A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study.

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

A novel mutation of sgk-1 gene in central serous chorioretinopathy.

AIM: To investigate the association of serum glucocorticoid kinase gene-1 (SGK-1) DNA variants with chronic central serous chorioretinopathy (CSC). METHODS: We enrolled 32 eyes of 32 patients who were diagnosed with chronic CSC and composed 32 normal eyes as a control group. Peripheral blood was used for DNA extraction and polymerase chain reaction (PCR) amplification. SGK1 gene was sequenced by using BigDye(®) Terminator v3.1 cycle sequencing KIT (Applied Biosystems, Foster City, CA, USA). The SGK1 gene and its variants were investigated in CSC patient group and control group. RESULTS: We identified a new polymorphism M32V in two person in the patient group (Minor allele frequency (MAF)=0.009) on the region of 1-60 amino acids. The rs1057293 was located in the encoder region of the SGK 1 gene but not associated with CSC (P=0.68). An intrinsic rs1743966 is also not associated (P=0.28). CONCLUSIONS: The new polymorphism M32V is located on the region of 1-60 amino acids which is necessary for localization to the mitochondria in CSC patient. This mutation is probably important for the energy metabolism and plays an important role in the cellular response to hyperosmotic stress and other stress stimuli. Both rs1057293 and rs1743966 are not associated with CSC.

Investigation of the serum glucocorticoid kinase 1 gene in patients with transient tachypnea of the newborn.

OBJECTIVE: The aim of this study was to investigate whether there is a role of the serum glucocorticoid kinase (SGK) 1 gene, which has an effect on the control of the epithelial sodium channels. MATERIALS AND METHOD: This study included patients who were diagnosed with transient tachypnea of the newborn (TTN) with more than 37 weeks of gestation. As the control group, healthy newborns of the same gestational age were included. From each group, within the first 5 d of their lives, 2 cc of whole blood was taken in EDTA tubes, and stored at -80 °C. The DNA extraction was performed. RESULTS: There were 32 patients in the TTN, and also 32 patients in the control group. The heterozygous allele rs1057293 (3/28) and rs1743966 (8/28) were located in the encoder region of the SGK 1 gene. In addition, in encoding region of the SGK 1 gene, the Arg97Ile (1/28), which causes the amino acid changes, had a genotype frequency of 0.0357, and a mutation was identified in Arg97Ile. DISCUSSION: We have defined polymorphisms rs1057293 and rs1743966 in the SGK 1 gene, and the Arg97Ile mutation, for the first time in patients with TTN. This pilot study gave us some clues about a genetic basis of TTN phenotype, next to the lack of the pulmonary maturation.

Keratoconus presenting with bilateral simultaneous acute corneal hydrops.

PURPOSE: To report a case of unknown keratoconus presenting with bilateral simultaneous acute corneal hydrops. METHODS: Case report. RESULTS: A case of a 12-year-old male patient with Leber congenital amaurosis (LCA) presented with sudden whitening and lacrimation for 2 days in both eyes simultaneously. At the initial examination, there were bilateral acute corneal hydrops, enophthalmic eyes and roving nystagmus. Ultrasonography revealed clear crystalline lenses and attached retina. Initial management consisted of topical hypertonic solutions, steroids and artificial tears. CONCLUSION: Bilateral simultaneous acute corneal hydrops has not been reported before in the literature. It may be the presenting sign of keratoconus.

CLOCK gene variants associate with sleep duration in two independent populations.

BACKGROUND: Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration. METHODS: Sleep duration was assessed in Central Europe, Estonia, and South Tyrol (n approximately 77,000) with the Munich ChronoType Questionnaire. It showed a Gaussian distribution in all investigated populations after averaging over a standard workweek and normalization according to age and gender. A follow-up, two-stage design, linkage disequilibrium-based association study was conducted with subjects from South Tyrol (discovery sample; n = 283) and with short (< 7 hours) and long (> 8.5 hours) sleepers from Estonia (confirmation sample; n = 1011). One hundred ninety-four single nucleotide polymorphism markers covering 19 candidate clock genes were genotyped in the discovery sample, and two of the best association signals (analyzed by a linear regression model) were investigated in the confirmation sample. RESULTS: Single and multi-marker associations were found within a CLOCK gene intronic region (rs12649507 and rs11932595). In a meta-analysis between South Tyrol and Estonia association signals, rs12649507 (p = .0087) remained significant. Significance persisted only for the multiple-marker association signal of the rs12649507/rs11932595 haplotype GGAA with long sleep (p = .0015). CONCLUSIONS: We report an association between variants of the human CLOCK gene and sleep duration in two independent populations. This adds another putative function for CLOCK besides its possible involvement in circadian timing, depression, obesity, and personality.

The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG).

AIMS: Atrial fibrillation (AF) is the most frequent arrhythmia in humans. Rare familial forms exist. Recent evidence indicates a genetic susceptibility to common forms of AF. The alpha-subunit of the myocardial I(Kr)-channel, encoded by the KCNH2 gene, is crucial to ventricular and atrial repolarization. Patients with mutations in KCNH2 present with higher incidence of AF. Common variants in KCNH2 have been shown to modify ventricular repolarization. We intended to investigate, whether such variants may also modulate atrial repolarization and predispose to AF. METHODS AND RESULTS: In a two-stage association study we analysed 1207 AF-cases and 2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms) from the KCNH2 genomic region were genotyped in 671 AF-cases and 694 controls. Of five associated variants, the common K897-allele of the KCNH2-K897T variant was replicated in n = 536 independent AF cases and n = 1781 controls in stage II [overall odds ratio 1.25, 95% confidence interval 1.11-1.41, P = 0.00033]. This association remained significant after adjustment for gender and age. CONCLUSION: We report a genetic association finding including positive replication between the K897-allele and higher incidence of AF. This provides a molecular correlate for complex genetic predispositions to AF. The consequences of the K897T variant at the atrial level will require further functional investigations.

The common non-synonymous variant G38S of the KCNE1-(minK)-gene is not associated to QT interval in Central European Caucasians: results from the KORA study.

AIMS: The QT interval in the general population is a complex trait with 30-50% heritability. QT prolongation is associated with an increased risk of sudden death. A recent family-based study found an association between QT interval and the common non-synonymous Glycin 38 Serine variant (G38S, rs1805127) of the KCNE1 gene coding for the minK-potassium channel subunit. We intended to replicate this finding in a large population sample of central European Caucasian ancestry as part of our ongoing search for genetic variants predisposing to arrhythmias. METHODS AND RESULTS: We studied 3966 unrelated individuals from the KORA S4 population-based study without atrial fibrillation, pacemaker implant, or pregnancy. Individuals were genotyped by MALDI-TOF mass spectrometry. We did not detect any significant association between the genotypes of the G38S variant and the QT interval in the entire population or in any gender. CONCLUSION: Unlike the common Lysine 897 Threonine variant of KCNH2 (K897T, rs1805123) the G38S variant of KCNE1 does not appear to have a strong modifying effect on QT interval. However, we cannot rule out an effect of G38S on QT in other ethnic groups, under exercise or medications or on the risk for arrhythmias and sudden death.