Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response
BACKGROUND—A functional polymorphism in the inhibitory IgG-Fc receptor gene FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activati...
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| Veröffentlicht in: | Circulation. Cardiovascular genetics 2012-06, Vol.5 (3), p.309-316 |
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| creator | Shrestha, Sadeep Wiener, Howard Shendre, Aditi Kaslow, Richard A Wu, Jianming Olson, Aaron Bowles, Neil E Patel, Hitendra Edberg, Jeffrey C Portman, Michael A |
| description | BACKGROUND—A functional polymorphism in the inhibitory IgG-Fc receptor gene FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (FcγRIIA, FcγRIIIA, and FcγRIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD.
METHODS AND RESULTS—We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA, and FcγRIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The FcγRIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16–1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the FcγRIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75–7.66; P=0.0006) and 3.60 (95% CI, 1.34–9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (ORadditive, 2.13; 95% CI, 1.11–4.0; P=0.02).
CONCLUSIONS—A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism. |
| doi_str_mv | 10.1161/CIRCGENETICS.111.962464 |
| format | Article |
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METHODS AND RESULTS—We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA, and FcγRIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The FcγRIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16–1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the FcγRIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75–7.66; P=0.0006) and 3.60 (95% CI, 1.34–9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (ORadditive, 2.13; 95% CI, 1.11–4.0; P=0.02).
CONCLUSIONS—A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.</description><identifier>ISSN: 1942-325X</identifier><identifier>ISSN: 1942-3268</identifier><identifier>EISSN: 1942-3268</identifier><identifier>DOI: 10.1161/CIRCGENETICS.111.962464</identifier><identifier>PMID: 22565545</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Adolescent ; Adult ; Aged ; Coronary Artery Disease - prevention & control ; Disease Susceptibility ; Female ; Genome-Wide Association Study ; Genotype ; GPI-Linked Proteins - genetics ; Humans ; Immunoglobulins, Intravenous - therapeutic use ; Linkage Disequilibrium ; Male ; Middle Aged ; Mucocutaneous Lymph Node Syndrome - drug therapy ; Mucocutaneous Lymph Node Syndrome - ethnology ; Mucocutaneous Lymph Node Syndrome - genetics ; Mutation ; Odds Ratio ; Polymorphism, Single Nucleotide ; Receptors, IgG - genetics ; Sequence Analysis, DNA ; Young Adult</subject><ispartof>Circulation. Cardiovascular genetics, 2012-06, Vol.5 (3), p.309-316</ispartof><rights>2012 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4958-99cf83fbc5671f4c39b5345435668fb0e328cf92dc76e25c60b94118c21ca1133</citedby><cites>FETCH-LOGICAL-c4958-99cf83fbc5671f4c39b5345435668fb0e328cf92dc76e25c60b94118c21ca1133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3674,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22565545$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shrestha, Sadeep</creatorcontrib><creatorcontrib>Wiener, Howard</creatorcontrib><creatorcontrib>Shendre, Aditi</creatorcontrib><creatorcontrib>Kaslow, Richard A</creatorcontrib><creatorcontrib>Wu, Jianming</creatorcontrib><creatorcontrib>Olson, Aaron</creatorcontrib><creatorcontrib>Bowles, Neil E</creatorcontrib><creatorcontrib>Patel, Hitendra</creatorcontrib><creatorcontrib>Edberg, Jeffrey C</creatorcontrib><creatorcontrib>Portman, Michael A</creatorcontrib><title>Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response</title><title>Circulation. Cardiovascular genetics</title><addtitle>Circ Cardiovasc Genet</addtitle><description>BACKGROUND—A functional polymorphism in the inhibitory IgG-Fc receptor gene FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (FcγRIIA, FcγRIIIA, and FcγRIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD.
METHODS AND RESULTS—We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA, and FcγRIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The FcγRIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16–1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the FcγRIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75–7.66; P=0.0006) and 3.60 (95% CI, 1.34–9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (ORadditive, 2.13; 95% CI, 1.11–4.0; P=0.02).
CONCLUSIONS—A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Coronary Artery Disease - prevention & control</subject><subject>Disease Susceptibility</subject><subject>Female</subject><subject>Genome-Wide Association Study</subject><subject>Genotype</subject><subject>GPI-Linked Proteins - genetics</subject><subject>Humans</subject><subject>Immunoglobulins, Intravenous - therapeutic use</subject><subject>Linkage Disequilibrium</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mucocutaneous Lymph Node Syndrome - drug therapy</subject><subject>Mucocutaneous Lymph Node Syndrome - ethnology</subject><subject>Mucocutaneous Lymph Node Syndrome - genetics</subject><subject>Mutation</subject><subject>Odds Ratio</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Receptors, IgG - genetics</subject><subject>Sequence Analysis, DNA</subject><subject>Young Adult</subject><issn>1942-325X</issn><issn>1942-3268</issn><issn>1942-3268</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd9u0zAUxiMEYmPwCuBLbjL8P8kN0lS6LmIC1A2JO8txT1ozxw5x0qrPxXvsmfDUUY0rLixbx7_z6Xzny7J3BJ8TIsmHWb2cLeZf5rf17CZVyHklKZf8WXZKKk5zRmX5_PgWP06yVzH-xFhyxuTL7IRSIYXg4jTbLoMDFFp0YUa71aP1a3Rp7n8v0QI8oG_B7bsw9Bsbu4isR5_1Tkd9Z9EnG0FHQDdTNNCPtrHOjnuk_QrVfhz0FnyYIqq7bvJh7UIzudS-hNgHH-F19qLVLsKbx_ss-345v51d5ddfF_Xs4jo3vBJlXlWmLVnbGCEL0nLDqkYwLjgTUpZtg4HR0rQVXZlCAhVG4qbihJSGEqMJYews-3jQ7aemg5WBh9Gc6gfb6WGvgrbq3x9vN2odtopxzgXhSeD9o8AQfk0QR9XZZNg57SH5U0QIIinjrPw_iinhAicyocUBNUOIcYD2OBHB6iFg9TTgVCHqEHDqfPvU0LHvb6IJ4AdgF9wIQ7xz0w4GtQHtxo3CaScFr4qcYkKxxBjn6eCS_QEzirVl</recordid><startdate>201206</startdate><enddate>201206</enddate><creator>Shrestha, Sadeep</creator><creator>Wiener, Howard</creator><creator>Shendre, Aditi</creator><creator>Kaslow, Richard A</creator><creator>Wu, Jianming</creator><creator>Olson, Aaron</creator><creator>Bowles, Neil E</creator><creator>Patel, Hitendra</creator><creator>Edberg, Jeffrey C</creator><creator>Portman, Michael A</creator><general>American Heart Association, Inc</general><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>7X8</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>201206</creationdate><title>Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response</title><author>Shrestha, Sadeep ; Wiener, Howard ; Shendre, Aditi ; Kaslow, Richard A ; Wu, Jianming ; Olson, Aaron ; Bowles, Neil E ; Patel, Hitendra ; Edberg, Jeffrey C ; Portman, Michael A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4958-99cf83fbc5671f4c39b5345435668fb0e328cf92dc76e25c60b94118c21ca1133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Coronary Artery Disease - prevention & control</topic><topic>Disease Susceptibility</topic><topic>Female</topic><topic>Genome-Wide Association Study</topic><topic>Genotype</topic><topic>GPI-Linked Proteins - genetics</topic><topic>Humans</topic><topic>Immunoglobulins, Intravenous - therapeutic use</topic><topic>Linkage Disequilibrium</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mucocutaneous Lymph Node Syndrome - drug therapy</topic><topic>Mucocutaneous Lymph Node Syndrome - ethnology</topic><topic>Mucocutaneous Lymph Node Syndrome - genetics</topic><topic>Mutation</topic><topic>Odds Ratio</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Receptors, IgG - genetics</topic><topic>Sequence Analysis, DNA</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shrestha, Sadeep</creatorcontrib><creatorcontrib>Wiener, Howard</creatorcontrib><creatorcontrib>Shendre, Aditi</creatorcontrib><creatorcontrib>Kaslow, Richard A</creatorcontrib><creatorcontrib>Wu, Jianming</creatorcontrib><creatorcontrib>Olson, Aaron</creatorcontrib><creatorcontrib>Bowles, Neil E</creatorcontrib><creatorcontrib>Patel, Hitendra</creatorcontrib><creatorcontrib>Edberg, Jeffrey C</creatorcontrib><creatorcontrib>Portman, Michael A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Circulation. Cardiovascular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shrestha, Sadeep</au><au>Wiener, Howard</au><au>Shendre, Aditi</au><au>Kaslow, Richard A</au><au>Wu, Jianming</au><au>Olson, Aaron</au><au>Bowles, Neil E</au><au>Patel, Hitendra</au><au>Edberg, Jeffrey C</au><au>Portman, Michael A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response</atitle><jtitle>Circulation. Cardiovascular genetics</jtitle><addtitle>Circ Cardiovasc Genet</addtitle><date>2012-06</date><risdate>2012</risdate><volume>5</volume><issue>3</issue><spage>309</spage><epage>316</epage><pages>309-316</pages><issn>1942-325X</issn><issn>1942-3268</issn><eissn>1942-3268</eissn><abstract>BACKGROUND—A functional polymorphism in the inhibitory IgG-Fc receptor gene FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (FcγRIIA, FcγRIIIA, and FcγRIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD.
METHODS AND RESULTS—We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA, and FcγRIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The FcγRIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16–1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the FcγRIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75–7.66; P=0.0006) and 3.60 (95% CI, 1.34–9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (ORadditive, 2.13; 95% CI, 1.11–4.0; P=0.02).
CONCLUSIONS—A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>22565545</pmid><doi>10.1161/CIRCGENETICS.111.962464</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation. Cardiovascular genetics, 2012-06, Vol.5 (3), p.309-316 |
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| source | MEDLINE; American Heart Association Journals |
| subjects | Adolescent Adult Aged Coronary Artery Disease - prevention & control Disease Susceptibility Female Genome-Wide Association Study Genotype GPI-Linked Proteins - genetics Humans Immunoglobulins, Intravenous - therapeutic use Linkage Disequilibrium Male Middle Aged Mucocutaneous Lymph Node Syndrome - drug therapy Mucocutaneous Lymph Node Syndrome - ethnology Mucocutaneous Lymph Node Syndrome - genetics Mutation Odds Ratio Polymorphism, Single Nucleotide Receptors, IgG - genetics Sequence Analysis, DNA Young Adult |
| title | Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response |
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