Correction: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

This corrects the article DOI: 10.1371/journal.pone.017299

Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage

Genetische Analyse kardiovaskulärer Erkrankungen

In dieser Arbeit wurde die Genetik von kardiovaskulären Krankheiten untersucht. Dafür wurden Familien mit gehäuft auftretenden Krankheitsfällen von koronarer Herzerkrankung/Herzinfarkt, dilatativer Kardiomyopathie oder hypertrophischer Kardiomyopathie rekrutiert. Die Exom-Sequenzierung von betroffenen Familien-mitgliedern sollte zur Identifizierung der genetischen Ursache in den Familien führen. Seltene Varianten, die von Familienmitgliedern geteilt wurden, wird ein starker Effekt zugeschrieben und daher als möglich kausal betrachtet. Bei der HI-Großfamilie wurden vier mögliche Varianten identifiziert, von denen zwei nach Betrachtung der Kausalität als plausibel angesehen wurden. Es handelte sich um Varianten in den Genen GUCY1A3, das für die α-Untereinheit der löslichen Guanylatzyklase kodiert, und CCT7, das für ein Chaperon des Chaperonin-enthaltenden-TCP1-Komplexes kodiert. Durch die Identifizierung kausaler Varianten in den Genen wurde der NO-sGC-cGMP Signalweg als neu für die Entstehung von KHK/HI vorgeschlagen. Die Exom-Sequenzierung von Mitgliedern einer DCM-Familie führte zur Identifizierung einer neuen Variante im Titin-Gen, die in der Einführung eines Stoppkodons resultierte. Aufgrund schwacher Penetranz dieser Variante in der Familie wird aber vermutet, dass eine zweite Variante (modifier) zur Entstehung der DCM in dieser Familie beiträgt. Die Variante im Gen KCNJ12, das für einen Kaliumkanal kodiert, wird dabei aufgrund der biologischen Plausibilität besonders ins Auge gefasst. Bei der untersuchten HCM-Familie wurden ebenso potentiell kausale Varianten identifiziert, wobei hier eine Variante im Gen RYR3, das für einen Ryanodin-Rezeptor kodiert, aufgrund der biologischen Plausibilität priorisiert wird. Die Exom-Sequenzierung in zwei weiteren DCM-Familien führte bislang nicht zur Identifizierung kausaler Varianten. Dieses Ergebnis spiegelt die Komplexität und die Limitationen der Methode wider. Die Exom-Sequenzierung wurde bisher erfolgreich als Methode genutzt, um kausale Varianten in monogenen Erkrankungen zu identifizieren. Diese Arbeit zeigt, dass die Exom-Sequenzierung auch in komplexen Erkrankungen zur Identifizierung kausaler Varianten führen kann

Clin Genet

Dilated cardiomyopathy (DCM) is a heart disease characterized by left ventricular dilatation and systolic dysfunction. In 30% of cases, pathogenic variants, essentially private to each patient, are identified in at least one of almost 50 reported genes. Thus, while costly, exons capture-based Next Generation Sequencing (NGS) of a targeted gene panel appears as the best strategy to genetically diagnose DCM. Here, we report a NGS strategy applied to pools of 8 DNAs from DCM patients and validate its robustness for rare variants detection at 4-fold reduced cost. Our pipeline uses Freebayes to detect variants with the expected 1/16 allele frequency. From the whole set of detected rare variants in 96 pools we set the variants quality parameters optimizing true positives calling. When compared to simplex DNA sequencing in a shared subset of 50 DNAs, 96% of SNVs/InsDel were accurately identified in pools. Extended to the 384 DNAs included in the study, we detected 100 variants (ACMG class 4 and 5), mostly in well-known morbid gene causing DCM such as TTN, MYH7, FLNC, and TNNT2. To conclude, we report an original pool-sequencing NGS method accurately detecting rare variants. This innovative approach is cost-effective for genetic diagnostic in rare diseases

Contribution of rare and common genetic variants to plasma lipid levels and carotid stiffness and geometry – a substudy of the Paris Prospective Study 3 Short title: Genetic variants and carotid stiffness

International audienceBackground: We assess the contribution of common and rare putatively functional genetic variants (most of them coding) present on the Illumina exome Beadchip to the variability of plasma lipids and stiffness of the common carotid artery. Methods and results: Measurements were obtained from 2283 men and 1398 women, and after filtering and exclusion of monomorphic variants, 32827 common (minor allele frequency >0.01) and 68770 rare variants were analyzed. A large fraction of the heritability of plasma lipids is attributable to variants present on the array, especially for Triglycerides (fraction of variance attributable to measured genotypes: V(G)/Vp=31.4%, P<3.1×10-11) and HDLc (V(G)/Vp=26.4%, P<4.2×10-12). Plasma lipids were associated with common variants located in known candidate genes but no implication of rare variants could be established, however this study had limited power to detect an effect of rare variants at the gene level. Gene-sets for plasma lipids, blood pressure and coronary artery disease were defined on the basis of recent meta-analyses of genome wide association studies (GWAS). We observed a strong association between the plasma lipids gene-set and plasma lipid variables but none of the 3 GWAS gene-sets was associated with the carotid parameters. Significant V(G)/Vp ratios were observed for external (14.5%, P<2.7×10-5) and internal diameter (13.4%, P<4.3×10-4), stiffness (12.5%, P< 8.0×10-4), intima-media thickness (10.6%, P<7.9×10-4) and wall cross sectional area (13.2%, P<2.4×10-5). A significant association was observed between the common rs2903692 polymorphism of the CLEC16A gene and the internal diameter (P<4.3×10-7). Conclusion: These results suggest an involvement of CLEC16A, a gene that has been reported to be associated with immune disorders, in the modulation of carotid vasodilatation

Involvement of BAG3 and HSPB7 loci in various etiologies of systolic heart failure: Results of a European collaboration assembling more than 2000 patients

International audienceHeart failure (HF), a major public health burden affecting 2% of industrialized populations, is a syndrome resulting from structural or functional myocardial impairment leading to inadequate cardiac output to meet the body's metabolic demands [1]. Half of HF patients present systolic dysfunction (systolic-HF), also called reduced ejection fraction (HF-REF), a disease related to various causes including idiopathic Dilated Cardiomyopathy (DCM) and Coronary Artery Diseases (CAD) (ischemic-HF). HF is usually a multifactorial disease but the genetic variants contributing to its susceptibility or its severity may be different according to its underlying causes [2] and their identification is only beginning.[...

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Aims: Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results: 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion: We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology