Genes Potentially Associated with Familial Hypercholesterolemia

Михайлова, С. В.; Ivanoshchuk, D.; Тимощенко, О. В.; Shakhtshneider, E.

doi:10.3390/biom9120807

Cited by 18 publications

(19 citation statements)

References 131 publications

(183 reference statements)

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“…Typically, novel, rare FH-associated variants have been discovered through pedigree studies. This was the case for the identification of CYP27A1 (cytochrome P450, subfamily XXVIIA, polypeptide 1), LIPA (lysosomal lipase A), LIPC (hepatic lipase), LIPG (endothelial lipase), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), PNPLA5 (patatin-like phospholipase domain containing 5) and some other gene variants responsible for the FH phenotype in particular families ( Lange et al, 2014 ; Al-Allaf et al, 2015 ; Pirillo et al, 2017 ; Corral et al, 2018 ; Mikhailova et al, 2019 ; Table 3 ).…”

Section: Familial Hypercholesterolemiamentioning

confidence: 99%

Genetics of Familial Hypercholesterolemia: New Insights

et al. 2020

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Familial hypercholesterolemia (FH) is one of the most common monogenic diseases, leading to an increased risk of premature atherosclerosis and its cardiovascular complications due to its effect on plasma cholesterol levels. Variants of three genes ( LDL-R , APOB and PCSK9 ) are the major causes of FH, but in some probands, the FH phenotype is associated with variants of other genes. Alternatively, the typical clinical picture of FH can result from the accumulation of common cholesterol-increasing alleles (polygenic FH). Although the Czech Republic is one of the most successful countries with respect to FH detection, approximately 80% of FH patients remain undiagnosed. The opportunities for international collaboration and experience sharing within international programs (e.g., EAS FHSC, ScreenPro FH, etc.) will improve the detection of FH patients in the future and enable even more accessible and accurate genetic diagnostics.

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Section: Familial Hypercholesterolemiamentioning

confidence: 99%

Genetics of Familial Hypercholesterolemia: New Insights

et al. 2020

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Section: Introductionmentioning

confidence: 99%

“…STAP1 (MIM#604298), also called B-cell antigen receptor downstream signaling 1 protein (BRDG1) or stem cell adaptor protein 1, was first discovered in immune cells with the highest expression documented in appendix, lymph nodes, and spleen [ 7 ]. The gene encoding STAP1 protein is located on chromosomal region 4q13.2 with 10 exons in the protein coding region [ 7 ]. Its relationship to lipid homeostasis was first suggested in 2007 in a clinical study finding a correlation between increased levels of circulatory triglycerides and STAP1 gene expression in leukocytes [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Mice lacking global Stap1 expression do not manifest hypercholesterolemia

et al. 2020

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Background Autosomal dominant familial hypercholesterolemia (ADH; MIM#143890) is one of the most common monogenic disorders characterized by elevated circulatory LDL cholesterol. Initial studies in humans with ADH identified a potential relationship with variants of the gene encoding signal transducing adaptor family member protein 1 (STAP1; MIM#604298). However, subsequent studies have been contradictory. In this study, mice lacking global Stap1 expression (Stap1−/−) were characterized under standard chow and a 42% kcal western diet (WD). Methods Mice were studied for changes in different metabolic parameters before and after a 16-week WD regime. Growth curves, body fats, circulatory lipids, parameters of glucose homeostasis, and liver architecture were studied for comparisons. Results Surprisingly, Stap1−/− mice fed the 16-week WD demonstrated no marked differences in any of the metabolic parameters compared to Stap1+/+ mice. Furthermore, hepatic architecture and cholesterol content in FPLC-isolated lipoprotein fractions also remained comparable to wild-type mice. Conclusion These results strongly suggest that STAP1 does not alter lipid levels, that a western diet did not exacerbate a lipid disorder in Stap1 deficient mice and support the contention that it is not causative for hyperlipidemia in ADH patients. These results support other published studies also questioning the role of this locus in human hypercholesterolemia.

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“…Long life elevated low density lipoprotein cholesterol (LDL-C) concentrations translate into advanced cardiovascular disease (CVD) [3][4][5]. Clinical criteria are useful for diagnosing FH and selecting patients for genetic testing of three genes coding for proteins that are involved in the clearance of LDL-C from blood: LDL-receptor (LDLR), apolipoprotein B (APOB), and pro-protein convertase subtilisin kexin 9 (PCSK9) [2,[6][7][8]. Nevertheless, the mutations in those three genes can only be detected in ∼40% of patients with a clinical diagnosis of FH [4].…”

Section: Introductionmentioning

confidence: 99%

Higher responsiveness to rosuvastatin in polygenic versus monogenic hypercholesterolaemia: a propensity score analysis

Mickiewicz

Futema

Ćwiklińska

et al. 2020

European Heart Journal

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Background The underlying monogenic defect in familial hypercholesterolemia (FH) can be detected in ∼40% of cases. The majority of mutation-negative patients have a polygenic cause of high LDL-cholesterol (LDL-C) due to having inherited a greater than average number of common LDL-C raising single nucleotide polymorphisms (SNPs). Purpose We sought to investigate, whether the monogenic or polygenic defect in FH is associated with the response to rosuvastatin. Methods Individuals with a clinical diagnosis of FH were tested for mutations in LDLR and APOB genes. A previously established LDL-C-specific polygenic risk score (PRS) was used to examine the possibility of polygenic hypercholesterolemia in mutation negative patients. The propensity score analysis was performed to evaluate the variables associated with the response to rosuvastatin. The type of hypercholesterolemia (polygenic or monogenic) and following variables: age, gender, LDL-baseline, statin intolerance, ezetimibe use, rosuvastatin dose, diabetes and cardiovascular disease (CVD), were examined to minimize the bias of this observational study. Results LDLR/APOB mutation was found in 47 (42%) patients, whereas polygenic hypercholesterolemia was diagnosed in 65 (58%) of patients. Mean age was comparable in both groups (54±13 vs 51±13, p=0.134). CVD was diagnosed in ≈26% of individuals in both cohorts (p=0.343). There was no difference in the distribution of CV risk factors, such as arterial hypertension, smoking, diabetes, body mass index and in rate of statin intolerance. Monogenic subjects had higher baseline LDL-C compared to polygenic (Table 1). Adjusted model showed a lower percentage of change in LDL-C after rosuvastatin treatment in monogenic vs. polygenic subjects (46% vs 55%, p<0.001) (Figure 1). The probability of achieving LDL-C targets in monogenic FH was lower than in polygenic subjects (0.075 vs. 0.245, p=0.004). Polygenic patients were more likely to achieve LDL-C goals, compared to mutation-positive patients (OR 3.28; 95% CI:1.23–8.72). Conclusion Our findings indicate an essentially higher responsiveness to rosuvastatin in patients with a polygenic cause, as compared to those carrying monogenic mutations. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): 1. Polish Ministry of Science and Higher Education European Regional Development Fund under the Programme Innovative Economy 2007–2013 (POIG.01.01.02-22-079/09). 2. British Heart Foundation (PG 08/008). 3. The National Institute for Health Research, University College London Hospitals, Biomedical Research Centre. 4. The Foundation Leducq Transatlantic Networks of Excellence Program grant (no. 14 CVD03)

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Genes Potentially Associated with Familial Hypercholesterolemia

Cited by 18 publications

References 131 publications

Genetics of Familial Hypercholesterolemia: New Insights

Genetics of Familial Hypercholesterolemia: New Insights

Mice lacking global Stap1 expression do not manifest hypercholesterolemia

Higher responsiveness to rosuvastatin in polygenic versus monogenic hypercholesterolaemia: a propensity score analysis

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