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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. Materials and 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. [ABSTRACT FROM AUTHOR]

Abstract: Heterozygous familial hypercholesterolemia (HFH) affects on average 1 in 500 individuals in European countries, and it is estimated that HeFH in Poland may affect more than 80,000 people. Cardiovascular mortality in individuals with FH between 20 and 39 years of age is 100 times higher than in the general population. HFH is a relatively common lipid disorder, but usually still remaining undiagnosed and untreated. A very high risk of cardiovascular diseases and a shortened lifespan in patients with this condition require early diagnosis and intensive treatment. The aim of the position paper was to present the importance and scale of this problem in Poland, which has not been raised enough so far, as well as the recommendations of diagnosis, treatment and prevention methods. [Copyright &y& Elsevier]