Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank

Journal of Translational Medicine

Research

Najeeb Syed¹  Mohammed Elanbari²  Borbala Mifsud³  Jamil Alenbawi³  Muhammad Kohailan⁴  Geethanjali Devadoss Gandhi⁴  Khalid A. Fakhro⁵  Younes Mokrab⁶  Charbel Abi Khalil⁷  Waleed Aamer⁸  Elbay Aliyev⁸  Aljazi Al-Maraghi⁸  Navaneethakrishnan Krishnamoorthy⁸ 

[1] Bioinformatics, Genomic Data Science Core, Sidra Medicine, Doha, Qatar;Clinical Research Centre, Sidra Medicine, Doha, Qatar;College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha, Qatar;College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha, Qatar;Human Genetics Department, Sidra Medicine, Doha, Qatar;College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha, Qatar;Human Genetics Department, Sidra Medicine, Doha, Qatar;Department of Genetic Medicine, Weill Cornell Medicine, Education City, Qatar;College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha, Qatar;Laboratory of Medical and Population Genomics, Sidra Medicine, Doha, Qatar;Department of Genetic Medicine, Weill Cornell Medicine, Education City, Qatar;Department of Genetic Medicine, Weill Cornell Medicine, Education City, Qatar;Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, US;Human Genetics Department, Sidra Medicine, Doha, Qatar;

关键词: Cholesterol;    Dyslipidemias;    LDL;    Lipoproteins/Receptors;    Premature coronary artery disease;    Dutch lipid Clinic Network;    LDLRAP1;    Sitosterolemia;    Polygenic risk scores;    Middle East region.;   

DOI  :  10.1186/s12967-022-03697-w

 received in 2022-09-06, accepted in 2022-10-06,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe genetic architecture underlying Familial Hypercholesterolemia (FH) in Middle Eastern Arabs is yet to be fully described, and approaches to assess this from population-wide biobanks are important for public health planning and personalized medicine.MethodsWe evaluate the pilot phase cohort (n = 6,140 adults) of the Qatar Biobank (QBB) for FH using the Dutch Lipid Clinic Network (DLCN) criteria, followed by an in-depth characterization of all genetic alleles in known dominant (LDLR, APOB, and PCSK9) and recessive (LDLRAP1, ABCG5, ABCG8, and LIPA) FH-causing genes derived from whole-genome sequencing (WGS). We also investigate the utility of a globally established 12-SNP polygenic risk score to predict FH individuals in this cohort with Arab ancestry.ResultsUsing DLCN criteria, we identify eight (0.1%) ‘definite’, 41 (0.7%) ‘probable’ and 334 (5.4%) ‘possible’ FH individuals, estimating a prevalence of ‘definite or probable’ FH in the Qatari cohort of ~ 1:125. We identify ten previously known pathogenic single-nucleotide variants (SNVs) and 14 putatively novel SNVs, as well as one novel copy number variant in PCSK9. Further, despite the modest sample size, we identify one homozygote for a known pathogenic variant (ABCG8, p. Gly574Arg, global MAF = 4.49E-05) associated with Sitosterolemia 2. Finally, calculation of polygenic risk scores found that individuals with ‘definite or probable’ FH have a significantly higher LDL-C SNP score than ‘unlikely’ individuals (p = 0.0003), demonstrating its utility in Arab populations.ConclusionWe design and implement a standardized approach to phenotyping a population biobank for FH risk followed by systematically identifying known variants and assessing putative novel variants contributing to FH burden in Qatar. Our results motivate similar studies in population-level biobanks – especially those with globally under-represented ancestries – and highlight the importance of genetic screening programs for early detection and management of individuals with high FH risk in health systems.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2023

【 图 表 】

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