{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:41:47Z","timestamp":1790329307428,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,12,23]],"date-time":"2015-12-23T00:00:00Z","timestamp":1450828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"NIH (National Heart, Lung, and Blood Institute)","doi-asserted-by":"crossref","award":["R03-HL-114937"],"award-info":[{"award-number":["R03-HL-114937"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NIH (National Heart, Lung, and Blood Institute)","doi-asserted-by":"crossref","award":["HL-102923"],"award-info":[{"award-number":["HL-102923"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NIH (National Heart, Lung, and Blood Institute)","doi-asserted-by":"crossref","award":["P50-HL-084946"],"award-info":[{"award-number":["P50-HL-084946"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension"},{"name":"Intramural Research Program of the National Human Genome Research Institute"},{"name":"Mary Beryl Patch Turnbull Scholar Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed whole\u2010exome sequencing of 78 European American patients with SSc, including 35 patients without pulmonary arterial hypertension (PAH) and 43 patients with PAH. Association testing of case\u2013control probability for rare variants was performed using the unified sequence kernel association test with optimal kernel weighting and small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the Exome Sequencing Project 5,500 exome data set. Replication genotyping was performed in an independent sample of 3,263 patients (415 patients with SSc and 2,848 controls). We conducted expression profiling of messenger RNA from 61 SSc patients (19 without PAH and 42 with PAH) and 41 corresponding controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>ATP8B4<\/jats:italic>\n                      gene was associated with a significant increase in the risk of SSc (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20092.77 \u00d7 10\n                      <jats:sup>\u22127<\/jats:sup>\n                      ). Among the 64\n                      <jats:italic>ATP8B4<\/jats:italic>\n                      variants tested, a single missense variant, c.1308C&gt;G (F436L, rs55687265), provided the most compelling evidence of association (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20099.35 \u00d7 10\n                      <jats:sup>\u221210<\/jats:sup>\n                      , odds ratio [OR] 6.11), which was confirmed in the replication cohort (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.012, OR 1.86) and meta\u2010analysis (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20091.92 \u00d7 10\n                      <jats:sup>\u22127<\/jats:sup>\n                      , OR 2.5). Genes involved in E3 ubiquitin\u2010protein ligase complex (\n                      <jats:italic>ASB10<\/jats:italic>\n                      ) and cyclic nucleotide gated channelopathies (\n                      <jats:italic>CNGB3<\/jats:italic>\n                      ) as well as\n                      <jats:italic>HLA\u2013DRB5<\/jats:italic>\n                      and\n                      <jats:italic>HSPB2<\/jats:italic>\n                      (heat\u2010shock protein 27) provided additional evidence of association (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ). Differential\n                      <jats:italic>ATP8B4<\/jats:italic>\n                      expression was observed among the SSc patients compared to the controls (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0005).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ATP8B4<\/jats:italic>\n                      may represent a putative genetic risk factor for SSc and pulmonary vascular complications.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.39449","type":"journal-article","created":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T15:58:51Z","timestamp":1445011131000},"page":"191-200","source":"Crossref","is-referenced-by-count":45,"title":["Identification of Rare Variants in\n                    <i>ATP8B4<\/i>\n                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