Ismail Umlai Umm-Kulthum, Toor Salman M, Al-Sarraj Yasser A, Mohammed Shaban, Al Hail Moza S H, Ullah Ehsan, Kunji Khalid, El-Menyar Ayman, Gomaa Mohammed, Jayyousi Amin, Saad Mohamad, Qureshi Nadeem, Al Suwaidi Jassim M, Albagha Omar M E
College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar; Qatar Genome Program (QGP), Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
J Lipid Res. 2025 Mar;66(3):100752. doi: 10.1016/j.jlr.2025.100752. Epub 2025 Feb 3.
The genetic determinants of low-density lipoprotein cholesterol (LDL-C) levels in blood have been predominantly explored in European populations and remain poorly understood in Middle Eastern populations. We investigated the genetic architecture of LDL-C variation in Qatar by conducting a genome-wide association study (GWAS) on serum LDL-C levels using whole genome sequencing data of 13,701 individuals (discovery; n = 5,939, replication; n = 7,762) from the population-based Qatar Biobank (QBB) cohort. We replicated 168 previously reported loci from the largest LDL-C GWAS by the Global Lipids Genetics Consortium (GLGC), with high correlation in allele frequencies (R = 0.77) and moderate correlation in effect sizes (Beta; R = 0.53). We also performed a multi-ancestry meta-analysis with the GLGC study using MR-MEGA (Meta-Regression of Multi-Ethnic Genetic Association) and identified one novel LDL-C-associated locus; rs10939663 (SLC2A9; genomic control-corrected P = 1.25 × 10). Lastly, we developed Qatari-specific polygenic score (PGS) panels and tested their performance against PGS derived from other ancestries. The multi-ancestry-derived PGS (PGS000888) performed best at predicting LDL-C levels, whilst the Qatari-derived PGS showed comparable performance. Overall, we report a novel gene associated with LDL-C levels, which may be explored further to decipher its potential role in the etiopathogenesis of cardiovascular diseases. Our findings also highlight the importance of population-based genetics in developing PGS for clinical utilization.
血液中低密度脂蛋白胆固醇（LDL-C）水平的遗传决定因素主要在欧洲人群中进行了探索，而在中东人群中仍知之甚少。我们通过对来自基于人群的卡塔尔生物银行（QBB）队列的13701名个体（发现组；n = 5939，复制组；n = 7762）的全基因组测序数据进行血清LDL-C水平的全基因组关联研究（GWAS），调查了卡塔尔LDL-C变异的遗传结构。我们重复了全球脂质遗传学联盟（GLGC）在最大的LDL-C GWAS中先前报道的168个位点，等位基因频率高度相关（R = 0.77），效应大小中度相关（β；R = 0.53）。我们还使用MR-MEGA（多民族遗传关联的元回归）与GLGC研究进行了多祖先元分析，并确定了一个新的LDL-C相关位点；rs10939663（SLC2A9；基因组对照校正P = 1.25 × 10）。最后，我们开发了卡塔尔特异性多基因评分（PGS）面板，并测试了它们相对于其他祖先来源的PGS的性能。多祖先来源的PGS（PGS000888）在预测LDL-C水平方面表现最佳，而卡塔尔来源的PGS表现相当。总体而言，我们报告了一个与LDL-C水平相关的新基因，可进一步探索其在心血管疾病发病机制中的潜在作用。我们的发现还强调了基于人群的遗传学在开发用于临床应用的PGS中的重要性。
