en Human Genetics Human Genetics Original Research Original Research <span style="font-size:13pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="text-autospace:none"><span style="font-family:&quot;Times New Roman&quot;,serif"><span style="font-style:italic"><b><span style="font-size:9.0pt"><span style="font-style:normal">Background: </span></span></b><span style="font-size:9.0pt"><span style="font-style:normal">Polygenic risk scores (PRSs) for coronary artery disease (CAD) may provide a quantitative assessment of inherited susceptibility that extends beyond conventional clinical risk factors. However, the relationship between CAD PRS and the incidence of CAD may differ across various cardiometabolic risk groups. This study aimed to evaluate whether baseline diabetes status influences the association between CAD PRS and the incidence of CAD.</span></span></span></span></span></span></span></span><br> <span style="font-size:13pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="text-autospace:none"><span style="font-family:&quot;Times New Roman&quot;,serif"><span style="font-style:italic"><span style="font-size:9.0pt"><span style="font-style:normal">&nbsp;&nbsp; <b>Methods:</b> This cohort comprised 5,139 adults from the Tehran Cardiometabolic Genetic Study (TCGS) who were free of CAD at baseline. The CAD PRS was constructed using a maximum clumping-and-thresholding approach based on external CAD genome-wide association summary statistics. Associations between the PRS and cumulative incident CAD were assessed according to diabetes status using logistic regression. Model discrimination and prediction error were evaluated using the area under the curve (AUC) and the Brier score.</span></span></span></span></span></span></span></span><br> <span style="font-size:13pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="text-autospace:none"><span style="font-family:&quot;Times New Roman&quot;,serif"><span style="font-style:italic"><span style="font-size:9.0pt"><span style="font-style:normal">&nbsp; &nbsp;<b>Results: </b>Among 5,139 participants, 1,171 had diabetes while 3,968 did not; incident CAD occurred in 334 diabetic and 427 non-diabetic participants. After adjusting for traditional risk factors, each 1-SD increase in the PRS was associated with higher odds of incident CAD in diabetic participants (OR, 1.36; 95% CI, 1.20&ndash;1.55) and non-diabetic participants (OR, 1.27; 95% CI, 1.14&ndash;1.41). A significant interaction between PRS quintiles and diabetes status was observed (</span></span><span style="font-size:9.0pt">P</span><span style="font-size:9.0pt"><span style="font-style:normal"> = 0.017). The model incorporating the PRS alongside traditional risk factors demonstrated greater discrimination in non-diabetic compared to diabetic participants (AUC, 0.776 vs 0.600).</span></span></span></span></span></span></span></span><br> <span style="font-size:13pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="text-autospace:none"><span style="font-family:&quot;Times New Roman&quot;,serif"><span style="font-style:italic"><span style="font-size:9.0pt"><span style="font-style:normal">&nbsp;&nbsp; <b>Conclusion:</b> CAD PRS was associated with incident CAD across diabetes-defined strata; however, its predictive relevance varied according to baseline diabetes status. These findings support the use of PRS as a marker of inherited susceptibility rather than as evidence for clinical risk reclassification or as a stand-alone predictive tool.</span></span></span></span></span></span></span></span><br> &nbsp; Coronary artery disease, Diabetes mellitus, Polygenic risk score, TLGS, Iran 795 805 http://mjiri.iums.ac.ir/browse.php?a_code=A-10-3971-2&slc_lang=en&sid=1 Farzad Maleki malekiifarzad@gmail.com 200319475328460099880 200319475328460099880 No Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mahdi Akbarzadeh akbarzadeh.ms@gmail.com 200319475328460099881 200319475328460099881 No Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Siamak Sabour s.sabour@gmail.com 200319475328460099882 200319475328460099882 No Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran Leila Najd-Hassan-Bonab leila_nhb26@yahoo.com 200319475328460099883 200319475328460099883 No Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Hossein Lanjanian hossein.lanjanian@gmail.com 200319475328460099884 200319475328460099884 No Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Maryam Sadat Daneshpour daneshpour@endocrine.ac.ir 200319475328460099885 200319475328460099885 No 2. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Ali Delpisheh delpisheh@sbmu.ac.ir 200319475328460099886 200319475328460099886 Yes Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran