{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:28:54Z","timestamp":1788305334982,"version":"build-2803163510"},"reference-count":15,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,10,17]],"date-time":"2017-10-17T00:00:00Z","timestamp":1508198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37\u2010AR\u2010042455"],"award-info":[{"award-number":["R37\u2010AR\u2010042455"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007820","name":"Alliance for Lupus Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007820","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Fetal exposure to maternal anti\u2010<jats:styled-content style=\"fixed-case\">SSA<\/jats:styled-content>\/Ro antibodies is necessary but not sufficient for the development of autoimmune congenital heart block (<jats:styled-content style=\"fixed-case\">CHB<\/jats:styled-content>), suggesting that other factors, such as fetal genetic predisposition, are important. Given the previously described association between major histocompatibility complex alleles and <jats:styled-content style=\"fixed-case\">CHB<\/jats:styled-content> risk, we undertook the present study to test the hypothesis that a variant form of <jats:styled-content style=\"fixed-case\">HLA<\/jats:styled-content>\u2013C Asn80Lys, which binds with high affinity to an inhibitory killer cell immunoglobulin\u2010like receptor (<jats:styled-content style=\"fixed-case\">KIR<\/jats:styled-content>) and thus renders natural killer (<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>) cells incapable of restricting inflammation, contributes to the development of <jats:styled-content style=\"fixed-case\">CHB<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Members of 192 pedigrees in the <jats:styled-content style=\"fixed-case\">US<\/jats:styled-content> and Europe (194 cases of <jats:styled-content style=\"fixed-case\">CHB<\/jats:styled-content>, 91 unaffected siblings, 152 fathers, 167 mothers) and 1,073 out\u2010of\u2010study controls were genotyped on the Immunochip single\u2010nucleotide polymorphism microarray. Imputation was used to identify associations at <jats:styled-content style=\"fixed-case\">HLA<\/jats:styled-content>\u2013C Asn80Lys (Asn, C1; Lys, C2) and <jats:styled-content style=\"fixed-case\">KIR<\/jats:styled-content>. Tests for association were performed using logistic regression. McNemar's test and the pedigree disequilibrium test (<jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content>) were used for matched analyses between affected and unaffected children.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with out\u2010of\u2010study controls of the same sex, the C2 allele was less frequent in the mothers (odds ratio [<jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content>] 0.63, <jats:italic>P<\/jats:italic> = 0.0014) and more frequent in the fathers (<jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> 1.40, <jats:italic>P<\/jats:italic> = 0.0123), yielding a significant sex\u2010by\u2010C2 interaction (<jats:italic>P<\/jats:italic> = 0.0002). The C2 allele was more frequent in affected siblings than in unaffected siblings (<jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> 3.67, <jats:italic>P<\/jats:italic> = 0.0025), which was consistent with the <jats:styled-content style=\"fixed-case\">PDT<\/jats:styled-content> results (<jats:italic>P<\/jats:italic> = 0.016); these results were observed in both sexes and across the <jats:styled-content style=\"fixed-case\">US<\/jats:styled-content> and European cohorts. There was no difference in the frequency of the inhibitory <jats:styled-content style=\"fixed-case\">KIR<\/jats:styled-content> genotype (<jats:styled-content style=\"fixed-case\">KIR AA<\/jats:styled-content>) between affected and unaffected children (<jats:italic>P<\/jats:italic> = 0.55).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data establish C2 as a novel genetic risk factor associated with <jats:styled-content style=\"fixed-case\">CHB<\/jats:styled-content>. This observation supports a model in which fetuses with C2 ligand expression and maternal anti\u2010<jats:styled-content style=\"fixed-case\">SSA<\/jats:styled-content>\/Ro positivity may have impaired <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell surveillance, resulting in unchecked cardiac inflammation and scarring.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40228","type":"journal-article","created":{"date-parts":[[2017,10,17]],"date-time":"2017-10-17T17:46:37Z","timestamp":1508262397000},"page":"2170-2174","source":"Crossref","is-referenced-by-count":14,"title":["Brief Report: Association of Natural Killer Cell Ligand Polymorphism <scp>HLA<\/scp>\u2013C Asn80Lys With the Development of Anti\u2010<scp>SSA<\/scp>\/Ro\u2013Associated Congenital Heart Block"],"prefix":"10.1002","volume":"69","author":[{"given":"Hannah C.","family":"Ainsworth","sequence":"first","affiliation":[{"name":"Wake Forest University Winston\u2010Salem North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda C.","family":"Marion","sequence":"additional","affiliation":[{"name":"Wake Forest University Winston\u2010Salem North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Bertero","sequence":"additional","affiliation":[{"name":"Ospedale Mauriziano Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Brucato","sequence":"additional","affiliation":[{"name":"Ospedale Papa Giovanni XXIII Bergamo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando","family":"Cimaz","sequence":"additional","affiliation":[{"name":"Meyer Children's Hospital and University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Costedoat\u2010Chalumeau","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Descartes\u2010Sorbonne Paris Cit\u00e9 Paris 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