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Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil

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Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by high levels of low-density lipoprotein-cholesterol (LDLc), associated to premature cardiovascular disease. The detection of the variants related to FH is important to improve the early diagnosis in probands / index-cases (ICs) and their relatives. We included ICs with FH and their relatives, living in a small region of Minas Gerais state-Brazil, which were classified according to Dutch Lipid Clinic Network Criteria (DLCNC) and submitted to sequencing of genes related to FH (LDLR, APOB, PCSK9, LDLRAP1, LIPA, STAP1, APOE, ABCG5 e ABCG8). In a total of 143 subjects (32 ICs and 111 relatives), eight variants were identified in 91 individuals. From these variants, five were in LDLR [p.(Asp224Asn), p.(Ser854Gly), p.(Cys34Arg), p.(Asp601His), deletion of exon15 in LDLR)], one in APOB [p.(Met499Val)], one in PCSK9 [p.(Arg237Trp)] and one in APOE [p.(Pro28Leu)] genes. The variants were detected in 100% of those subjects classified as definitive, 87% as probable and 69% as possible FH cases based on DLCNC. The LDLc level was higher in individuals with corneal arch and xanthomas or xanthelasmas, as well as in pathogenic or probably pathogenic variants carriers. This study showed higher frequency of LDLR gene variants compared to other genes related to LDL metabolism in individuals with FH in Minas Gerais – Brazil and the presence of FH in relatives without previous diagnosis. Our data reinforce the importance of molecular and clinical evaluation of FH relatives in order to early diagnosis the FH, as well as cardiovascular diseases prevention.

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References

  1. Moltuski AG (1989) Genetic Familial Hypercholesterolemia and its diagnosis. Atherosclerosis 9:13–17

    Google Scholar 

  2. Yang KC, Su YN, Shew JY, Yang KY, Tseng WK, Wu CC, LEE YT, (2007) LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population. J Formos Med Assoc 106:799–807

    CAS  PubMed  Google Scholar 

  3. Abifadel M, Varret M, Rabès JP et al (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156

    CAS  PubMed  Google Scholar 

  4. Nitika S, Movva S, Balakrishnan P, Biji IK, Sawhney JPS, Puri R, Arora A, Saxena R, Mishra S, Apte S, Kulshrestha S et al (2019) Genetic analysis of familial hypercholesterolemia in Asian Indians a single center study. J Clin Lipidol 14:35–45

    Google Scholar 

  5. Al-Allaf FA, Abduljaleel AAZ, Taher MM, Bouazzaoui A, Abalkhail H, Athar AFAM (2017) Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient. ABP 64:75–79

    CAS  Google Scholar 

  6. Leigh S, Futema M, Whittall R, Taylor-Beadling A, Williams M, Dunnen JT, Humphries SE (2017) The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. J Med Genet 54(4):217–233

    CAS  PubMed  Google Scholar 

  7. Shah NP et al (2020) Familial hypercholesterolemia: Detect, treat, and ask about family. Cleve Clin J Med 87:109–120

    PubMed  Google Scholar 

  8. Williams RR, Hunt SC, Schumacher MC et al (1993) Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 72:171–176

    CAS  PubMed  Google Scholar 

  9. World Health Organization Familial Hypercholesterolaemia (FH): Report of a Second WHO Consultation (1999) World Health Organization, Geneva (World Health Organization)

  10. Nordestgaard BG, Chapman MJ, Humphries SE et al (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J 34:3478–3490

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Khera AV, Chaffin M, Aragam KG et al (2018) Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 50:1219–1224

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Steyn K, Goldberg YP, Kotze MJ, Steyn M, Swanepoel AS, Fourie JM, Coetzee GA, Van Der Westhuyzen DR (1996) Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. Hum Genet 98:479–484

    CAS  PubMed  Google Scholar 

  13. Nordestgaard BG, Benn M (2017) (2017) Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol: who does it in the world? Eur Heart J 38:1580–1583

    PubMed  Google Scholar 

  14. Harada PH, Miname MH, Benseñora IM, Santos RD, Lotufo PA (2018) Familial hypercholesterolemia prevalence in an admixed racial society: Sex and race matter.The ELSA-Brasil. Atherosclerosis 277:273–277. https://doi.org/10.1016/j.atherosclerosis.2018.08.021

    Article  CAS  PubMed  Google Scholar 

  15. Benito-Vicente A, Uribe K, Jebari S, Galicia-Garcia U, Ostolaza H, Martin C (2018) Familial hypercholesterolemia: the mos frequent cholesterol metabolism disorder caused disease. Int J MolSci 19:1–21 pii:E3426

  16. Santos RD, Gidding SS, Hegele RA et al (2016) International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Definingsevere familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol 4:850–861

    PubMed  Google Scholar 

  17. Versmissen J et al (2008) Efficacy of statins in familial hypercholesterolaemia a long term cohort study. BMJ 337:1–6

    Google Scholar 

  18. Friedewald WT, Levy RIF (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without the use of preparative ultracentrifugue. Clin Chem 18:499–552

    CAS  PubMed  Google Scholar 

  19. Foody JM et al (2013) Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy. Vasc Health Risk Manag 9:719–727

    PubMed  PubMed Central  Google Scholar 

  20. Ballantyne CM et al (2014) Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high risk patients: results of the GRAVITY randomized study. Atherosclerosis 232:86–93

    CAS  PubMed  Google Scholar 

  21. Salazar LA, Hirata MH, CavalliSA NER, Forti N, Jaime Diament J, Giannini SD, Bertolami MC, Hirata RDC (2002) Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations. Hum Mutat 19:462–463

    PubMed  Google Scholar 

  22. Jannes CE, Dias RS, Silva PRS, Turolla L, Gagliardi ACM, Marsiglia JDC, Chacra AP, Miname MH, Rocha VZ, Salgado-Filho W, Krieger JE, Pereira AC (2015) Familialhypercholesterolemia in Brazil: cascadescreeningprogram, clinicalandgeneticaspects. Atherosclerosis 238:101–107

    CAS  PubMed  Google Scholar 

  23. Garg A, Fazio S, Duell PB, Baass A, Udata C, Joh T, Riel T, Sirota M, Dettling D, Liang H, Garzone PD, Gumbiner B, Wan H (2019) Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort. J Endocr Soc 20:1–16

    Google Scholar 

  24. Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick CR (2016) Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 133:1067–1072

    PubMed  Google Scholar 

  25. Maglio C, Mancina RM, Motta BM et al (2014) Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing. J Intern Med 276:396–403

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hsiung Y, Linb P, Chena C, Tungc Y, Yanga W, Chena L, Sub T (2018) Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan. Atherosclerosis 277:440–447

    CAS  PubMed  Google Scholar 

  27. Liu H, Li J (2015) Aging and dyslipidemia A review of potential mechanisms. Ageing Res Rev 19:43–52

    CAS  PubMed  Google Scholar 

  28. De Lorenzo A, Silva JDL, Jannes CE, Pereira AC, Moreira ASB (2018) Anthropometric and Biochemical Characteristics of Patients with or without Genetically Confirmed Familial Hypercholesterolemia. Arq Bras Cardiol 110:119–123

    PubMed  PubMed Central  Google Scholar 

  29. Futema M et al (2013) Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis 229:161–168

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Grenkowitz T, Kassner U, Wühle-Demuth M, Salewsky B, Rosada A, Zemojtel T, Hopfenmüller W, Isermann B, Borucki K et al (2016) Clinical characterization and mutation spectrum of German patients with familial hypercholesterolemia. Atherosclerosis 253:88–93

    CAS  PubMed  Google Scholar 

  31. Medeiros AM, Alves AC, Chora JR, Bourbon M (2017) Portuguese familial hypercholesterolaemiastudy. Instituto_Nacional de Saúde Dr. Ricardo Jorge- Doenças não-transmissíveis- artigos breves 3:15–18

    Google Scholar 

  32. Iacocca MA, Chora JR, Carrie A, Freiberger T, Leigh SE, Defesche JC et al (2018) ClinVardatabaseof global familial hypercholesterolemiaassociated DNA variants. Hum Mutat 39:1631–1640

    PubMed  PubMed Central  Google Scholar 

  33. Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK (2008) Familial hypercholesterolaemia in Portugal- Investigators of Portuguese FH Study. Atheroclerosis 196:633–642

    CAS  Google Scholar 

  34. Südhof TC, Russell DW, Goldstein JL, Brown MS, Sanchez-Pescador R, Bell JI (1985) Cassette of eight exons shared by genes for LDL receptor and EGF precursor. Science 228(4701):893–895

    PubMed  Google Scholar 

  35. Maruyama T, Yamashita S, Matsuzawa Y, Bujo H, Takahashi K, Saito Y et al (2004) Mutations in Japanese Subjects with Primary Hyperlipidemia - Results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996. J AtherosclerThromb 11:131–145

    CAS  Google Scholar 

  36. Lehrman MA, Goldstein JL, Russell DW, Brown MS (1987) Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell 48:827–835

    CAS  PubMed  Google Scholar 

  37. Hobbs HH, Brown MS, Goldstein JL (1992) Molecular Genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466

    CAS  PubMed  Google Scholar 

  38. Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V (2005) Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. J Molecular Medicine 84:203–214

    Google Scholar 

  39. Porntadavity S, Jeenduang N (2019) Structure-Function Relationships of LDL Receptor Missense Mutations Using Homology Modeling. Protein J 38:447–462

    CAS  PubMed  Google Scholar 

  40. Chora JR, Medeiros AM, Alves AC, Bourbon M (2018) Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet Med 20:591–598

    CAS  PubMed  Google Scholar 

  41. Cameron J, Holla OL, Ranheim T, Kulseth MA et al (2006) Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. HumMol Genet 15:1551–1558

    CAS  Google Scholar 

  42. Benito-Vicente A, Etxebarria A, Stef M, Ostolaza H, Palacios L, Martin C (2015) Activity-associated effect of LDL receptor missense variants located in the cysteine-rich repeats. Atherosclerosis 238:304–312

    PubMed  Google Scholar 

  43. Etxebarria A, Palacios L, Stef M, Tejedor D, Uribe KB, Oleaga A, Irigoyen L, Torres B, Ostolaza H, Martin C (2012) Functional Characterization of Splicing and Ligand-Binding Domain Variants in the LDL Receptor. Hum Mutat 33:232–243

    CAS  PubMed  Google Scholar 

  44. Resende FH (2018) – Bom Despacho 300 anos: Homens que construíram Tomo I: Dos primórdios do Arraial de Nossa Senhora do Bom Despacho (1715) à emancipação político-administrativa (1912). Cap. II Velha Serrana- A sétima vila do ouro da capitania de Minas Gerais 1:15–27

    Google Scholar 

  45. Bhatnagar D, Morgan J, Siddiq S et al (2000) Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. Brit Med J 321:1497–1500

    CAS  PubMed  Google Scholar 

  46. Hendricks-Sturrup RM, Lu CY (2019) Understanding Implementation Challenges to Genetic Testing for Familial Hypercholesterolemia in the United States. J Pers Med 9:1–7

    Google Scholar 

  47. Séguro F, Rabès J-P, Taraszkiewicz D, Ruidavets J-B, Bongard V, Ferrières J (2018) Genetic diagnosis of familial hypercholesterolemia is associated with a premature and high coronary heart disease risk. Clin Cardiol 41:385–391

    PubMed  PubMed Central  Google Scholar 

  48. Khera AV, Won HH, Peloso GM et al (2016) Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 67:2578–2589

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Silvino, J.; Jannes, C.; Tada, M.; Lima, I. and Gomes, K.

Funding

KBG is grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq for the research fellowship. Amgen® Brasil proveded financial resources for this research.

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Authors and Affiliations

  1. Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerias, Brazil

    Júnea Paolucci de Paiva Silvino & Karina Braga Gomes

  2. Laboratório de Genética e Cardiologia Molecular do Instituto do Coração de São Paulo (INCOR), Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil

    Cinthia Elim Jannes, Mauricio Teruo Tada, Isabella Ramos Lima & Alexandre Costa Pereira

  3. Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, Brazil

    Iêda de Fátima Oliveira Silva & Karina Braga Gomes

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  1. Júnea Paolucci de Paiva Silvino
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  2. Cinthia Elim Jannes
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  3. Mauricio Teruo Tada
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Correspondence to Karina Braga Gomes.

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Ethical approval

The study was approved by the Ethics Comitte of Federal University of Minas Gerais (CAAE- 76387417.6.0000.5149) and by the Ethics Comitte of the University of São Paulo (CAPPesqprotocol00594212.1001.0068). The project was carried out in accordance with the guidelines of the Declaration of Helsinki.

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11033_2020_6014_MOESM1_ESM.docx

Genetic variants related to Familial Hypercholesterolemia found in 19 index cases from Bom Despacho city, Minas Gerais state - southeastern region from Brazil.Genetic variants related to Familial Hypercholesterolemia found in 19 index cases from Bom Despacho city, Minas Gerais state - southeastern region from Brazil. Supplementary file1 (DOCX 13 KB)

Clinical variables according to the presence of genetic variants. Supplementary file2 (PDF 441 KB)

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de Paiva Silvino, J.P., Jannes, C.E., Tada, M.T. et al. Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil. Mol Biol Rep 47, 9279–9288 (2020). https://doi.org/10.1007/s11033-020-06014-0

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