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Furthermore, genetic association studies may uncover biomarkers that can be used to identify susceptible individuals, and contribute toward developing vaccine and novel therapeutic targets. Genetic predisposition to rheumatic fever and RHD has been hypothesized by findings from familial studies and observed associations between genes located in the human leukocyte antigens on chromosome 6p21.3 and elsewhere in the genome. We sought to summarize, from published Genetic association studies in RHD, evidence on genetic variants implicated in RHD susceptibility. Using HuGENet\u2122 systematic review methods, we evaluated 66 studies reporting on 42 genes. Existing meta\u2010analyses of candidate gene studies suggest that <jats:italic>TGF\u2010\u03b21<\/jats:italic> [rs1800469], and <jats:italic>IL\u20101\u03b2<\/jats:italic> [rs2853550] single nucleotide polymorphisms (SNPs) contribute to susceptibility to RHD, whereas the <jats:italic>TNF\u2010\u03b1<\/jats:italic> [rs1800629 and rs361525], <jats:italic>TGF\u2010\u03b21<\/jats:italic> [rs1800470 and rs4803457], <jats:italic>IL\u20106<\/jats:italic> [rs1800795], <jats:italic>IL\u201010<\/jats:italic> [rs1800896] were not associated with RHD. However, candidate gene studies in RF\/RHD are relatively small, thus lacking statistical power to identify reliable and reproducible findings, emphasizing the need for large\u2010scale multicenter studies with different populations.<\/jats:p>","DOI":"10.1002\/ajmg.c.31773","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T10:34:46Z","timestamp":1582281286000},"page":"159-177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Genetic variants in rheumatic fever and rheumatic heart disease"],"prefix":"10.1002","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4832-0671","authenticated-orcid":false,"given":"Babu","family":"Muhamed","sequence":"first","affiliation":[{"name":"Department of Medicine University of Cape Town  Cape Town South Africa"},{"name":"Hatter Institute for Cardiovascular Diseases Research in Africa  Observatory South Africa"},{"name":"Division of Cardiology Children's National Health System  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gasnat","family":"Shaboodien","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cape Town  Cape Town South Africa"},{"name":"Hatter Institute for Cardiovascular Diseases Research in Africa  Observatory South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1334-8829","authenticated-orcid":false,"given":"Mark E.","family":"Engel","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cape Town  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00098"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-015-1245-y"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-011-0692-7"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.15537\/smj.2015.2.10267"},{"issue":"1","key":"e_1_2_8_6_1","first-page":"7","article-title":"Angiotensin\u2010converting enzyme genotype predicts valve damage in acute rheumatic fever","volume":"12","author":"Atalar E.","year":"2003","journal-title":"The Journal of Heart Valve Disease"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/10937400701436460"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2009.09.003"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2016.06.029"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2004.06.007"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-005-0677-x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/03009740510026760"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2019.03.035"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2018.01.001"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2015-309188"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.792135"},{"issue":"1","key":"e_1_2_8_17_1","first-page":"109","article-title":"The MTHFR C677T polymorphism is associated with mitral valve rheumatic heart disease","volume":"20","author":"Carlus S. 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