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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events., (© 2024. The Author(s).)

Background: Hypertrophic cardiomyopathy is a heterogeneous myocardial disease. Mutations appearing in several genes might be a potential cause of the disease. The aim of the study was to analyze selected exons of the sarcomeric and non-sarcomeric genes, with the purpose to identify potential candidate genetic variants and to understand etiopathogenetic mechanisms of hypertrophic cardiomyopathy in East Slovak patients., Methods: This study recruited 23 unrelated patients with hypertrophic cardiomyopathy, namely, 13 men and 10 women (mean age of 58.09±15.82 years) and 25 healthy controls in order to determine the candidate sequence variants, in the selected exons of six cardiomyopathy genes (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2), by conventional capillary-based Sanger sequencing method and standard protocols., Results: Molecular genetic results confirmed the presence of 43 sequence variants in the selected exons of six cardiomyopathy genes, 58.14% of detected variants were novel. The majority of detected sequence variants were confirmed within exon 23 of MYH7 gene. Only 11 genetic alterations were predicted to be potentially pathogenic., Conclusions: In our study, we identified known and novel sequence variants in 23 unrelated patients with hypertrophic cardiomyopathy, but we did not observe any strong mutation hotspot. The results of our study assumed that exon 23 of MYH7 gene can be in potential affinity to hypertrophic cardiomyopathy in our cohort of patients. The sequence variants identified in this study may be further investigated in order to determine their functions in disease pathogenesis and improve management, diagnosis, and treatment in Slovak patients., (© 2017 Wiley Periodicals, Inc.)

Background: As the leading cause of congestive heart failure, cardiomyopathy represents a heterogenous group of heart muscle disorders. Despite considerable progress being made in the genetic diagnosis of cardiomyopathy by detection of the mutations in the most prevalent cardiomyopathy genes, the cause remains unsolved in many patients. High-throughput mutation screening in the disease genes for cardiomyopathy is now possible because of using target enrichment followed by next-generation sequencing. The aim of the study was to analyze a panel of genes associated with dilated or hypertrophic cardiomyopathy based on previously published results in order to identify the subjects at risk., Methods: The method of next-generation sequencing by IlluminaHiSeq 2500 platform was used to detect sequence variants in 16 individuals diagnosed with dilated or hypertrophic cardiomyopathy. Detected variants were filtered and the functional impact of amino acid changes was predicted by computational programs., Results: DNA samples of the 16 patients were analyzed by whole exome sequencing. We identified six nonsynonymous variants that were shown to be pathogenic in all used prediction softwares: rs3744998 (EPG5), rs11551768 (MGME1), rs148374985 (MURC), rs78461695 (PLEC), rs17158558 (RET) and rs2295190 (SYNE1). Two of the analyzed sequence variants had minor allele frequency (MAF)<0.01: rs148374985 (MURC), rs34580776 (MYBPC3)., Conclusion: Our data support the potential role of the detected variants in pathogenesis of dilated or hypertrophic cardiomyopathy; however, the possibility that these variants might not be true disease-causing variants but are susceptibility alleles that require additional mutations or injury to cause the clinical phenotype of disease must be considered., (© 2017 Wiley Periodicals, Inc.)

Objectives: To clarify the connection between two selected mononucleotide polymorphisms (rs4957014 and rs3756712) in programmed cell death gene 6 (PDCD6) and endometriosis development risk in patients belonging to the majority population of Slovakia., Methods: From all women involved in the research a buccal DNA sample was taken. A genetic analysis of selected polymorphisms was implemented using Real-time PCR method. Variance in allelic and genotype frequencies was statistically evaluated between the controlgroup and the group of patients., Results: The analysed group consisted of 52 women suffering from endometriosis and the control group of 63 women. Variant G allele frequency in the group of patients in case of polymorphism rs3756712 had a value of 0.42 and in the control group 0.29; that represents its statistically and significantly higher occurrence in the group of patients suffering from endometriosis (p = 0.029 and OR = 1.833). Presence of G allele is related to almost 1.9 times higher risk of endometriosis development., Conclusion: Achieved results show that polymorphism rs3756712 is significantly associated with the risk of endometriosis development in Slovak women. Polymorphism rs4957014 did not show any connection with development of endometriosis (Tab. 5, Ref. 10).

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245&#95;1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245&#95;1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245&#95;1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245&#95;1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations.

Aims: Hereditary as well as acquired thrombophilia is associated with a higher incidence of severe obstetric complications such as preeclampsia, spontaneous pregnancy loss, placental abruption, and fetal growth retardation. The aim of our study was to examine the association of selected thrombophilic polymorphisms (factor V Leiden, MTHFR C677T, and MTHFR A1298C) with pregnancy complications in the Slovak majority population and the Roma (Gypsy) ethnic population. The study included 354 women; 120 patients and 105 controls from the Slovak majority population, 50 patients and 79 controls from the Slovak Roma population. Genotyping was performed by the real-time polymerase chain reaction method using TaqMan(®) MGB probes., Results: A statistically significant higher frequency of factor V Leiden (p=0.001, odds ratio [OR]=5.9) and MTHFR C677T polymorphism (p=0.011, OR=1.7) was observed in the Slovak majority patient group compared to the control group. The incidence of MTHFR A1298C polymorphism between patients and controls did not differ significantly. None of the three polymorphisms studied was in association with pregnancy complications in the group of Roma women., Conclusions: Our study has confirmed the variable distribution of selected thrombophilic polymorphisms in different ethnic groups as well as their various effects on the clinical phenotype.

Autosomal recessive forms of Charcot-Marie-Tooth disease (CMT) account for less than 10 % of all CMT cases, but are more frequent in the populations with a high rate of consanguinity. Roma (Gypsies) are a transnational minority with an estimated population of 10 to 14 million, in which a high degree of consanguineous marriages is a generally known fact. Similar to the other genetically isolated founder populations, the Roma harbour a number of unique or rare autosomal recessive disorders, caused by "private" founder mutations. There are three subtypes of autosomal recessive CMT with mutations private to the Roma population: CMT4C, CMT4D and CMT4G. We report on the molecular examination of four families of Roma origin in Slovakia with early-onset demyelinating neuropathy and autosomal recessive inheritance. We detected mutation p.R148X (g.631C>T) in the NDRG1 (NM&#95;006096.3) gene in two families and mutation g.9712G>C in the HK1 (NM&#95;033498) gene in the other two families. These mutations cause CMT4D and CMT4G, respectively. The success of molecular genetic analysis in all families confirms that autosomal recessive forms of CMT caused by mutations on the NDRG1 and HK1 genes are common causes of inherited neuropathies among Slovak Roma. Providing genetic analysis of these genes for patients with Roma origin as a common part of diagnostic procedure would contribute to a better rate of diagnosed cases of demyelinating neuropathy in Slovakia and in other countries with a Roma minority.

Philadelphia chromosome (Ph) is a characteristic chromosomal marker that is associated with chronic myelogenous leukemia (CML). Philadelphia chromosome in bone marrow cells in patients with suspected diagnosis of CML in the Presov region (1995-2004) was detected in 94.4 % of cases. In one patient a complex translocation involving the chromosomes 8, 9 and 22 was identified. One patient has showed extra numerical and structural chromosomal aberrations. The mosaic karyotype of Ph chromosome was found in 5.9 % of cases. The conventional cytogenetic analysis remains the standard method for the purpose of diagnosis and monitoring of the therapeutic response and minimal residual disease in patients with chronic myeloid leukemia (Tab. 1, Fig. 1, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Prenatal genetic diagnostics is a part of prenatal care. Prenatal karyotyping is used to identify major genetic and congenital abnormalities in a developing fetus. In the Presov region (Slovakia) in 1999-2004 370 amniotic fluid samples were analysed by G-banding. Abnormal karyotypes were detected in 3.8% of samples. A karyotype using classical banding methods is the only fully informative method able to detect all chromosomal abnormalities. Identification of fetal abnormal chromosomes in high risk pregnancies allows proper pediatric and obstetric managment of the cases as well as genetic counselling (Tab. 1, Fig. 2, Ref. 5).

Charcot–Marie–Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims. [ABSTRACT FROM AUTHOR]

Demyelinating Charcot–Marie–Tooth 4G (CMT4G) results from a recessive mutation in the 5′UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance. [ABSTRACT FROM AUTHOR]

Several cytokines have been indicated to be significantly involved in urological diseases. Interleukin 17A (IL-17A) and interleukin 23 (IL-23) have recently received attention for their involvement in inflammatory diseases and cancers. The aim of the study was to show changes in the level of pro-inflammatory interleukins IL-17A and IL-23 in patients with bladder cancer (BC) and selected urological diseases. An important cognitive aspect was to study the interdependencies between the studied interleukins and to assess their diagnostic value for such diseases. The material for the study was urine sample from patients with BC, urinary tract infection (UTI), urolithiasis, benign prostatic hyperplasia (BPH), US (urethral stricture), which was compared to the urine sample of healthy people without urological disorders. Interleukin concentrations were measured by the immunoenzymatic method. The levels of IL-17A and IL-23 in the urine of patients with BC, UTI, BPH and US were significantly higher compared to the control group. Statistically significant differences were found in the level of both interleukins compared to the control group in all diseases except urolithiasis. IL-17A and IL-23 correlated with each other in patients with all urological diseases except urolithiasis. The results of the conducted studies showed that selected urological diseases changed the levels of IL-17A and IL-23 in the urine of patients. The observations made confirmed the participation of these interleukins in the course of the urological diseases, especially in BC, and allowed to classify them as potentially useful parameters for diagnostic purposes. [ABSTRACT FROM AUTHOR]

It is known to all that Wnt signaling pathway plays an important role in the early development of tooth. Our previous research found that Wnt signaling pathway played crucial roles in dental development, and mutations in antagonist of Wnt signaling pathway may lead to the formation of supernumerary teeth. However, the expression pattern of Wnt signaling molecules in early development of tooth, especially genes with stage specificity, remains unclear. Hence, we applied RNA-seq analysis to determine the expression levels of wnt signal molecules at five different stages of rat first molar tooth germ. In addition, after literature review we summarized the function of Wnt signaling molecules during tooth development and the relationship between Wnt signaling molecules variation and tooth agenesis. Our research may have implications for exploring the role of Wnt signaling molecules in different stages of tooth development. [ABSTRACT FROM AUTHOR]

Background: Within Europe, Roma, Gypsy, and Traveller groups have been marginalized and discriminated against by larger society. Persecution and displacement have resulted in high rates of unemployment, reduced access to education, and poorer health, with significantly increased risk of poverty compared with the general population. In pregnancy, there appears to be a gap in the literature surrounding the experiences and outcomes of pregnant people within these ethnic groups., Objectives: The aim of this study was therefore to scope published research, specifically questioning "What is the experience of Roma Gypsy and Traveller pregnant people who access maternity care?" and "What are the obstetric outcomes within these groups?", Search Strategy: This review followed frameworks proposed by Arksey and O'Malley, Levac, and the Joanna Brigg's Institute. The PRISMA extension for Scoping Reviews (PRISMA-ScR) tool was used. The search strategy and specific terms were chosen using the population-concepts-context framework., Selection Criteria: Titles and abstracts were reviewed independently by two reviewers. Inclusion and exclusion criteria were defined to set clear guidance for reviewers to identify appropriate studies., Data Collection and Analysis: Five electronic databases were searched (CINAHL, EMBASE, MEDLINE [OVID] Web of Science and SCOPUS). A charting form was developed to record key characteristics systematically and uniformly from the studies., Main Results: Five themes were identified: systemic issues, antenatal care, complications of pregnancy, birth experience, and postnatal care. Systemic issues included racism, barriers to care, and adapted antenatal care. Antenatal issues included teenage pregnancy, smoking, risk of venous thrombus embolism, dietary issues, risk of communicable diseases, domestic violence, and mental health concerns. Increased risks of congenital abnormalities, growth restriction, premature labor, and perinatal and early childhood mortality were identified. For Roma women, negative birth experiences were reported, whereas the experiences of Traveller women varied., Conclusions: The findings identified in this study serve to create a framework upon which healthcare providers can tailor the way in which pregnant people from a Roma, Gypsy, or Irish Traveller background are cared for. Using such a framework would hopefully begin to reduce the systematic marginalization and discrimination of these minorities., (© 2024 International Federation of Gynecology and Obstetrics.)

Human height and related traits are highly complex, and extensively research has shown that these traits are determined by both genetic and environmental factors. Such factors may partially affect these traits through epigenetic programing. Epigenetic programing is dynamic and plays an important role in controlling gene expression and cell differentiation during (early) development. DNA methylation (DNAm) is the most commonly studied epigenetic feature. In this study we conducted an epigenome-wide DNAm association analysis on height-related traits in a Sub-Saharan African population, in order to detect DNAm biomarkers across four height-related traits. DNAm profiles were acquired in whole blood samples of 704 Ghanaians, sourced from the Research on Obesity and Diabetes among African Migrants study, using the Illumina Infinium HumanMethylation450 BeadChip. Linear models were fitted to detect differentially methylated positions (DMPs) and regions (DMRs) associated with height, leg-to-height ratio (LHR), leg length, and sitting height. No epigenome-wide significant DMPs were recorded. However we did observe among our top DMPs five informative probes associated with the height-related traits: cg26905768 (leg length), cg13268132 (leg length), cg19776793 (height), cg23072383 (LHR), and cg24625894 (sitting height). All five DMPs are annotated to genes whose functions were linked to bone cell regulation and development. DMR analysis identified overlapping DMRs within the gene body of HLA-DPB1 gene, and the HOXA gene cluster. In this first epigenome-wide association studies of these traits, our findings suggest DNAm associations with height-related heights, and might influence development and maintenance of these traits. Further studies are needed to replicate our findings, and to elucidate the molecular mechanism underlying human height-related traits. [ABSTRACT FROM AUTHOR]

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings. [ABSTRACT FROM AUTHOR]

Knowledge of uric acid (UA) crystallopathies preceded the identification of this compound. How the body handles and transports UA proved even more elusive. Over several decades, advances in molecular phenotyping have illuminated this hitherto nebulous field. Closely parallel to the characterization of the transport mechanisms of UA in the body was the development of drugs designed to manipulate UA levels. In this review, we highlight the study of UA transport and transporters. This is an evolving field, and we expect our knowledge of the transport mechanisms to both widen and deepen further. We focus on the best‐characterized transporters rather than an exhaustive catalog of all suspected transporters. We review the established and novel compounds that modulate UA transport. [ABSTRACT FROM AUTHOR]

The review summarizes the current knowledge on the role that genetic factors play in primary or Mendelian cardiomyopathies (CMs) and certain secondary CM forms. Dozens of genes with pathogenic or likely pathogenic variants were described for primary CMs. The spectrum of causal genetic variants is specific to particular CMs in most cases, but common genes and variants were also discovered. Genetic causes of the disease remain unknown in part of primary CM cases, and pathogenic variants of Mendelian disease genes are found in secondary CMs as well. The genetic component in the development of both primary and secondary CMPs was additionally established in genome-wide association studies (GWASs). Single nucleotide polymorphisms (SNPs) associated with primary and secondary CMs are, in most cases, specific to different CM types and contribute little to an individual's overall risk. Certain SNPs were associated with electrocardiogram or echocardiogram features of the morphologically normal heart in humans. Most of the CMs-associated SNPs are in noncoding genome regions, but have a regulatory potential, acting as loci that affect the level of expression (eQTLs), splicing (sQTLs) or epigenetic modifications in the heart. It is noteworthy that the effects of eQTL and sQTL genotypes are not equivalent in different anatomical regions of the heart in some cases. The phenotype and clinical presentation of CMs in general can be determined by a wide range of rare pathogenic or likely pathogenic variants with a strong effect and common polymorphisms with a small effect and modified by epigenetic factors. [ABSTRACT FROM AUTHOR]

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect. [ABSTRACT FROM AUTHOR]

Non-syndromic tooth agenesis (NSTA) is one of the most common dental developmental malformations affected by genetic factors predominantly. Among all 36 candidate genes reported in NSTA individuals, EDA, EDAR, and EDARADD play essential roles in ectodermal organ development. As members of the EDA/EDAR/NF-κB signaling pathway, mutations in these genes have been implicated in the pathogenesis of NSTA, as well as hypohidrotic ectodermal dysplasia (HED), a rare genetic disorder that affects multiple ectodermal structures, including teeth. This review provides an overview of the current knowledge on the genetic basis of NSTA, with a focus on the pathogenic effects of the EDA/EDAR/NF-κB signaling pathway and the role of EDA, EDAR, and EDARADD mutations in developmental tooth defects. We also discuss the phenotypic overlap and genetic differences between NSTA and HED. Ultimately, this review highlights the importance of genetic analysis in diagnosing and managing NSTA and related ectodermal disorders, and the need for ongoing research to improve our understanding of these conditions. [ABSTRACT FROM AUTHOR]

Objective: Premolar agenesis is a common subtype of tooth agenesis. Although a genome‐wide study (GWAS) has identified some variants involved in tooth agenesis in Europeans, the genetic mutation related to premolar agenesis in the Chinese population remains unclear. Materials and methods: We present a GWAS in 218 premolar agenesis cases and 1,222 controls using the Illumina Infinium® Global Screening Array. 5,585,618 single nucleotide polymorphisms (SNPs) were used for tests of associations with premolar agenesis. Results: Four independent SNPs on chromosome 2 were identified as susceptibility loci, including rs147680216, rs79743039, rs60540881, and rs6738629. The genome‐wide significant SNP rs147680216 (p = 6.09 × 10−9) was predicted to change the structure of the WNT10A protein and interact with hedgehog signaling pathway components. Meta‐analysis showed that the rs147680216 A allele significantly increased the risk of tooth agenesis (p = 0.000). The other three SNPs with nominal significance are novel susceptibility loci. Of them, rs6738629 (p = 5.40 × 10−6) acts as a potential transcriptional regulator of GCC2, a gene playing a putative role in dental and craniofacial development. Conclusion: Our GWAS indicates that rs147680216 and additional three novel susceptibility loci on chromosome 2 are associated with the risk of premolar agenesis in the Chinese population. [ABSTRACT FROM AUTHOR]

Leisure-time physical activity (LTPA) is one of the modifiable lifestyle factors that play an important role in the prevention of non-communicable (especially cardiovascular) diseases. Certain genetic factors predisposing to LTPA have been previously described, but their effects and applicability on different ethnicities are unknown. Our present study aims to investigate the genetic background of LTPA using seven single nucleotide polymorphisms (SNPs) in a sample of 330 individuals from the Hungarian general (HG) and 314 from the Roma population. The LTPA in general and three intensity categories of it (vigorous, moderate, and walking) were examined as binary outcome variables. Allele frequencies were determined, individual correlations of SNPs to LTPA, in general, were determined, and an optimized polygenetic score (oPGS) was created. Our results showed that the allele frequencies of four SNPs differed significantly between the two study groups. The C allele of rs10887741 showed a significant positive correlation with LTPA in general (OR = 1.48, 95% CI: 1.12–1.97; p = 0.006). Three SNPs (rs10887741, rs6022999, and rs7023003) were identified by the process of PGS optimization, whose cumulative effect shows a strong significant positive association with LTPA in general (OR = 1.40, 95% CI: 1.16–1.70; p < 0.001). The oPGS showed a significantly lower value in the Roma population compared with the HG population (oPGSRoma: 2.19 ± SD: 0.99 vs. oPGSHG: 2.70 ± SD: 1.06; p < 0.001). In conclusion, the coexistence of genetic factors that encourage leisure-time physical activity shows a more unfavorable picture among Roma, which may indirectly contribute to their poor health status. [ABSTRACT FROM AUTHOR]

Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy. [ABSTRACT FROM AUTHOR]

Our previous gene expression studies in a PCB-exposed cohort of young children in Slovakia revealed that early-life exposures to PCBs and other organochlorine compounds were associated with significant alterations across several pathogenetic pathways. The present study was undertaken to further explore the high-throughput qRT-PCR-based gene expression effects by using TaqMan low-density array (TLDA) for selected genes in a sample of 55 children from the cohort. We analyzed the transcriptional changes of 11 genes in relation to PCB and organochlorine pesticide exposure levels (including DDT, DDE, HCH, and HCB), and to BMI and ethnicity in this cohort. The results indicated an overall downregulation of expression of these genes. Maximum downregulation (in fold change) was observed in the ENTPD3 gene, and the minimum level of downregulation was in CYP2D6. As per our multinomial regression model study, downregulation of LEPR gene was significantly directly correlated with all the exposure variables. Downregulation of APC, ARNT, CYP2D6, LEPR, LRP12, and MYC genes was directly correlated with BMI (kg/m2) of the individuals. Gender-specific differences in gene expression were observed in CYP2D6 (p-value 0.0001) and LEPR (p-value 0.028), while downregulation of CYP2D6 (p-value 0.01), LEPR (p-value 0.02), LRP12 (p-value 0.04), and MYC (p-value 0.02) genes was consistently observed in Roma children compared to Caucasians. The investigation of such health disparities must be emphasized in future research, together with interventions to reduce the health consequences of PCB exposures. In this context, we emphasize the importance of biomarker-based approaches to future research on genetic susceptibility to the effects of these compounds. [ABSTRACT FROM AUTHOR]

Hypouricemia is recognized as a rare disorder, defined as a serum uric acid level of 2.0 mg/dL or less. Hypouricemia is divided into an overexcretion type and an underproduction type. The former typical disease is xanthinuria, and the latter is renal hypouricemia (RHUC). The frequency of nephrogenic hypouricemia due to a deficiency of URAT1 is high in Japan, accounting for most asymptomatic and persistent cases of hypouricemia. RHUC results in a high risk of exercise-induced acute kidney injury and urolithiasis. It is vital to promote research on RHUC, as this will lead not only to the elucidation of its pathophysiology but also to the development of new treatments for gout and hyperuricemia. [ABSTRACT FROM AUTHOR]

Objectives Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. Methods A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12 , the two most common causative variants of RHUC in Japanese. Results Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. Conclusion Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia. [ABSTRACT FROM AUTHOR]

Summary: The meta-analysis of osteoprotegerin (OPG) (TNFRSF11B) polymorphisms from genetic association studies and genome-wide association studies was performed in order to test the hypothesis of association between OPG polymorphisms and fracture. The findings showed a significant 13% to 37% protective effect of OPG on fractures in postmenopausal women (PSM) (rs2073618), overall, ≥ 60y and Western subjects (rs3134069 and rs3134070). Purpose: Fractures in older people usually result from compromised bone integrity. The multifactorial aetiology of fractures includes both genetic and environmental factors. Inconsistency of reported associations of osteoprotegerin (OPG) (TNFRSF11B) polymorphisms with fracture in the older adult population warranted a meta-analysis to determine more precise estimates. Methods: We searched for all available literature on OPG (TNFRSF11B) and fracture. Four polymorphisms were examined, one exonic (rs2073618) and three intronic (rs3134069, rs3134070 and rs3102735). The first two intron polymorphisms were combined (OPGI: osteoprotegerin intron) on account of complete linkage disequilibrium. Risks were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using the allele-genotype model that included variant (var), wild-type (wt) and heterozygote (het). Multiple comparisons were Bonferroni-corrected. We used meta-regression to examine sources of heterogeneity. Zero heterogeneity (homogeneity: I2 = 0%) and high significance (Pa < 0.00001) were the criteria for strength of evidence. Significant outcomes were subjected to sensitivity analysis and publication bias assessment. Results: From 13 articles (11 genetic association and two genome-wide), this meta-analysis generated five significant pooled ORs, all indicating reduced risks (ORs 0.44–0.87). Of the five, four highly significant comparisons (Pa ≤ 0.00001–0.002) survived the Bonferroni correction, one in rs2073618 het model of the postmenopausal women (OR 0.87, 95% CI 0.81–0.92, I2 = 0%) and the other three in OPGI wt model of the overall analysis, ≥ 60 y and Western subjects (ORs 0.63–0.71, 95% CI 0.47–0.86, I2 = 97–99%). These findings were consistent, had high significance and high statistical power and were robust and without evidence of publication bias. Four covariates (year of publication, study quality, fracture type/site and sample size) were the sources of heterogeneity in the OPGI overall outcomes (Pa = 0.0001–0.03). Conclusion: Evidence showed that the OPG (TNFRSF11B) polymorphisms reduced the risk for fracture in older adults, particularly protective among postmenopausal women, ≥ 60 y and Western subjects. [ABSTRACT FROM AUTHOR]

Inherited cardiomyopathies are a major cause of mortality and morbidity worldwide and can be caused by mutations in a wide range of proteins located in different cellular compartments. The present review is based on Dr. Ju Chen's 2021 Robert M. Berne Distinguished Lectureship of the American Physiological Society Cardiovascular Section, in which he provided an overview of the current knowledge on the cardiomyopathy-associated proteins that have been studied in his laboratory. The review provides a general summary of the proteins in different compartments of cardiomyocytes associated with cardiomyopathies, with specific focus on the proteins that have been studied in Dr. Chen's laboratory. [ABSTRACT FROM AUTHOR]

Wnts include more than 19 types of secreted glycoproteins that are involved in a wide range of pathological processes in oral and maxillofacial diseases. The transmission of Wnt signalling from the extracellular matrix into the nucleus includes canonical pathways and noncanonical pathways, which play an important role in tooth development, alveolar bone regeneration, and related diseases. In recent years, with the in‐depth study of Wnt signalling in oral and maxillofacial‐related diseases, many new conclusions and perspectives have been reached, and there are also some controversies. This article aims to summarise the roles of Wnt signalling in various oral diseases, including periodontitis, dental pulp disease, jaw disease, cleft palate, and abnormal tooth development, to provide researchers with a better and more comprehensive understanding of Wnts in oral and maxillofacial diseases. [ABSTRACT FROM AUTHOR]

Objectives Gout, caused by chronic elevation of serum uric acid levels, is the commonest form of inflammatory arthritis. The causative effect of common and rare variants of ATP-binding cassette transporter G2 (ABCG2/BCRP) on gout risk has been studied, but little attention has been paid to the effect of common (rs121907892, p.W258X) and rare variants of urate transporter 1 (URAT1/SLC22A12) on gout, despite dysfunctional variants of URAT1 having been identified as pathophysiological causes of renal hypouricaemia. Methods To address this important but overlooked issue, we investigated the effects of these URAT1 variants on gout susceptibility, using targeted exon sequencing on 480 clinically defined gout cases and 480 controls of Japanese males in combination with a series of functional analyses of newly identified URAT1 variants. Results Our results show that both common and rare dysfunctional variants of URAT1 markedly decrease the risk of gout (OR 0.0338, reciprocal OR 29.6, P = 7.66 × 10−8). Interestingly, we also found that the URAT1 -related protective effect on gout eclipsed the ABCG2 -related causative effect (OR 2.30–3.32). Our findings reveal only one dysfunctional variant of URAT1 to have a substantial anti-gout effect, even in the presence of causative variants of ABCG2 , a 'gout gene'. Conclusion Our findings provide a better understanding of gout/hyperuricaemia and its aetiology that is highly relevant to personalized health care. The substantial anti-gout effect of common and rare variants of URAT1 identified in the present study support the genetic concept of a 'Common Disease, Multiple Common and Rare Variant' model. [ABSTRACT FROM AUTHOR]

The THSD7A gene has recently been described as a "obesity gene". The product of this gene significantly modulates angiogenesis, a process linked to adipogenesis, growth of adipose tissue and the development of an obese phenotype. It can therefore be assumed that the role of this gene in obesity may be due to its angiogenic activity. The aim of this study was to analyze allele and genotypic frequencies of rs1526538 polymorphism in THSD7A gene and investigate its possible relationship with obesity indicators. The study included 407 individuals of Roma origin and 229 individuals of the majority population in eastern Slovakia. Anthropometric measurements of body height (cm), body weight (kg), waist circumference (cm), and hip circumference (cm) were performed by standard methods to all participants, and BMI, WHR and WHTR indexes were calculated. Buccal mucosa sample were obtained from all the participants and DNA isolation was performed by the commercial kit. SNP genotyping was done using the TaqMan SNP Genotyping Assays. The frequency of the risk allele A was 47.9% in the Roma population and 60.9% in the Slovak majority, suggesting ethnic variability in the frequency of this polymorphism. No significant relationship of this polymorphism with obesity was confirmed in association analysis. Our study provided the evidence for ethnic difference frequency of rs1526538 in THSD7A gene, but did not confirm relationship between this polymorphism and obesity traits. However, further studies are needed to confirm or reject the hypothesis that this genetic determinant of angiogenesis is involved in the etiopathogenesis of obesity. [ABSTRACT FROM AUTHOR]

Mutations in WNT10A have frequently been reported as etiologic for tooth agenesis (TA). However, the effects of WNT10A variation on gene/protein function and contribution to TA phenotypes remain poorly understood. Here, we performed bioinformatic and functional characterization analysis of WNT10A variants. In silico prediction of variant function was performed with VIPUR for all WNT10A missense variants reported in the Exome Aggregation Consortium database. Functional characterization experiments were then performed for selected WNT10A variants previously associated with TA. Expression vectors for wild-type and mutant WNT10A were made and transfected into stem cells from human exfoliated deciduous teeth (SHED) for evaluation of gene/protein function, WNT signaling activity, and effects on expression of relevant genes. While 75% of WNT10A variants were predicted neutral, most of the TA-associated variants received deleterious scores by potentially destabilizing or preventing the disulfide bond formation required for proper protein function. WNT signaling was significantly decreased with 8 of 13 variants tested, whereas wild-type–like activity was retained with 4 of 13 variants. WNT10A- mutant cells (T357I, R360C, and R379C mutants) showed reduced or impaired binding affinity to FZD5, suggesting a potential mechanism for the decreased WNT signaling. Mutant cells also had decreased WNT10A protein expression in comparison to wild-type cells. mRNA expression of PAX9, MSX1, AXIN2, and RUNX2 (known tooth development genes) was perturbed in mutant cells and quite significantly for PAX9 and RUNX2. Transcriptome analysis of wild-type and T357I-mutant cells identified 36 differentially expressed genes (26 downregulated, 10 upregulated) involved in skeletal system development and morphogenesis and pattern specification. WNT10A variants deemed pathogenic for TA likely affect protein folding and/or stabilization, leading to decreased WNT signaling and concomitant dysregulated expression of relevant genes. These findings may allow for improved interpretation of TA phenotypes upon clinical diagnosis while providing important insights toward the development of future tooth replacement therapies. [ABSTRACT FROM AUTHOR]

The study presents a full analysis of the Y-chromosome variability of the modern male Polish population. It is the first study of the Polish population to be conducted with such a large set of data (2,705 individuals), which includes genetic information from inhabitants of all voivodeships, i.e., the first administrative level, in the country and the vast majority of its counties, i.e., the second level. In addition, the available data were divided into clusters corresponding to more natural geographic regions. Genetic analysis included the estimation of F ST distances, the visualization with the use of multidimensional scaling plots and analysis of molecular variance. Y-chromosome binary haplogroups were classified and visualized with the use of interpolation maps. Results showed that the level of differentiation within Polish population is quite low, but some differences were indicated. It was confirmed that the Polish population is characterized by a high degree of homogeneity, with only slight genetic differences being observed at the regional level. The use of regional clustering as an alternative to counties and voivodeships provided a more detailed view of the genetic structure of the population. Those regional differences identified in the present study highlighted the need for additional division of the population by cultural and ethnic criteria in such studies rather than just by geographical or administrative regionalization. [ABSTRACT FROM AUTHOR]

Increased serum uric acid (SUA) levels cause gout and are associated with multiple diseases, including chronic kidney disease. Previous genome-wide association studies (GWAS) have identified more than 180 loci that contribute to SUA levels. Here, we investigated genetic determinants of SUA level in the Korean population. We conducted a GWAS for SUA in 6,881 Korean individuals, calculated polygenic risk scores (PRSs) for common variants, and validated the association of low-frequency variants and PRS with SUA levels in 3,194 individuals. We identified two low-frequency and six common independent variants associated with SUA. Despite the overall similar effect sizes of variants in Korean and European populations, the proportion of variance for SUA levels explained by the variants was greater in the Korean population. A rare, nonsense variant SLC22A12 p.W258X showed the most significant association with reduced SUA levels, and PRSs of common variants associated with SUA levels were significant in multiple Korean cohorts. Interestingly, an East Asian-specific missense variant (rs671) in ALDH2 displayed a significant association on chromosome 12 with the SUA level. Further genetic epidemiological studies on SUA are needed in ethnically diverse cohorts to investigate rare or low-frequency variants and determine the influence of genetic and environmental factors on SUA. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid‐filled cyst development leading to end‐stage renal disease. The rate of disease progression in ADPKD exhibits high inter‐ and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well‐delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24‐year‐old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next‐generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan. [ABSTRACT FROM AUTHOR]