Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank
<h3>Background</h3><p dir="ltr">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 personaliz...
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2022
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| author | Geethanjali Devadoss Gandhi (14056966) |
| author2 | Waleed Aamer (14056969) Navaneethakrishnan Krishnamoorthy (391608) Najeeb Syed (12561967) Elbay Aliyev (14056972) Aljazi Al-Maraghi (14056975) Muhammad Kohailan (748774) Jamil Alenbawi (14056978) Mohammed Elanbari (11822375) Borbala Mifsud (3907267) Younes Mokrab (6367) Charbel Abi Khalil (781797) Khalid A. Fakhro (3158862) Qatar Genome Program Research Consortium (QGPRC) (18295378) |
| author2_role | author author author author author author author author author author author author author |
| author_facet | Geethanjali Devadoss Gandhi (14056966) Waleed Aamer (14056969) Navaneethakrishnan Krishnamoorthy (391608) Najeeb Syed (12561967) Elbay Aliyev (14056972) Aljazi Al-Maraghi (14056975) Muhammad Kohailan (748774) Jamil Alenbawi (14056978) Mohammed Elanbari (11822375) Borbala Mifsud (3907267) Younes Mokrab (6367) Charbel Abi Khalil (781797) Khalid A. Fakhro (3158862) Qatar Genome Program Research Consortium (QGPRC) (18295378) |
| author_role | author |
| dc.creator.none.fl_str_mv | Geethanjali Devadoss Gandhi (14056966) Waleed Aamer (14056969) Navaneethakrishnan Krishnamoorthy (391608) Najeeb Syed (12561967) Elbay Aliyev (14056972) Aljazi Al-Maraghi (14056975) Muhammad Kohailan (748774) Jamil Alenbawi (14056978) Mohammed Elanbari (11822375) Borbala Mifsud (3907267) Younes Mokrab (6367) Charbel Abi Khalil (781797) Khalid A. Fakhro (3158862) Qatar Genome Program Research Consortium (QGPRC) (18295378) |
| dc.date.none.fl_str_mv | 2022-11-03T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12967-022-03697-w |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Assessing_the_genetic_burden_of_familial_hypercholesterolemia_in_a_large_middle_eastern_biobank/25532941 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Cholesterol Dyslipidemias LDL Lipoproteins/Receptors Premature coronary artery disease Dutch lipid Clinic Network LDLRAP1 Sitosterolemia Polygenic risk scores Middle East region |
| dc.title.none.fl_str_mv | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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, andPCSK9) and recessive (LDLRAP1,ABCG5,ABCG8, andLIPA) 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.</p><h3>Results</h3><p dir="ltr">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 inPCSK9. 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.</p><h3>Conclusion</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Translational Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12967-022-03697-w" target="_blank">https://dx.doi.org/10.1186/s12967-022-03697-w</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_a2c3ed9bebbf8b0a453b6da61516c80e |
| identifier_str_mv | 10.1186/s12967-022-03697-w |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25532941 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobankGeethanjali Devadoss Gandhi (14056966)Waleed Aamer (14056969)Navaneethakrishnan Krishnamoorthy (391608)Najeeb Syed (12561967)Elbay Aliyev (14056972)Aljazi Al-Maraghi (14056975)Muhammad Kohailan (748774)Jamil Alenbawi (14056978)Mohammed Elanbari (11822375)Borbala Mifsud (3907267)Younes Mokrab (6367)Charbel Abi Khalil (781797)Khalid A. Fakhro (3158862)Qatar Genome Program Research Consortium (QGPRC) (18295378)Biological sciencesBiochemistry and cell biologyGeneticsBiomedical and clinical sciencesClinical sciencesCholesterolDyslipidemiasLDLLipoproteins/ReceptorsPremature coronary artery diseaseDutch lipid Clinic NetworkLDLRAP1SitosterolemiaPolygenic risk scoresMiddle East region<h3>Background</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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, andPCSK9) and recessive (LDLRAP1,ABCG5,ABCG8, andLIPA) 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.</p><h3>Results</h3><p dir="ltr">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 inPCSK9. 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.</p><h3>Conclusion</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Translational Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12967-022-03697-w" target="_blank">https://dx.doi.org/10.1186/s12967-022-03697-w</a></p>2022-11-03T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12967-022-03697-whttps://figshare.com/articles/journal_contribution/Assessing_the_genetic_burden_of_familial_hypercholesterolemia_in_a_large_middle_eastern_biobank/25532941CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/255329412022-11-03T03:00:00Z |
| spellingShingle | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank Geethanjali Devadoss Gandhi (14056966) Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Cholesterol Dyslipidemias LDL Lipoproteins/Receptors Premature coronary artery disease Dutch lipid Clinic Network LDLRAP1 Sitosterolemia Polygenic risk scores Middle East region |
| status_str | publishedVersion |
| title | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| title_full | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| title_fullStr | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| title_full_unstemmed | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| title_short | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| title_sort | Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank |
| topic | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Clinical sciences Cholesterol Dyslipidemias LDL Lipoproteins/Receptors Premature coronary artery disease Dutch lipid Clinic Network LDLRAP1 Sitosterolemia Polygenic risk scores Middle East region |