{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:15:06Z","timestamp":1783350906621,"version":"3.54.6"},"reference-count":33,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Kingdom of Saudi Arabia was provided by the Research, Development and Innovation Authority","award":["-uqu-2023-UQU-R-3-1-HW-13013"],"award-info":[{"award-number":["-uqu-2023-UQU-R-3-1-HW-13013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Coronary artery disease (CAD) arises from the convergence of genetic susceptibility, lipid dysregulation, and modifiable environmental exposures. The polymorphism rs4977574, located proximal to the CDKN2A\/CDKN2B gene cluster, has been repeatedly implicated in CAD risk across several populations, yet its relationship to intermediate cardiometabolic phenotypes and pharmacological treatment patterns in Saudi individuals remains poorly characterized. Objective: This study aimed to evaluate the association of rs4977574 with CAD status, lipid-related phenotypes, smoking history, obesity, and atorvastatin exposure in a Saudi cardiovascular cohort, and to assess the robustness of observed associations through sensitivity-adjusted analyses excluding participants with major metabolic confounders. Methods: A case\u2013control genetic association study was conducted in Saudi participants with clinically confirmed CAD and healthy controls. Genomic DNA was genotyped for rs4977574 using TaqMan\u00ae allelic discrimination assays. Genotype\u2013phenotype associations were examined using chi-square testing, binary logistic regression under additive and dominant inheritance models, and one-way ANOVA for continuous lipid traits. Hardy\u2013Weinberg equilibrium (HWE) was assessed in controls. Sensitivity analyses were conducted by sequentially excluding participants with obesity, smoking, diabetes mellitus, hypertension, dyslipidaemia, and statin use. Results: After covariate adjustment, rs4977574 was not independently associated with CAD case\u2013control status under any inheritance model. Genotype-stratified analyses identified significant differences in HDL-cholesterol and triglyceride concentrations among cases, with no equivalent effects on total cholesterol or LDL-cholesterol. A significant association was observed between rs4977574 genotype and atorvastatin prescribing patterns. Sensitivity-adjusted analyses were directionally consistent with primary findings. HWE deviation persisted in controls after sequential metabolic exclusions, implicating population stratification or regional genetic heterogeneity rather than sample selection bias. Conclusions: Although rs4977574 did not associate independently with CAD susceptibility, its relationship with HDL-cholesterol, triglycerides, and atorvastatin exposure indicates that this locus contributes to cardiometabolic phenotypic heterogeneity in this Saudi cohort. These findings support phenotype-oriented and pharmacogenetically informed approaches in regional cardiovascular genetics and highlight the need for larger, ancestry-stratified investigations across Middle Eastern populations.<\/jats:p>","DOI":"10.3390\/jcm15135237","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:43:14Z","timestamp":1783345394000},"page":"5237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of rs4977574 with Lipid Phenotypes, Smoking Status, and Statin Exposure in a Saudi Cardiovascular Cohort: A Sensitivity-Adjusted Genetic Association Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7071-0492","authenticated-orcid":false,"given":"Neda M.","family":"Bogari","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4027-480X","authenticated-orcid":false,"given":"Hind Mansour","family":"Naffadi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lujain Ibrahim","family":"Essa","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8694-1500","authenticated-orcid":false,"given":"Amr A.","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia"},{"name":"Faculty of Medicine, Ain-Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Obaid","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine at Al-Qunfudah, Umm Al-Qura University, Al-Qunfudah 21912, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9157-0302","authenticated-orcid":false,"given":"Reem M.","family":"Allam","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"De Kovel, C.G., Mulder, F., Van Setten, J., van \u2018t Slot, R., Al-Rubaish, A., Alshehri, A.M., Al Faraidy, K., Al-Ali, A., Al-Madan, M., and Al Aqaili, I. 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