Whole-exome sequencing identified compound heterozygous variants in the TTN gene causing Salih myopathy with dilated cardiomyopathy in an Iranian family

Background: Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics. Method: In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern. Results: Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing. Conclusions: The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.

Choroidal thickness in children with type 1 diabetes depending on the pubertal status and metabolic parameters analyzed by optical coherence tomography

To assess choroidal thickness (CT) in children with type 1diabetes (T1D) regarding their pubertal status and seek for factors influencing this parameter, using optical coherence tomography. Material and methods: 333 eyes out of 167 children with T1D without symptoms of diabetic retinopathy (mean age 12.81 ± 3.63 years, diabetes duration 4.59 ± 3.71 years) were enrolled. CT in all quadrants was evaluated. The studied population was divided into three groups: prepubertal, pubertal and postpubertal. The multivariate regression model was carried out using all metabolic parameter and then it was built using only the significant ones. Results: Significant differences in CT between males and females, except nasal and superior quadrants were observed. We revealed significant differences in CT between the three independent groups (Chi-square 18.6, p < 0.0001). In the statistically significant multiple regression model (R = 0.9, R2 = 0.82, p < 0.0000), the serum level of free thyroxine, triiodothyronine, total hemoglobin, uric acid, low- and high-density cholesterol, daily insulin dose per kilogram, weight and level of vitamin D were significant. Conclusion: In our studied group CT increases during puberty. Metabolic parameters such as cholesterol, uric acid, thyroid hormones, and hemoglobin concentration even within the normal range, significantly influence the CT, and these factors likely affect other blood vessels in the body.

Analysis of Metabolic Markers in Patients with Chronic Heart Failure before and after LVAD Implantation

Chronic heart failure (HF) is a clinical syndrome characterized by functional impairments of the myocardium. Metabolic and clinical changes develop with disease progression. In an advanced state, left ventricular assist devices (LVADs) are implanted for mechanical unloading. Our study aimed to assess the effects of LVAD implantation on the metabolic phenotypes and their potential to reverse the latter in patients with advanced HF. Plasma metabolites were analyzed by LC–MS/MS in 20 patients with ischemic cardiomyopathy (ICM), 20 patients with dilative cardiomyopathy (DCM), and 20 healthy controls. Samples were collected in HF patients before, 30 days after, and >100 days after LVAD implantation. Out of 188 measured metabolites, 63 were altered in HF. Only three metabolites returned to pre-LVAD concentrations 100 days after LVAD implantation. Pre-LVAD differences between DCM and ICM were mainly observed for amino acids and biogenic amines. This study shows a reversal of metabolite abnormalities in HF as a result of LVAD implantation. The etiology of the underlying disease plays an essential role in defining which specific metabolic parameter is altered in HF and reversed by LVAD implantation. Our findings provide a detailed insight into the disease pattern of ICM and DCM and the potential for reversibility of metabolic abnormalities in HF.

The Prognostic Significance of Body Mass Index and Metabolic Parameter Variabilities in Predialysis CKD: A Nationwide Observational Cohort Study

BackgroundThe association between variabilities in body mass index (BMI) or metabolic parameters and prognosis of patients with CKD has rarely been studied.MethodsIn this retrospective observational study on the basis of South Korea’s national health screening database, we identified individuals who received ≥3 health screenings, including those with persistent predialysis CKD (eGFR <60 ml/min per 1.73 m2 or dipstick albuminuria ≥1). The study exposure was variability in BMI or metabolic parameters until baseline assessment, calculated as the variation independent of the mean and stratified into quartiles (with Q4 the highest quartile and Q1 the lowest). We used Cox regression adjusted for various clinical characteristics to analyze risks of all-cause mortality and incident myocardial infarction, stroke, and KRT.ResultsThe study included 84,636 patients with predialysis CKD. Comparing Q4 versus Q1, higher BMI variability was significantly associated with higher risks of all-cause mortality (hazard ratio [HR], 1.66; 95% confidence interval [95% CI], 1.53 to 1.81), P [for trend] <0.001), KRT (HR, 1.20; 95% CI, 1.09 to 1.33; P<0.001), myocardial infarction (HR, 1.19; 95% CI, 1.05 to 1.36, P=0.003), and stroke (HR, 1.19; 95% CI, 1.07 to 1.33, P=0.01). The results were similar in the subgroups divided according to positive or negative trends in BMI during the exposure assessment period. Variabilities in certain metabolic syndrome components (e.g., fasting blood glucose) also were significantly associated with prognosis of patients with predialysis CKD. Those with a higher number of metabolic syndrome components with high variability had a worse prognosis.ConclusionsHigher variabilities in BMI and certain metabolic syndrome components are significantly associated with a worse prognosis in patients with predialysis CKD.

POS0138 ALTERED RISK OF GOUT ACCORDING TO CHANGE OF METABOLIC PARAMETERS IN YOUNG ADULTS

Background:Many studies have shown a link between gout and metabolic syndrome (MetS). It is well known that lifestyle modifications such as weight reduction and abstinence from alcohol are effective in the treatment of gout, but data are lacking on how exactly the change of metabolic parameters affects gout.Objectives:The purpose of this study was to investigate the relationship between gout risk and metabolic parameters in a nationwide population based young adult cohort, and to determine whether changes in metabolic parameters affect gout risk changes.Methods:Among adults aged 20-39 years who participated in national health check-up programs from 2009 to 2012, a total of 6,290,914 subjects were included in the study, excluding subjects who were previously diagnosed with gout. To determine the effect of changes in metabolic parameters on gout incidence, 2,701,138 subjects who participated in the health examination once more 2 years later were used for the analysis. Outcome was defined as the occurrence of gout, when the ICD-10 code (M10) was registered twice in the claim database. The Cox proportional hazard model and Kaplan Meier curve were used for the analysis.Results:The incidence rate of gout was higher in those with MetS compared to those without (10.1 vs. 3.6 per 1,000 person-years). The risk of gout in people with MetS was 85% higher (adjusted HR 1.85, 95% CI 1.83-1.87) and was more significant in men than in women (adjusted HR 1.88 in male and 1.56 in female). Each component of MetS was also associated with increased gout risk, and hypertriglyceridemia showed the highest adjusted HR. The greater the number of MetS components, the higher the gout risk. The risk of gout was 70% higher in those who had MetS consistently (adjusted HR 1.71, 95% CI 1.67-1.75) and 44% higher in those with newly developed MetS (adjusted HR 1.47, 95% CI 1.40-1.48) than those who did not have MetS at the two health examinations. Similar risk patterns were observed according to the change of each metabolic parameter. Among the metabolic parameters, the change in hypertriglyceridemia was associated with the greatest difference in the change in gout risk.Conclusion:In young adults, MetS was associated with a higher risk of gout, especially with more components, the higher the risk. Since the occurrence of MetS is associated with an increased risk of gout, prevention of MetS would be important to reduce gout incidence.Disclosure of Interests:None declared

Predicting anthropometric and metabolic traits with a genetic risk score for obesity in a sample of Pakistanis

Obesity is an outcome of multiple factors including environmental and genetic influences. Common obesity is a polygenic trait indicating that multiple genetic variants act synergistically to influence its expression. We constructed a genetic risk score (GRS) based on five genetic variants (MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752) and examined its association with obesity-related traits in a sample of Pakistanis. The study involved 306 overweight/obese (OW/OB) and 300 normal-weight (NW) individuals. The age range of the study participants was 12–63 years. All anthropometric and metabolic parameters were measured for each participant via standard procedures and biochemical assays, respectively. The genetic variants were genotyped by allelic discrimination assays. The age- and gender-adjusted associations between the GRS and obesity-related anthropometric and metabolic measures were determined using linear regression analyses. The results showed that OW/OB individuals had significantly higher mean ranks of GRS than NW individuals. Moreover, a significant association of the GRS with obesity-related anthropometric traits was seen. However, the GRS did not appear to affect any obesity-related metabolic parameter. In conclusion, our findings indicate the combined effect of multiple genetic variants on the obesity-related anthropometric phenotypes in Pakistanis.

Choroidal Thickness in Children With Type 1 Diabetes Depending On the Pubertal Status and Metabolic Parameters Analyzed By Optical Coherence Tomography

To assess choroidal thickness (CT) in children with type 1diabetes (T1D) regarding their pubertal status and seek for factors influencing this parameter, using optical coherence tomography (OCT). Material and methods: 333 eyes out of 167 children with T1D without symptoms of diabetic retinopathy (mean age 12,81±3,63 years, diabetes duration 4,59±3,71 years) were enrolled. CT in all quadrants was evaluated. The studied population was divided into three groups: prepubertal, pubertal and postpubertal. The multivariate regression model was carried out using all metabolic parameter and then it was built using only the significant ones. Results: Significant differences in CT between males and females, except nasal and superior quadrants were observed. We revealed significant differences in CT between the three independent groups (Chi-square 18,6, p<0,0001). In the statistically significant multiple regression model (R=0,9, R2=0,82, p<0,0000), the serum level of free thyroxine, triiodothyronine, total hemoglobin, uric acid, low- and high-density cholesterol, daily insulin dose per kilogram, weight and level of vitamin D were significant. Conclusion: In our studied group CT increases during puberty. Metabolic parameters such as cholesterol, uric acid, thyroid hormones, and anemia even within the normal range, significantly influence the CT, which is similarly observed in other blood vessels in the body.