{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T02:11:00Z","timestamp":1782353460674,"version":"3.54.5"},"reference-count":89,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T00:00:00Z","timestamp":1696809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013302","name":"King Abdullah International Medical Research Center","doi-asserted-by":"publisher","award":["RC19-083-R"],"award-info":[{"award-number":["RC19-083-R"]}],"id":[{"id":"10.13039\/501100013302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Sickle cell disease (SCD) is a Mendelian disease characterized by multigenic phenotypes. Previous reports indicated a higher rate of thromboembolic events (TEEs) in SCD patients. A number of candidate polymorphisms in certain genes (e.g., FVL, PRT, and MTHFR) were previously reported as risk factors for TEEs in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlie TEEs in SCD patients. Methodology: A multi-center genome-wide association study (GWAS) involving Saudi SCD adult patients with a history of TEEs (n = 65) and control patients without TEE history (n = 285) was performed. Genotyping used the 10\u00d7 Affymetrix Axiom array, which includes 683,030 markers. Fisher\u2019s exact test was used to generate p-values of TEE associations with each single-nucleotide polymorphism (SNP). The haplotype analysis software tool version 1.05, designed by the University of G\u00f6ttingen, Germany, was used to identify the common inherited haplotypes. Results: No association was identified between the targeted single-nucleotide polymorphism rs1801133 in MTHFR and TEEs in SCD (p = 0.79). The allele frequency of rs6025 in FVL and rs1799963 in PRT in our cohort was extremely low (&lt;0.01); thus, both variants were excluded from the analysis as no meaningful comparison was possible. In contrast, the GWAS analysis showed novel genome-wide associations (p &lt; 5 \u00d7 10\u22128) with seven signals; five of them were located on Chr 11 (rs35390334, rs331532, rs317777, rs147062602, and rs372091), one SNP on Chr 20 (rs139341092), and another on Chr 9 (rs76076035). The other 34 SNPs located on known genes were also detected at a signal threshold of p &lt; 5 \u00d7 10\u22126. Seven of the identified variants are located in olfactory receptor family 51 genes (OR51B5, OR51V1, OR51A1P, and OR51E2), and five variants were related to family 52 genes (OR52A5, OR52K1, OR52K2, and OR52T1P). The previously reported association between rs5006884-A in OR51B5 and fetal hemoglobin (HbF) levels was confirmed in our study, which showed significantly lower levels of HbF (p = 0.002) and less allele frequency (p = 0.003) in the TEE cases than in the controls. The assessment of the haplotype inheritance pattern involved the top ten significant markers with no LD (rs353988334, rs317777, rs14788626882, rs49188823, rs139349992, rs76076035, rs73395847, rs1368823, rs8888834548, and rs1455957). A haplotype analysis revealed significant associations between two haplotypes (a risk, TT-AA-del-AA-ins-CT-TT-CC-CC-AA, and a reverse protective, CC-GG-ins-GG-del-TT-CC-TT-GG-GG) and TEEs in SCD (p = 0.024, OR = 6.16, CI = 1.34\u201328.24, and p = 0.019, OR = 0.33, CI = 0.13\u20130.85, respectively). Conclusions: Seven markers showed novel genome-wide associations; two of them were exonic variants (rs317777 in OLFM5P and rs147062602 in OR51B5), and less significant associations (p &lt; 5 \u00d7 10\u22126) were identified for 34 other variants in known genes with TEEs in SCD. Moreover, two 10-SNP common haplotypes were determined with contradictory effects. Further replication of these findings is needed.<\/jats:p>","DOI":"10.3390\/genes14101919","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T10:48:33Z","timestamp":1696848513000},"page":"1919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Impact of Genetic Variations on Thromboembolic Risk in Saudis with Sickle Cell Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-6254","authenticated-orcid":false,"given":"Mohammad A.","family":"Alshabeeb","sequence":"first","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Riyadh 11426, Saudi Arabia"},{"name":"King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deemah","family":"Alwadaani","sequence":"additional","affiliation":[{"name":"King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"},{"name":"Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Riyadh 11481, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farjah H.","family":"Al Qahtani","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology Center, King Saud University Medical City (KSUMC), Riyadh 11411, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0828-3469","authenticated-orcid":false,"given":"Salah","family":"Abohelaika","sequence":"additional","affiliation":[{"name":"Research Department, Qatif Central Hospital (QCH), Qatif 32654, Saudi Arabia"},{"name":"Pharmacy Department, Qatif Central Hospital (QCH), Qatif 32654, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"},{"name":"King Fahad Hospital, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Al Zayed","sequence":"additional","affiliation":[{"name":"Hematology Department, Qatif Central Hospital (QCH), Qatif 32654, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussain H.","family":"Al Saeed","sequence":"additional","affiliation":[{"name":"Hematology Department, Qatif Central Hospital (QCH), Qatif 32654, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Al Ajmi","sequence":"additional","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Riyadh 11426, Saudi Arabia"},{"name":"King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barrak","family":"Alsomaie","sequence":"additional","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Riyadh 11426, Saudi Arabia"},{"name":"King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoon","family":"Rashid","sequence":"additional","affiliation":[{"name":"King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia"},{"name":"Department of AI and Bioinformatics, King Abdullah International Medical Research Center (KAIMRC), Riyadh 11481, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann K.","family":"Daly","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.4103\/0256-4947.81540","article-title":"Epidemiology of sickle cell disease in Saudi Arabia","volume":"31","author":"Jastaniah","year":"2011","journal-title":"Ann. 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