Details

Autor(en) / Beteiligte

• Gandhi, Geethanjali Devadoss
• Aamer, Waleed
• Krishnamoorthy, Navaneethakrishnan
• Syed, Najeeb
• Aliyev, Elbay
• Al-Maraghi, Aljazi
• Kohailan, Muhammad
• Alenbawi, Jamil
• Elanbari, Mohammed
• Mifsud, Borbala
• Mokrab, Younes
• Abi Khalil, Charbel
• Fakhro, Khalid A

Titel

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

Ist Teil von

• Journal of translational medicine, 2022-11, Vol.20 (1), p.502-502, Article 502

Ort / Verlag

England: BioMed Central Ltd

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The 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. We 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. Using 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. We 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.