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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2022

Open Access 01-12-2022 | Hypercholesterolemia | Research

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

Authors: Geethanjali Devadoss Gandhi, Waleed Aamer, Navaneethakrishnan Krishnamoorthy, Najeeb Syed, Elbay Aliyev, Aljazi Al-Maraghi, Muhammad Kohailan, Jamil Alenbawi, Mohammed Elanbari, Borbala Mifsud, Younes Mokrab, Charbel Abi Khalil, Khalid A. Fakhro, Qatar Genome Program Research Consortium (QGPRC)

Published in: Journal of Translational Medicine | Issue 1/2022

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.
Appendix
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Metadata
Title
Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank
Authors
Geethanjali Devadoss Gandhi
Waleed Aamer
Navaneethakrishnan Krishnamoorthy
Najeeb Syed
Elbay Aliyev
Aljazi Al-Maraghi
Muhammad Kohailan
Jamil Alenbawi
Mohammed Elanbari
Borbala Mifsud
Younes Mokrab
Charbel Abi Khalil
Khalid A. Fakhro
Qatar Genome Program Research Consortium (QGPRC)
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03697-w

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