Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

Brænne, Ingrid; Kleinecke, Mariana; Reiz, Benedikt; Graf, Elisabeth; Strom, Tim M.; Wieland, Thomas; Fischer, Marcus; Kessler, Thorsten; Hengstenberg, Christian; Meitinger, Thomas; Erdmann, Jeanette; Schunkert, Heribert

doi:10.1038/ejhg.2015.100

Cited by 74 publications

(48 citation statements)

References 60 publications

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“…Recently APOE , which encodes apolipoprotein E that directs removal of chylomicron and very low-density lipoprotein remnants from the circulation, has been implicated in the pathogenesis of FH. 11–13 Using family-based linkage analysis and whole exome sequencing, Fouchier et al 14 and Braenne et al 15 identified 5 variants in STAP1 , which has been proposed as the fourth gene causing FH. Affected individuals had a relatively mild FH phenotype.…”

Section: Pathogenesis and Geneticsmentioning

confidence: 99%

My Approach to the Patient With Familial Hypercholesterolemia

Safarova

Kullo

2016

Mayo Clinic Proceedings

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Familial hypercholesterolemia (FH), a relatively common Mendelian genetic disorder, is associated with a dramatically increased lifetime risk of premature atherosclerotic cardiovascular disease due to elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The diagnosis of FH is based on clinical presentation or genetic testing. Early identification of patients with FH is of great public health importance because preventive strategies can lower the absolute lifetime cardiovascular risk and screening can detect affected relatives. However, low awareness, detection, and control of FH pose hurdles in the prevention of FH-related cardiovascular events. Of the estimated 0.65 million to 1 million patients with FH in the United States, less than 10% carry a diagnosis of FH. Based on registry data, a substantial proportion of patients with FH are receiving no or inadequate lipid-lowering therapy. Statins remain the mainstay of treatment for patients with FH. Lipoprotein apheresis and newly approved lipid-lowering drugs are valuable adjuncts to statin therapy, particularly when the LDL-C–lowering response is suboptimal. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 provide an additional approximately 60% lowering of LDL-C levels and are approved for use in patients with FH. For homozygous FH, 2 new drugs that work independent of the LDL receptor pathway are available: an apolipoprotein B antisense oligonucleotide (mipomersen) and a microsomal triglyceride transfer protein inhibitor (lomitapide). This review attempts to critically examine the available data to provide a summary of the current evidence for managing patients with FH, including screening, diagnosis, treatment, and surveillance.

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Section: Pathogenesis and Geneticsmentioning

confidence: 99%

My Approach to the Patient With Familial Hypercholesterolemia

Safarova

Kullo

2016

Mayo Clinic Proceedings

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“…One of these is the GUCY1A3 locus 3 . Interestingly, only a few CAD risk loci, like those harboring LDLR and PCSK9 6–9 , contain mutations which were also found to co-segregate with CAD in a Mendelian pattern of inheritance. We have recently observed such allelic series at the GUCY1A3 CAD risk locus, for which a heterozygous loss-of-function allele was identified by linkage and a common variant by GWAS analysis to affect CAD risk, respectively 3,10 .…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus

et al. 2017

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Background A chromosomal locus at 4q32.1 has been genome-wide significantly associated with coronary artery disease risk. The locus encompasses GUCY1A3, which encodes the α1-subunit of the soluble guanylyl cyclase (sGC), a key enzyme in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway. The mechanism linking common variants in this region with coronary risk is not known. Methods Gene and protein expression were analyzed using quantitative polymerase chain reaction (qPCR) and immunoblotting, respectively. Putative allele-specific transcription factors were identified using in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed using reporter gene assays. To assess the effect of ZEB1, siRNA-mediated knockdown as well as overexpression experiments were performed. Association of GUCY1A3 genotype and cellular phenotypes were analyzed using vascular smooth muscle cell (VSMC) migration assays and platelet aggregation analyses. Results Whole blood GUCY1A3 mRNA levels were significantly lower in individuals homozygous for the lead (rs7692387) risk variant. Likewise, reporter gene assays demonstrated significantly lower GUCY1A3 promoter activity for constructs carrying this allele. In silico analyses located a DNase I hypersensitivity site to rs7692387 and predicted binding of the transcription factor ZEB1 rather to the non-risk allele, which was confirmed experimentally. Knockdown of ZEB1 resulted in more profound reduction of non-risk allele promoter activity, as well as a significant reduction of endogenous GUCY1A3 expression. Ex vivo studied platelets from homozygous non-risk allele carriers displayed enhanced inhibition of adenosine diphosphate-induced platelet aggregation by the NO donor sodium nitroprusside and the phosphodiesterase 5 inhibitor sildenafil as compared to homozygous risk allele carriers. Moreover, pharmacologic stimulation of sGC led to reduced migration only in VSMC homozygous for the non-risk allele. In the Hybrid Mouse Diversity Panel higher levels of GUCY1A3 expression correlated with less atherosclerosis in the aorta. Conclusions Rs7692387 is located in an intronic site that modulates GUCY1A3 promoter activity. The transcription factor ZEB1 binds preferentially to the non-risk allele leading to an increase in GUCY1A3 expression, higher sGC levels, and higher sGC activity after stimulation. Finally, human and mouse data link augmented sGC expression to lower risk of atherosclerosis.

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“…In the 2KJPN reference panel, we identified two reported pathogenic missense variants (Table 3). One of the variants, p.Arg3527Gln, is a well-characterized pathogenic missense variant [67] in APOB, and was identified in only one heterozygous individual among the 2049 individuals (allele frequency = 0.0002). Another missense variant, p. Ile3768Thr [68], was registered as DM in HGMD, and was identified in 2KJPN in a heterozygous individual.…”

Section: Apobmentioning

confidence: 99%

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

et al. 2017

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

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Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

Cited by 74 publications

References 60 publications

My Approach to the Patient With Familial Hypercholesterolemia

My Approach to the Patient With Familial Hypercholesterolemia

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

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