A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema
Angiotensin I‐converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life‐threatening reaction, ACEi‐angioedema. Impaired metabolism of bradykinin and des‐Arg9‐bradykinin by aminopeptidase P (APP) is a key contributor to ACEi‐angioedema. Th...
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| Veröffentlicht in: | Human mutation 2011-11, Vol.32 (11), p.1326-1331 |
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| creator | Cilia La Corte, Amy L. Carter, Angela M. Rice, Gillian I. Duan, Qing Ling Rouleau, Guy A Adam, Albert Grant, Peter J. Hooper, Nigel M. |
| description | Angiotensin I‐converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life‐threatening reaction, ACEi‐angioedema. Impaired metabolism of bradykinin and des‐Arg9‐bradykinin by aminopeptidase P (APP) is a key contributor to ACEi‐angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi‐angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (−338 bp to −147 bp) and an enhancer region (−2,502 bp to −2,238 bp). Three polymorphisms (c.‐2399C>A, c.‐1612G>T, and c.‐393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.‐2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi‐angioedema, haplotype ATG was significantly associated with ACEi‐angioedema (OR 4.87 [1.78–13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi‐angioedema through a reduction in APP. Hum Mutat 32:1326–1331, 2011. ©2011 Wiley Periodicals, Inc. |
| doi_str_mv | 10.1002/humu.21579 |
| format | Article |
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Impaired metabolism of bradykinin and des‐Arg9‐bradykinin by aminopeptidase P (APP) is a key contributor to ACEi‐angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi‐angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (−338 bp to −147 bp) and an enhancer region (−2,502 bp to −2,238 bp). Three polymorphisms (c.‐2399C>A, c.‐1612G>T, and c.‐393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.‐2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi‐angioedema, haplotype ATG was significantly associated with ACEi‐angioedema (OR 4.87 [1.78–13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi‐angioedema through a reduction in APP. Hum Mutat 32:1326–1331, 2011. ©2011 Wiley Periodicals, Inc.</description><identifier>ISSN: 1059-7794</identifier><identifier>ISSN: 1098-1004</identifier><identifier>EISSN: 1098-1004</identifier><identifier>DOI: 10.1002/humu.21579</identifier><identifier>PMID: 21898657</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>ACE inhibitor angioedema ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alzheimer's disease ; Aminopeptidase ; aminopeptidase P ; Aminopeptidases - blood ; Aminopeptidases - genetics ; Amyloid precursor protein ; angioedema ; Angioedema - chemically induced ; Angiotensin-Converting Enzyme Inhibitors - adverse effects ; Antihypertensives ; Bradykinin ; Enhancers ; Female ; Gene deletion ; Genetic factors ; haplotype ; Haplotypes ; hepatic nuclear factor 4 ; Humans ; Liver ; Male ; Metabolism ; Middle Aged ; Pedigree ; Peptidyl-dipeptidase A ; Promoter Regions, Genetic ; Promoters ; Regulatory Elements, Transcriptional ; Reporter gene ; transcription regulatory elements ; X chromosome</subject><ispartof>Human mutation, 2011-11, Vol.32 (11), p.1326-1331</ispartof><rights>2011 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4639-f64ee50a60a77cd3dad74d71d87bc7f403fc8bc95e400741d8db21ccef181033</citedby><cites>FETCH-LOGICAL-c4639-f64ee50a60a77cd3dad74d71d87bc7f403fc8bc95e400741d8db21ccef181033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhumu.21579$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhumu.21579$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21898657$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cilia La Corte, Amy L.</creatorcontrib><creatorcontrib>Carter, Angela M.</creatorcontrib><creatorcontrib>Rice, Gillian I.</creatorcontrib><creatorcontrib>Duan, Qing Ling</creatorcontrib><creatorcontrib>Rouleau, Guy A</creatorcontrib><creatorcontrib>Adam, Albert</creatorcontrib><creatorcontrib>Grant, Peter J.</creatorcontrib><creatorcontrib>Hooper, Nigel M.</creatorcontrib><title>A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema</title><title>Human mutation</title><addtitle>Hum. Mutat</addtitle><description>Angiotensin I‐converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life‐threatening reaction, ACEi‐angioedema. Impaired metabolism of bradykinin and des‐Arg9‐bradykinin by aminopeptidase P (APP) is a key contributor to ACEi‐angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi‐angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (−338 bp to −147 bp) and an enhancer region (−2,502 bp to −2,238 bp). Three polymorphisms (c.‐2399C>A, c.‐1612G>T, and c.‐393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.‐2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi‐angioedema, haplotype ATG was significantly associated with ACEi‐angioedema (OR 4.87 [1.78–13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi‐angioedema through a reduction in APP. Hum Mutat 32:1326–1331, 2011. ©2011 Wiley Periodicals, Inc.</description><subject>ACE inhibitor angioedema</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alzheimer's disease</subject><subject>Aminopeptidase</subject><subject>aminopeptidase P</subject><subject>Aminopeptidases - blood</subject><subject>Aminopeptidases - genetics</subject><subject>Amyloid precursor protein</subject><subject>angioedema</subject><subject>Angioedema - chemically induced</subject><subject>Angiotensin-Converting Enzyme Inhibitors - adverse effects</subject><subject>Antihypertensives</subject><subject>Bradykinin</subject><subject>Enhancers</subject><subject>Female</subject><subject>Gene deletion</subject><subject>Genetic factors</subject><subject>haplotype</subject><subject>Haplotypes</subject><subject>hepatic nuclear factor 4</subject><subject>Humans</subject><subject>Liver</subject><subject>Male</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Pedigree</subject><subject>Peptidyl-dipeptidase A</subject><subject>Promoter Regions, Genetic</subject><subject>Promoters</subject><subject>Regulatory Elements, Transcriptional</subject><subject>Reporter gene</subject><subject>transcription regulatory elements</subject><subject>X chromosome</subject><issn>1059-7794</issn><issn>1098-1004</issn><issn>1098-1004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAURiMEoqWw4QGQJRYgpBQ7TvyznA7DFKktU6kV7CzHvmHcJnGwE8E8Aa-Nh7RdsOjK9qdzj3T9Zdlrgo8JxsXH7dRNxwWpuHySHRIsRZ7i8un-Xsmcc1keZC9ivMEYi6qiz7ODgggpWMUPsz8L1Ey9GZ3vdYu-by42q02BhuA7P0JAWz20ftwNgFrQNqLRowB2MmDR0OrYaaQ71_sBhtFZHQFtkO4tcr0JkJ4WBRdvkW_QYrlK6dbVbvQhd_3s0P0P58FCp19mzxrdRnh1dx5lV59XV8vT_Ozr-stycZabklGZN6wEqLBmWHNuLLXa8tJyYgWvDW9KTBsjaiMrKDHmZcptXRBjoCGCYEqPsnezNm34c4I4qs5FA22re_BTVEJKUnIqZSLfP0oSTLhkjBKS0Lf_oTd-Cuk_E8UZE4XgskjUh5kywccYoFFDcJ0Ou6RS-x7Vvkf1r8cEv7lTTnUH9gG9Ly4BZAZ-uRZ2j6jU6fX59b00n2dcHOH3w4wOt4pxyiv17WKtzi_lp5NLulac_gUZprhE</recordid><startdate>201111</startdate><enddate>201111</enddate><creator>Cilia La Corte, Amy L.</creator><creator>Carter, Angela M.</creator><creator>Rice, Gillian I.</creator><creator>Duan, Qing Ling</creator><creator>Rouleau, Guy A</creator><creator>Adam, Albert</creator><creator>Grant, Peter J.</creator><creator>Hooper, Nigel M.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Hindawi Limited</general><scope>BSCLL</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>7X8</scope></search><sort><creationdate>201111</creationdate><title>A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema</title><author>Cilia La Corte, Amy L. ; Carter, Angela M. ; Rice, Gillian I. ; Duan, Qing Ling ; Rouleau, Guy A ; Adam, Albert ; Grant, Peter J. ; Hooper, Nigel M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4639-f64ee50a60a77cd3dad74d71d87bc7f403fc8bc95e400741d8db21ccef181033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>ACE inhibitor angioedema</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alzheimer's disease</topic><topic>Aminopeptidase</topic><topic>aminopeptidase P</topic><topic>Aminopeptidases - blood</topic><topic>Aminopeptidases - genetics</topic><topic>Amyloid precursor protein</topic><topic>angioedema</topic><topic>Angioedema - chemically induced</topic><topic>Angiotensin-Converting Enzyme Inhibitors - adverse effects</topic><topic>Antihypertensives</topic><topic>Bradykinin</topic><topic>Enhancers</topic><topic>Female</topic><topic>Gene deletion</topic><topic>Genetic factors</topic><topic>haplotype</topic><topic>Haplotypes</topic><topic>hepatic nuclear factor 4</topic><topic>Humans</topic><topic>Liver</topic><topic>Male</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Pedigree</topic><topic>Peptidyl-dipeptidase A</topic><topic>Promoter Regions, Genetic</topic><topic>Promoters</topic><topic>Regulatory Elements, Transcriptional</topic><topic>Reporter gene</topic><topic>transcription regulatory elements</topic><topic>X chromosome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cilia La Corte, Amy L.</creatorcontrib><creatorcontrib>Carter, Angela M.</creatorcontrib><creatorcontrib>Rice, Gillian I.</creatorcontrib><creatorcontrib>Duan, Qing Ling</creatorcontrib><creatorcontrib>Rouleau, Guy A</creatorcontrib><creatorcontrib>Adam, Albert</creatorcontrib><creatorcontrib>Grant, Peter J.</creatorcontrib><creatorcontrib>Hooper, Nigel M.</creatorcontrib><collection>Istex</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>MEDLINE - Academic</collection><jtitle>Human mutation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cilia La Corte, Amy L.</au><au>Carter, Angela M.</au><au>Rice, Gillian I.</au><au>Duan, Qing Ling</au><au>Rouleau, Guy A</au><au>Adam, Albert</au><au>Grant, Peter J.</au><au>Hooper, Nigel M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema</atitle><jtitle>Human mutation</jtitle><addtitle>Hum. Mutat</addtitle><date>2011-11</date><risdate>2011</risdate><volume>32</volume><issue>11</issue><spage>1326</spage><epage>1331</epage><pages>1326-1331</pages><issn>1059-7794</issn><issn>1098-1004</issn><eissn>1098-1004</eissn><abstract>Angiotensin I‐converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life‐threatening reaction, ACEi‐angioedema. Impaired metabolism of bradykinin and des‐Arg9‐bradykinin by aminopeptidase P (APP) is a key contributor to ACEi‐angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi‐angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (−338 bp to −147 bp) and an enhancer region (−2,502 bp to −2,238 bp). Three polymorphisms (c.‐2399C>A, c.‐1612G>T, and c.‐393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.‐2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi‐angioedema, haplotype ATG was significantly associated with ACEi‐angioedema (OR 4.87 [1.78–13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi‐angioedema through a reduction in APP. Hum Mutat 32:1326–1331, 2011. ©2011 Wiley Periodicals, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21898657</pmid><doi>10.1002/humu.21579</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | ACE inhibitor angioedema Adolescent Adult Aged Aged, 80 and over Alzheimer's disease Aminopeptidase aminopeptidase P Aminopeptidases - blood Aminopeptidases - genetics Amyloid precursor protein angioedema Angioedema - chemically induced Angiotensin-Converting Enzyme Inhibitors - adverse effects Antihypertensives Bradykinin Enhancers Female Gene deletion Genetic factors haplotype Haplotypes hepatic nuclear factor 4 Humans Liver Male Metabolism Middle Aged Pedigree Peptidyl-dipeptidase A Promoter Regions, Genetic Promoters Regulatory Elements, Transcriptional Reporter gene transcription regulatory elements X chromosome |
| title | A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema |
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