BackgroundGenome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.ResultsHere, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.ConclusionsOur approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1457-6) contains supplementary material, which is available to authorized users.

The embryonic extracellular matrix (ECM) undergoes transition to mature ECM as development progresses, yet few mechanisms ensuring ECM proteostasis during this period are known. Fibrillin microfibrils are macromolecular ECM complexes serving structural and regulatory roles. In mice, Fbn1 and Fbn2, encoding the major microfibrillar components, are strongly expressed during embryogenesis, but fibrillin-1 is the major component observed in adult tissue microfibrils. Here, analysis of Adamts6 and Adamts10 mutant mouse embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics discovery of ADAMTS6-cleaved sites, identifies a proteostatic mechanism contributing to postnatal fibrillin-2 reduction and fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development defined by a drastic reduction of aggrecan and cartilage link protein, impaired BMP signaling in cartilage, and increased GDF5 sequestration in fibrillin-2-rich tissue. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of the defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.

Objective: ATP binding cassette transporter A1 (ABCA1) controls the reverse cholesterol transport. Some ABCA1 variants are correlated with serum high-density lipoprotein cholesterol (HDL-C) and other lipid concentrations. We aimed to explore the relationship of ABCA1 gene with both the lipid profile and coronary heart disease (CHD) risk. Methods: Selected 627 individuals of the Turkish Adult Risk Factor Study were genotyped for ABCA1 R219K polymorphism using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method. Student's t-test, one-way ANOVA, Chi-square test, linear and logistic regression was used for statistical analysis. Results: We demonstrated a gender-specific effect of the R219K polymorphism on plasma lipids and CHD. In men, while homozygosity of the K allele was associated with increased plasma low-density lipoprotein cholesterol (LDL-C) (p<0.05) and total cholesterol concentrations (p<0.05), carriage of this allele was associated with higher HDL-C concentrations (p<0.05) after adjustment for associated risk factors, but not with CHD. In women, however, without being related to HDL-C levels, each 219K allele was associated with 10% higher triglycerides (TG) concentrations (p<0.05). R219K heterozygosity in women independently doubled (95% CI 1.00; 3.80) the odds ratio for CHD risk in regression models, after adjustment for several variables. Interaction of TG elevation (>140 mg/dL) with CHD was demonstrated in female 219RK genotype carriers. Conclusion: R219 allele of the ABCA1 gene independently confers CHD risk in heterozygote Turkish women, not via reduced HDL-C, but interacting with elevated TG expressed by the 219K allele, but not in men. (Anadolu Kardiyol Derg 2014; 14: 18-25)

The eNOS4a/b gene polymorphism may be associated with early development of atherosclerosis and myocardial infarction possibly secondary to deterioration of the endothelial function.

Hipertrofik kardiyomiyopatide BOP geni varyasyonları 303ÖZET Amaç: Bop mutant farelerde, az gelişmiş sağ ventrikül ve aşırı büyümüş sol ventrikül varlığı, insan BOP geni ile hipertrofik kardiyomiyopati (HKMP) arasında olası bir ilişkiyi düşündürmektedir. Bu çalışmamızda, BOP genindeki varyasyonlar ile HKMP için noninvazif bir aritmik risk göstergesi olan QT dispersiyonu arasındaki olası ilişkiyi araştırdık. Yöntemler: Enine-kesitli niteliğindeki çalışmaya 50 HKMP'li hasta ve 60 sağlıklı kontrol alındı. BOP geni ekson bölgeleri, polimeraz zincir reaksiyonu (PCR) ile çoğaltıldı ve çoğaltılan ekson bölgeleri, Tek İplikli Konformasyon Polimorfizm (SSCP) analizi ile incelendi. Farklı bantlara sahip örnekler otomatik dizileme yöntemi kullanılarak dizilendi. Sürekli değişkenler eşleştirilmemiş bağımsız örneklem t-testi ya da Mann-Whitney U testi ile karşı-laştırıldı. Genotip-hastalık ilişkisi Ki-kare testi ile test edildi. Bulgular: Ekson 2 ve 7'deki G275>A ve C965>A tek nükleotid değişimleri (TND) sadece HK grubunda belirlendi. Ekson 6 ve 9'daki G707>C, C710>T, T761>C, T1217>C TND'lerine kontrol grubunda da rastlandı. İki grup arasındaki fark ise anlamlı bulundu (p=0.002 ve p<0.001). Ekzon 6'daki TND'lerin haplotip oluşturduğu ve bu haplotipin nadir alleli (707C/710T/761C) için homozigot taşıyıcı olan HK hastalarında QT dispersiyonu ve düzeltilmiş QT dispersiyonu, diğer genotiplere göre anlamlı derecede düşük bulundu (p=0.032 ve p=0.030). Sonuç: Bu çalışma, insanda BOP geni ile HKMP arasındaki ilişkiyi araştıran ilk çalışmadır. Üç farklı TND'yi içeren 707C/710T/761C haplotip takımını taşıyan HK'li olgularda QT dispersiyonu ve düzeltilmiş QT dispersiyonunun anlamlı derecede uzamış bulunması, BOP genindeki bu haplotipin ventikü-ler aritmilerle ve dolayısı ile ani ölümle ilişkili olabileceğini akla getirmektedir. (Anadolu Kardiyol Derg 2010; 10: 303-9) Anah tar ke li me ler: BOP, hipertrofik kardiyomiyopati, klinik farklılık, modifiye edici gen, genetik varyasyon, QT dispersiyonu ABSTRACT Objective: The observation that Bop null allele mice show underdeveloped right ventricle and excessive development of left ventricle, suggests the possible relationship between human BOP gene and hypertrophic cardiomyopathy (HCMP). In our study, we investigated this possible relationship between BOP gene variations and QT dispersion, a noninvasive arrhythmic risk marker for HCMP. Methods: This cross-sectional study consisted of 50 patients clinically diagnosed with HCMP and 60 healthy subjects. Exonic regions of BOP gene were amplified by polymerase chain reaction and amplified exonic regions were analyzed by Single-Strand Conformation Polymorphisms (SSCP). The samples with different migration patterns were sequenced through an automated sequencing system. Continuous variables were compared by unpaired t-test for independent samples or Mann-Whitney U test. Genotype-disease relationship was tested by Chi-square test. Results: The nucleotide substitutions G275>A and C965>A in exon 2 and 7 were determined only in HCMP group. The G707>C, C7...

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Our results showed that SET is significantly overexpressed in pediatric acute lymphoblastic leukemia samples, and an increased level of SET might contribute to leukemic process.

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