Abstract
BackgroundFamilial 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. Materials and methods161 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. ResultsWe 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. ConclusionsThese 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.
Highlights
Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a frequency of 1 in 200 to 500 in European populations [1]
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 apolipoprotein B gene (APOB), and overall the detection rate was 43.4%
Mutations in the LDLR gene were identified in 57 patients and accounted for the majority (81.4%) of all the mutations found in this cohort
Summary
Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a frequency of 1 in 200 to 500 in European populations [1]. It is characterized by a raised concentration of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease [2]. An FH-causing mutation can be found in 60–80% of patients with a clinical diagnosis of definite FH and 20–30% of those with possible FH [4]. The aim of this study is to assess the spectrum of FH-causing mutations in the Malopolska population in east-southern Poland. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. We analyzed the genetic spectrum of the disease in the understudied Polish population
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