics</topic><topic>Life Sciences</topic><topic>Malaria</topic><topic>Malaria, Cerebral - genetics</topic><topic>Medical sciences</topic><topic>Microbiology and Parasitology</topic><topic>Molecular and cellular biology</topic><topic>Odds Ratio</topic><topic>Parasitic diseases</topic><topic>Polymorphism, Genetic</topic><topic>Promoter Regions, Genetic</topic><topic>Protozoal diseases</topic><topic>Receptors, Interleukin-12 - genetics</topic><topic>STAT4 Transcription Factor - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marquet, Sandrine</creatorcontrib><creatorcontrib>Doumbo, Ogobara</creatorcontrib><creatorcontrib>Cabantous, Sandrine</creatorcontrib><creatorcontrib>Poudiougou, Belco</creatorcontrib><creatorcontrib>Argiro, Laurent</creatorcontrib><creatorcontrib>Safeukui, Innocent</creatorcontrib><creatorcontrib>Konate, Salimata</creatorcontrib><creatorcontrib>Sissoko, Sibiri</creatorcontrib><creatorcontrib>Chevereau, Estelle</creatorcontrib><creatorcontrib>Traore, Abdoulaye</creatorcontrib><creatorcontrib>Keita, Mamadou M.</creatorcontrib><creatorcontrib>Chevillard, Christophe</creatorcontrib><creatorcontrib>Abel, Laurent</creatorcontrib><creatorcontrib>Dessein, Alain J.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marquet, Sandrine</au><au>Doumbo, Ogobara</au><au>Cabantous, Sandrine</au><au>Poudiougou, Belco</au><au>Argiro, Laurent</au><au>Safeukui, Innocent</au><au>Konate, Salimata</au><au>Sissoko, Sibiri</au><au>Chevereau, Estelle</au><au>Traore, Abdoulaye</au><au>Keita, Mamadou M.</au><au>Chevillard, Christophe</au><au>Abel, Laurent</au><au>Dessein, Alain J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A functional promoter variant in IL12B predisposes to cerebral malaria</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2008-07-15</date><risdate>2008</risdate><volume>17</volume><issue>14</issue><spage>2190</spage><epage>2195</epage><pages>2190-2195</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><coden>HNGEE5</coden><abstract>The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-γ. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49–2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-γ and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>18413324</pmid><doi>10.1093/hmg/ddn118</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-7011-6496</orcidid><orcidid>https://orcid.org/0000-0001-7016-6493</orcidid><orcidid>https://orcid.org/0000-0002-5269-8813</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Biological and medical sciences Child Cohort Studies Fundamental and applied biological sciences. Psychology Genetic Predisposition to Disease Genetics of eukaryotes. Biological and molecular evolution Heterozygote Human protozoal diseases Humans Infectious diseases Interleukin-12 Subunit p35 - genetics Interleukin-12 Subunit p40 - genetics Life Sciences Malaria Malaria, Cerebral - genetics Medical sciences Microbiology and Parasitology Molecular and cellular biology Odds Ratio Parasitic diseases Polymorphism, Genetic Promoter Regions, Genetic Protozoal diseases Receptors, Interleukin-12 - genetics STAT4 Transcription Factor - genetics |
| title | A functional promoter variant in IL12B predisposes to cerebral malaria |
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