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Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update

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Abstract

Familial combined hyperlipidemia (FCHL) is one of the most common familial lipoprotein disorders of the lipoproteins, with a prevalence of 0.5% to 2% in different populations. About 10% of these patients suffer from cardiovascular disease and this number is increased by up to 11.3% in the young survivors of myocardial infarction and by 40% among all the survivors of myocardial infarction. Although initially thought to be that FCHL has an inheritance pattern of monogenic, the disease’s etiology is still not fully understood and it appears that FCHL has a complex pattern related to genetic variants, environmental factors, and lifestyles. Two strategies have been used to identify its complex genetic background: candidate gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL with a variable degree of scientific evidence. Until now, more than 30 different genetic variants have been identified related to FCHL. In this study, we aimed to review the individual genes that have been described in FCHL and how these genes and variants can be related to the current concept of metabolic pathways resulting in familial combined hyperlipidemia.

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References

  • Aguilar-Salinas CA, Tusie-Luna T, Pajukanta P (2014) Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia. Metabolism 63(7):887–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beeks E, Janssen RG, Kroon AA, Keulen ET, Geurts JM, De Leeuw PW et al (2001) Association between the α-adducin Gly460Trp polymorphism and systolic blood pressure in familial combined hyperlipidemia. Am J Hypertens 14(12):1185–1190

    Article  CAS  PubMed  Google Scholar 

  • Brouwers MC, Van Greevenbroek MM, Stehouwer CD, De Graaf J, Stalenhoef AF (2012) The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol 8(6):352

    Article  CAS  PubMed  Google Scholar 

  • Brouwers MCGJ, van Greevenbroek MMJ, Stehouwer CDA, de Graaf J, Stalenhoef AFH (2012) The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol 8:352

    Article  CAS  PubMed  Google Scholar 

  • Brouwers MC, de Graaf J, Simons N, Meex S, ten Doeschate S, van Heertum S et al (2020) Incidence of type 2 diabetes in familial combined hyperlipidemia. BMJ Open Diabetes Res Care 8(1):e001107

    Article  PubMed  PubMed Central  Google Scholar 

  • Civeira F, Jarauta E, Cenarro A, García-Otín AL, Tejedor D, Zambón D et al (2008) Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting. J Am Coll Cardiol 52(19):1546–1553

    Article  CAS  PubMed  Google Scholar 

  • Dawson MI, Xia Z (2012) The retinoid X receptors and their ligands. Biochim Biophys Acta (BBA)-Mole Cell Biol Lipids 1821(1):21–56

    CAS  Google Scholar 

  • De Castro-Orós I, Civeira F, Pueyo MJ, Mateo-Gallego R, Bolado-Carrancio A, Lamíquiz-Moneo I et al (2016) Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia. J Clin Lipidol 10(4):790–797

    Article  PubMed  Google Scholar 

  • Demirkan A, van Duijn CM, Ugocsai P, Isaacs A, Pramstaller PP, Liebisch G et al (2012) Genome-wide association study identifies novel loci associated with circulating phospho-and sphingolipid concentrations. PLoS Genetics 8(2):e1002490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dennedy MC, Vidal-Puig A (2014) An adipocentric view of the metabolic syndrome and cardiovascular disease. Curr Cardiovasc Risk Rep 8(3):379

    Article  Google Scholar 

  • Di Taranto MD, Staiano A, D’Agostino MN, D’Angelo A, Bloise E, Morgante A et al (2015) Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population. Mol Cell Probes 29(1):19–24

    Article  PubMed  Google Scholar 

  • Domínguez-Reyes T, Astudillo-López CC, Salgado-Goytia L, Muñoz-Valle JF, Salgado-Bernabé AB, Guzmán-Guzmán IP et al (2015) Interaction of dietary fat intake with APOA2, APOA5 and LEPR polymorphisms and its relationship with obesity and dyslipidemia in young subjects. Lipids Health Dis 14(1):106

    Article  PubMed  PubMed Central  Google Scholar 

  • Ellis KL, Pang J, Chan DC, Hooper AJ, Bell DA, Burnett JR et al (2016) Familial combined hyperlipidemia and hyperlipoprotein(a) as phenotypic mimics of familial hypercholesterolemia: frequencies, associations and predictions. J Clin Lipidol 10(6):1329–37.e3

    Article  PubMed  Google Scholar 

  • Engelbrechtsen L, Hansen T, Mahendran Y, Pyl P, Andersson E, Jonsson A et al (2017) Homozygous carriers of the TCF7L2 rs7903146 T-allele show altered postprandial response in triglycerides and triglyceride-rich lipoproteins. Sci Rep 7:43128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farbstein D, Soloveichik YZ, Levy NS, Levy AP (2011) Genetics of redox systems and their relationship with cardiovascular disease. Curr Atheroscler Rep 13(3):215–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farhan SMK, Robinson JF, McIntyre AD, Marrosu MG, Ticca AF, Loddo S et al (2014) A novel LIPE nonsense mutation found using exome sequencing in siblings with late-onset familial partial lipodystrophy. Can J Cardiol 30(12):1649–1654

    Article  PubMed  Google Scholar 

  • Gaddi A, Cicero A, Odoo F (2007) Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. Vasc Health Risk Manag 3(6):877

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gallardo-Blanco HL, Villarreal-Perez JZ, Cerda-Flores RM, Figueroa A, Sanchez-Dominguez CN, Gutierrez-Valverde JM et al (2017) Genetic variants in KCNJ11, TCF7L2 and HNF4A are associated with type 2 diabetes, BMI and dyslipidemia in families of Northeastern Mexico: a pilot study. Exp Ther Med 13(2):523–529

    Article  CAS  PubMed  Google Scholar 

  • Garcia CK, Mues G, Liao Y, Hyatt T, Patil N, Cohen JC et al (2001) Sequence diversity in genes of lipid metabolism. Genome Res 11(6):1043–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gw Go, Srivastava R, Hernandez-Ono A, Gang G, Smith SB, Booth CJ et al (2014) The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell Metab 19(2):209–220

    Article  Google Scholar 

  • Horra A, Salazar J, Ferré R, Vallvé J-C, Guardiola M, Rosales R et al (2009) Prox-1 and FOXC2 gene expression in adipose tissue: a potential contributory role of the lymphatic system to familial combined hyperlipidaemia. Atherosclerosis 206(2):343–345

    Article  CAS  PubMed  Google Scholar 

  • Huertas-Vazquez A, Plaisier CL, Geng R, Haas BE, Lee J, Greevenbroek MM et al (2010) A nonsynonymous SNP within PCDH15 is associated with lipid traits in familial combined hyperlipidemia. Hum Genet 127(1):83

    Article  CAS  PubMed  Google Scholar 

  • Janssen MC, Van Engelen B, Kapusta L, Lammens M, Van Dijk M, Fischer J et al (2013) Symptomatic lipid storage in carriers for the PNPLA2 gene. Eur J Hum Genet 21(8):807

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Tian Y, Shan D, Wang Y, Gerhard E, Xia J et al (2018) pH protective Y1 receptor ligand functionalized antiphagocytosis BPLP-WPU micelles for enhanced tumor imaging and therapy with prolonged survival time. Biomaterials 170:70–81

    Article  CAS  PubMed  Google Scholar 

  • Johansen CT, Kathiresan S, Hegele RA (2011) Genetic determinants of plasma triglycerides. J Lipid Res 52(2):189–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE et al (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41(1):56

    Article  CAS  PubMed  Google Scholar 

  • Leduc V, Bourque L, Poirier J, Dufour R (2016) Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenet Genomics 26(1):1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JC, Weissglas-Volkov D, Kyttälä M, Dastani Z, Cantor RM, Sobel EM et al (2008) WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels. Am J Hum Genet 83(2):180–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z-K, Hu M, Baum L, Thomas GN, Tomlinson B (2010) Associations of polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster with familial combined hyperlipidaemia in Hong Kong Chinese. Atherosclerosis 208(2):427–432

    Article  CAS  PubMed  Google Scholar 

  • López-Ruiz A, Jarabo MM, Martínez-Triguero ML, Morales-Suárez-Varela M, Solá E, Bañuls C et al (2009) Small and dense LDL in familial combined hyperlipidemia and N291S polymorphism of the lipoprotein lipase gene. Lipids Health Dis 8(1):12

    Article  PubMed  PubMed Central  Google Scholar 

  • Luijten J, van Greevenbroek MM, Schaper NC, Meex SJ, van der Steen C, Meijer LJ et al (2019) Incidence of cardiovascular disease in familial combined hyperlipidemia: a 15-year follow-up study. Atherosclerosis 280:1–6

    Article  CAS  PubMed  Google Scholar 

  • Luo X, Yu C, Fu C, Shi W, Wang X, Zeng C et al (2015) Identification of the differentially expressed genes associated with familial combined hyperlipidemia using bioinformatics analysis. Mol Med Rep 11(6):4032–4038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mabuchi H, Nohara A, Inazu A (2014) Cholesteryl ester transfer protein (CETP) deficiency and CETP inhibitors. Mol Cells 37(11):777

    Article  PubMed  PubMed Central  Google Scholar 

  • Manolescu BN, Busu C, Badita D, Stanculescu R, Berteanu M (2015) Paraoxonase 1–an update of the antioxidant properties of high-density lipoproteins. Maedica 10(2):173

    PubMed  PubMed Central  Google Scholar 

  • Marcil M, Vu H, Cui W, Dastani Z, Engert JC, Gaudet D et al (2006) Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia. Arterioscler Thromb Vasc Biol 26(7):1619–1625

    Article  CAS  PubMed  Google Scholar 

  • Mar-Heyming R, Miyazaki M, Weissglas-Volkov D, Kolaitis NA, Sadaat N, Plaisier C et al (2008) Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 28(6):1193–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meex SJ, Weissglas-Volkov D, van der Kallen CJ, Thuerauf DJ, van Greevenbroek MM, Schalkwijk CG et al (2009) The ATF6-Met [67] Val substitution is associated with increased plasma cholesterol levels. Arterioscler Thromb Vasc Biol 29(9):1322–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minicocci I, Prisco C, Montali A, Di Costanzo A, Ceci F, Pigna G et al (2015) Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach. Atherosclerosis 242(2):618–624

    Article  CAS  PubMed  Google Scholar 

  • Mirdamadi HZ, Sztanek F, Derdak Z, Seres I, Harangi M, Paragh G (2008) The human paraoxonase-1 phenotype modifies the effect of statins on paraoxonase activity and lipid parameters. Br J Clin Pharmacol 66(3):366–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochemical Journal 441(3):789–802

    Article  CAS  Google Scholar 

  • Naukkarinen J, Ehnholm C, Peltonen L (2006) Genetics of familial combined hyperlipidemia. Curr Opin Lipidol 17(3):285–290

    Article  CAS  PubMed  Google Scholar 

  • Pajukanta P, Allayee H, Krass KL, Kuraishy A, Soro A, Lilja HE et al (2003) Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q. Am J Hum Genet 72(4):903–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M et al (2004) Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 36(4):371–376

    Article  CAS  PubMed  Google Scholar 

  • Paththinige C, Sirisena N, Dissanayake V (2017) Genetic determinants of inherited susceptibility to hypercholesterolemia–a comprehensive literature review. Lipids Health Dis 16(1):103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patni N, Ahmad Z, Wilson DP (2000) Genetics and dyslipidemia. MDText.com, Inc., South Dartmouth, MA

  • Perttilä J, Merikanto K, Naukkarinen J, Surakka I, Martin NW, Tanhuanpää K et al (2009) OSBPL10, a novel candidate gene for high triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid metabolism. J Mol Med 87(8):825–835

    Article  PubMed  PubMed Central  Google Scholar 

  • Plaisier CL, Horvath S, Huertas-Vazquez A, Cruz-Bautista I, Herrera MF, Tusie-Luna T et al (2009) A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. PLoS Genet 5(9):e1000642

    Article  PubMed  PubMed Central  Google Scholar 

  • Plaisier CL, Kyttälä M, Weissglas-Volkov D, Sinsheimer JS, Huertas-Vazquez A, Riba L et al (2009) Galanin preproprotein is associated with elevated plasma triglycerides. Arterioscler Thromb Vasc Biol 29(1):147–152

    Article  CAS  PubMed  Google Scholar 

  • Poursharifi P, Rezvani R, Gupta A, Lapointe M, Marceau P, Tchernof A et al (2014) Association of immune and metabolic receptors C5aR and C5L2 with adiposity in women. Med Inflamm 2014:1–10

    Article  Google Scholar 

  • Ramasamy I (2016) Update on the molecular biology of dyslipidemias. Clin Chim Acta 454:143–185

    Article  CAS  PubMed  Google Scholar 

  • Ribalta J, Figuera L, Fernández-Ballart J, Vilella E, Castro Cabezas M, Masana L et al (2002) Newly identified apolipoprotein AV gene predisposes to high plasma triglycerides in familial combined hyperlipidemia. Clin Chem 48(9):1597–1600

    Article  CAS  PubMed  Google Scholar 

  • Ripatti P, Rämö JT, Söderlund S, Surakka I, Matikainen N, Pirinen M et al (2016) The contribution of GWAS loci in familial dyslipidemias. PLoS Genet 12(5):e1006078

    Article  PubMed  PubMed Central  Google Scholar 

  • Roy C, Gupta A, Fisette A, Lapointe M, Poursharifi P, Richard D et al (2013) C5a receptor deficiency alters energy utilization and fat storage. PLoS ONE 8(5):e62531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saarela JS, Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J, Saarela J, Laakso M, Ehnholm C, Taskinen MR, Peltonen L (2004) Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 36:371–376

    Article  PubMed  Google Scholar 

  • Sáez ME, González-Pérez A, Martínez-Larrad MT, Gayán J, Real LM, Serrano-Ríos M et al (2010) WWOX gene is associated with HDL cholesterol and triglyceride levels. BMC Med Genet 11(1):148

    Article  PubMed  PubMed Central  Google Scholar 

  • Sathiyakumar V, Kapoor K, Jones SR, Banach M, Martin SS, Toth PP (2018) Novel therapeutic targets for managing dyslipidemia. Trends Pharmacol Sci 39(8):733–747

    Article  CAS  PubMed  Google Scholar 

  • Savel J, Lafitte M, Pucheu Y, Pradeau V, Tabarin A, Couffinhal T (2012) Very low levels of HDL cholesterol and atherosclerosis, a variable relationship–a review of LCAT deficiency. Vasc Health Risk Manag 8:357

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sentinelli F, Minicocci I, Montali A, Nanni L, Romeo S, Incani M et al (2013) Association of RXR-gamma gene variants with familial combined hyperlipidemia: genotype and haplotype analysis. J Lipids 2013:1–7

    Article  Google Scholar 

  • Smathers RL, Petersen DR (2011) The human fatty acid-binding protein family: evolutionary divergences and functions. Hum Genomics 5(3):170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solanas-Barca M, de Castro-Orós I, Mateo-Gallego R, Cofán M, Plana N, Puzo J et al (2012) Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. Atherosclerosis 222(2):449–455

    Article  CAS  PubMed  Google Scholar 

  • Tabassum R, Mahajan A, Chauhan G, Dwivedi OP, Dubey H, Sharma V et al (2011) No association of TNFRSF1B variants with type 2 diabetes in Indians of Indo-European origin. BMC Med Genet 12(1):110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taghizadeh E, Esfehani RJ, Sahebkar A, Parizadeh SM, Rostami D, Mirinezhad M et al (2019) Familial combined hyperlipidemia: an overview of the underlying molecular mechanisms and therapeutic strategies. IUBMB Life 71(9):1221–1229

    Article  CAS  PubMed  Google Scholar 

  • Taghizadeh E, Mardani R, Rostami D, Taghizadeh H, Bazireh H, Hayat SMG (2019) Molecular mechanisms, prevalence, and molecular methods for familial combined hyperlipidemia disease: a review. J Cell Biochem 120(6):8891–8898

    Article  CAS  PubMed  Google Scholar 

  • Taghizadeh E, Ghayour-Mobarhan M, Ferns GA, Pasdar A (2020) A novel variant in LPL gene is associated with familial combined hyperlipidemia. BioFactors 46(1):94–99

    Article  CAS  PubMed  Google Scholar 

  • Talmud PJ, Futema M, Humphries SE (2014) The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes. Curr Opin Lipidol 25(4):274–281

    Article  CAS  PubMed  Google Scholar 

  • Weissglas-Volkov D, Plaisier CL, Huertas-Vazquez A, Cruz-Bautista I, Riano-Barros D, Herrera-Hernandez M et al (2010) Identification of two common variants contributing to serum apolipoprotein B levels in Mexicans. Arterioscler Thromb Vasc Biol 30(2):353–359

    Article  CAS  PubMed  Google Scholar 

  • Wiesbauer F, Blessberger H, Azar D, Goliasch G, Wagner O, Gerhold L et al (2009) Familial-combined hyperlipidaemia in very young myocardial infarction survivors (≤ 40 years of age). Eur Heart J 30(9):1073–1079

    Article  PubMed  Google Scholar 

  • Wijsman EM, Rothstein JH, Igo RP, Brunzell JD, Motulsky AG, Jarvik GP (2010) Linkage and association analyses identify a candidate region for apoB level on chromosome 4q32.3 in FCHL families. Hum Genet 127(6):705–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Manichaikul A, Hu Y, Chen Y-DI, Liang S, Steffen LM et al (2017) Meta-analysis of genome-wide association studies identifies three novel loci for saturated fatty acids in East Asians. Eur J Nutr 56(4):1477–84

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all colleagues in the Department of Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences. I deeply appreciate and thank Darioush Rostami for assistance in this research.

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This research received no specific Grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Eskandar Taghizadeh

  2. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

    Eskandar Taghizadeh & Hassan Taghizadeh

  3. Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran

    Najmeh Farahani

  4. Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran

    Rajab Mardani

  5. Shahrekord Branch, Islamic Azad University, Shahrekord, Iran

    Forough Taheri

  6. Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, P.O. Box: 91735-951, Yazd, Iran

    Seyed Mohammad Gheibihayat

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  1. Eskandar Taghizadeh
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Taghizadeh, E., Farahani, N., Mardani, R. et al. Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update. Biochem Genet 60, 453–481 (2022). https://doi.org/10.1007/s10528-021-10130-2

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