Circulation: Cardiovascular Genetics最新文献

Background: Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization.

Methods and results: Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; P=3.5×10^-11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ≈7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in APOC3 (rs147210663) and 3 established functional SNPs in APOA5. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (β=-0.92±0.059 SD unit; P=9.6×10^-55 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 APOA5 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null.

Conclusions: APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.

Background: Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach.

Methods and results: Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance.

Conclusions: Although congenital heart disease is reported in families with mutations in FLNA, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family.

Background: Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes.

Methods and results: We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). FLNC encodes filamin C-a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls.

Conclusion: We have identified a novel variant in FLNC as pathogenic variant for familial RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.

Background: The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality.

Methods: On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives.

Conclusions: We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.

Background: Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP.

Methods and results: We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide-associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (NPPA-NPPB and POC1B-GALNT4) and 1 novel locus (PPP3CC) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The NPPA-NPPB locus containing the adjacent genes encoding ANP and BNP harbored 4 independent cis variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene PPP3CC and the polypeptide N-acetylgalactosaminyltransferase 4 gene GALNT4 associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (P=8.2×10^-4).

Conclusions: Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure-lowering effect of ANP in the general population.