title: The genetic spectrum of familial hypercholesterolemia in south-eastern Poland.
abstract: BACKGROUND
  Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population.
  
  
  METHODS
  161 unrelated subjects with a clinical diagnosis of FH from the south-eastern region of Poland were recruited. High resolution melt and direct sequencing of PCR products were used to screen 18 exons of LDLR, a region of exon 26 in the APOB gene and exon 7 of PCSK9. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions and insertions in LDLR. Genotypes of six LDL-C raising SNPs were used for a polygenic gene score calculation.
  
  
  RESULTS
  We found 39 different pathogenic mutations in the LDLR gene with 10 of them being novel. 13 (8%) individuals carried the p.Arg3527Gln mutation in APOB, and overall the detection rate was 43.4%. Of the patients where no mutation could be found, 53 (84.1%) had a gene score in the top three quartiles of the healthy comparison group suggesting that they have a polygenic cause for their high cholesterol.
  
  
  CONCLUSIONS
  These results confirm the genetic heterogeneity of FH in Poland, which should be considered when designing a diagnostic strategy in the country. As in the UK, in the majority of patients where no mutation can be found, there is likely to be a polygenic cause of their high cholesterol level.
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Sharifi
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical School, Kraków, Poland; Department of Medical Didactics, Jagiellonian University Medical School, Kraków, Poland. Electronic address: m.walus-miarka@uj.edu.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Walus-Miarka
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical School, Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Idzior-Waluś
authors.affiliation: Department of Metabolic Diseases, Jagiellonian University Medical School, Kraków, Poland.
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Malecki
authors.affiliation: 2nd Department of Internal Medicine, Institute of Molecular Biology and Clinical Genetics, Jagiellonian University Medical School, Kraków, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Sanak
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Whittall
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Ka Wah
authors.initials: KW
authors.lastname: Li
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK. Electronic address: steve.humphries@ucl.ac.uk.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000453:epidemiology / Q000235:genetics*; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011044:Poland / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Familial hypercholesterolemia; LDL-C gene score; LDLR mutation