{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:58:31Z","timestamp":1792047511317,"version":"4.4.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,8,12]],"date-time":"2020-08-12T00:00:00Z","timestamp":1597190400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["U24\u2010HL\u2010135600"],"award-info":[{"award-number":["U24\u2010HL\u2010135600"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["1U01HG007459\u201001"],"award-info":[{"award-number":["1U01HG007459\u201001"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1ZIAHG200362"],"award-info":[{"award-number":["1ZIAHG200362"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less\u2010than\u2010optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non\u2010availability of specific effective interventions for SCA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a \u201clong survivor\u201d group (age over 40 years), a \u201cstroke\u201d group (at least one episode of overt stroke), and a \u201crandom\u201d group (patients younger than 40 years without overt cerebrovascular disease). Fifty\u2010eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss\u2010of\u2010function variants per gene against a null model was estimated for each group, and gene\u2010set association tests were conducted to test differences between groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the \u201clong survivor\u201d group, deleterious\/loss\u2010of\u2010function variants were enriched in genes including <jats:italic>CLCN6<\/jats:italic> (a voltage\u2010dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and <jats:italic>OGHDL<\/jats:italic> (important in arginine metabolism, which is a therapeutic target in SCA). In the \u201cstroke\u201d group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, <jats:italic>SERPINC1<\/jats:italic>, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in \u201clong survivors\u201d group. Published transcriptomic evidence provides functional support for the role of the identified pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.152","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T02:50:03Z","timestamp":1597287003000},"source":"Crossref","is-referenced-by-count":29,"title":["Genetic modifiers of long\u2010term survival in sickle cell anemia"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-9051","authenticated-orcid":false,"given":"Ambroise","family":"Wonkam","sequence":"first","affiliation":[{"name":"Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences University of Cape Town  Cape Town South Africa"},{"name":"Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences University of Cape Town  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile 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