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Nonsyndromic hypodontia is a congenital absence of less than six permanent teeth, with a most common subtype maxillary lateral incisor agenesis (MLIA). Mutations in several genes have been described in severe tooth agenesis. The aim of this study was to search for the variants in wingless-type MMTV-integration site family member (WNT10A), paired box 9 (PAX9) and axis inhibitor 2 (AXIN2) genes, and investigate their potential role in the pathogenesis of non-syndromic hypodontia. Clinical examination and panoramic radiograph were performed in the cohort of 60 unrelated Slovak patients of Caucasian origin with nonsyndromic hypodontia including 37 MLIA cases and 48 healthy controls. Genomic DNA was isolated from buccal swabs and Sanger sequencing of WNT10A, PAX9 and AXIN2 was performed. Altogether, we identified 23 single-nucleotide variants, of which five were novel. We have found three rare nonsynonymous variants in WNT10A (p.Gly165Arg; p.Gly213Ser and p.Phe228Ile) in eight (13.33%) of 60 patients. Analysis showed potentially damaged WNT10A variant p.Phe228Ile predominantly occurred only in MLIA patients, and with a dominant form of tooth agenesis (odds ratio (ORdom)=9.841; P=0.045; 95% confidence interval (CI) 0.492-196.701; ORrec=0.773; P=1.000; 95% CI 0.015-39.877). In addition, the WNT10A variant p.Phe228Ile showed a trend associated with familial nonsyndromic hypodontia (P=0.024; OR = 1.20; 95% CI 0.97-1.48). After Bonferroni correction, these effects remained with borderline tendencies. Using a 3D WNT10A protein model, we demonstrated that the variant Phe228Ile changes the protein secondary structure. In PAX9 and AXIN2, common variants were detected. Our findings suggest that the identified WNT10A variant p.Phe228Ile could represent risk for the inherited nonsyndromic hypodontia underlying MLIA. However, further study in different populations is required. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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]

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]

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]

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]

Background: Fat mass and obesity-associated gene (FTO) is the most studied obesity-related gene up to date. We aimed to assess anthropometric indices in carriers of FTO rs9939609 polymorphism with overweight across Iranian population (Shiraz) to find out the associations of this polymorphism with obesity indices. Methods: This was a cross-sectional study conducted on 198 overweight healthy adults aged 20-45 years old. We assessed the body composition of the participants using bioelectrical impedance analyzer. In addition, we measured the waist circumference (WC) and hip circumference (HC). Waist to hip ratio (WHR) and waist to height ratio (WHtR) were also calculated by equations. The participants' genotype was determined by ARMS-PCR. Also, data analysis was performed using SPSS software version 20 and R software version 3.6.2. Results: The mean values of body mass index (BMI) and age of the participants were 26.93 ± 1.13 kg/m2 and 33.33 ± 6.35 years old, respectively. Homozygous carriers of A-allele had significantly higher values for BMI (0.60 kg/m2, p = 0.026), WHR (0.04 unit, p = 0.003), and WHtR (0.02 unit, p = 0.030) than the homozygous carriers of T-allele. Individuals with AA genotype had greater WC (2.66 cm, p = 0.042, and 4.03 cm, p = 0.002), fat mass (2.24 kg, p = 0.004, and 3.02 kg, p = 0.001), and trunk fat (1.53 kg, p = 0.001, and 2.08 kg, p = 0.001) compared to those with AT and TT genotypes, respectively. Interestingly, after adjustment of the confounders, significant associations were observed among rs9939609 polymorphism and BMI, Wt, WC, trunk fat percentage, WHR, and WHtR. Conclusions: A-allele of the FTO rs9939609 polymorphism was indicated to be associated with greater general and central obesity in adult population of Shiraz, Iran. [ABSTRACT FROM AUTHOR]

Prolonged hyperuricemia is a cause of gout and an independent risk factor for chronic health conditions including diabetes and chronic kidney diseases. Genome-wide association studies (GWASs) for serum uric acid (SUA) concentrations have repeatedly confirmed genetic loci including those encoding uric acid transporters such as ABCG2 and SLC9A2. However, many single nucleotide polymorphisms (SNPs) found in GWASs have been common variants with small effects and unknown functions. In addition, there is still much heritability to be explained. To identify the causative genetic variants for SUA concentrations in Korean subjects, we conducted a GWAS (1902 males) and validation study (2912 males and females) and found four genetic loci reaching genome-wide significance on chromosomes 4 (ABCG2) and 11 (FRMD8, EIF1AD and SLC22A12-NRXN2). Three loci on chromosome 11 were distributed within a distance of 1.3 megabases and they were in weak or moderate linkage disequilibrium (LD) states (r2 = 0.02–0.68). In a subsequent association analysis on the GWAS loci of chromosome 11 using closely positioned markers derived from whole genome sequencing data, the most significant variant to be linked with the nearby GWAS signal was rs121907892 (c.774G>A, p.W258*) of the SLC22A12 gene. This variant, and each of the three GWAS SNPs, were in LD (r2 = 0.06–0.32). The strength of association of SNPs with SUA concentration (negative logarithm of P-values) and the genetic distance (r2 of LD) between rs121907892 and the surrounding SNPs showed a quantitative correlation. This variant has been found only in Korean and Japanese subjects and is known to lower the SUA concentration in the general population. Thus, this low-frequency variant, rs121907892, known to regulate SUA concentrations in previous studies, is responsible for the nearby GWAS signals. [ABSTRACT FROM AUTHOR]

The aim of this study was to present and compare anthropometric characteristics of Roma pregnant women in Virovitica-Podravina County to the majoritarian non-Roma group. A retrospective study on deliveries of Roma women at the Maternity Ward of the General Hospital Virovitica, Croatia, was carried out in the period from 1991 to 2010. The study included 204 Roma and 408 non-Roma pregnant women. The values analysed were prepregnancy body weight and height, body mass index (BMI), body weight before delivery, gestational weight gain (GWG) and external dimensions of the pelvis. Roma women give birth while being on average younger, 7.6 cm smaller, 4.70 kg lighter at the beginning and 5.13 kg at the end of the pregnancy, compared to the non-Roma women. The values of BMI and GWG are similar in both groups, however a higher frequency of the underweight, overweight and obese pregnant women was found in the Roma group. All three outer dimensions of the pelvis (Distancia cristarum, spinarum and trochanterica) are on average 1 cm smaller in Roma group. The differences in anthropometric characteristics between Roma and non-Roma pregnant women in Virovitica-Podravina County can be explained by ethnical origin, interaction with environmental factors and lifestyle. [ABSTRACT FROM AUTHOR]

We presented an update in the field of hypouricemia, which is defined as a serum urate concentration of < 2 mg/dL (119 μmol/L), for the practicing rheumatologist, who usually is the consulting physician in cases of disorders of urate metabolism. We performed a narrative review through a literature search for original and review articles in the field of human hypouricemia published between January 1950 and July 2018. We divided the etiology of hypouricemia into two main categories: those associated with a decrease in urate production and those promoting the elimination of urate via the kidneys. The most common conditions associated with these categories are discussed. Furthermore, the etiology of hypouricemia may be associated with certain medications prescribed by the practicing rheumatologists, such as the following: urate-lowering drugs (allopurinol and febuxostat); recombinant uricase (pegloticase); uricosuric agents (probenecid, benzbromarone); urate transporter URAT1 inhibitor (lesinurad); angiotensin II receptor blocker (losartan); fenofibrate; high-dose trimethoprim-sulfamethoxazole; some NSAID; and high-dose salicylate therapy. The rheumatologist is considered an expert in the metabolism of urate and its associated pathological conditions. Therefore, specialists must recognize hypouricemia as a biomarker of various pathological and potentially harmful conditions, highlighting the importance of conducting a deeper clinical investigation to reach a more accurate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

This article put the genetic association exploration of osteoprotegerin (OPG) gene polymorphisms in promoter region (A‐163G, T‐245G) and fracture risk first and hoped to explain the ethology of fracture. The genotyping of OPG gene polymorphisms was conducted with the method of polymerase chain reaction‐restriction fragment length polymorphism in 125 fracture patients and 138 relative controls. The genotype frequencies of selected controls based on OPG gene polymorphisms were checked by the χ2 test whether conformed to Hardy–Weinberg equilibrium (HWE). The relative risk was represented with odds ratio (OR) and 95% confidence interval (95% CI) between gene polymorphism and disease. The linkage disequilibrium (LD) and haplotype were also analyzed. The genotypes distributions of selected controls in OPG polymorphisms conformed to HWE. The G allele of A‐163G polymorphism carriers had the tendency to suffer from fracture in the same condition, compared with A allele carriers (OR = 1.63, 95% CI = 1.04–2.55). TG and TG/GG genotypes of OPG T‐245G polymorphism also showed the increased risk of fracture development, but not TT genotype (OR = 2.22, 95% CI = 1.15–4.28; OR = 2.45, 95% CI = 1.28–4.68). Likely, the mutant allele G had an abnormally higher frequency in cases than controls (14.00% and 6.16%). These two polymorphisms existed the LD and the haplotype G ‐163–G ‐245 obviously increased the risk of fracture. OPG A‐163G, T‐245G polymorphisms were associated with the onset of fracture and both the independent risk factors. [ABSTRACT FROM AUTHOR]

Renal hypouricemia (RHUC) is caused by an inherited defect in the main (reabsorptive) renal urate transporters, URAT1 and GLUT9. RHUC is characterized by decreased concentrations of serum uric acid and an increase in its excretion fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report the clinical, biochemical, and genetic findings of a pediatric patient with hypouricemia. Sequencing analysis of the coding region of SLC22A12 and SLC2A9 and a functional study of a novel RHUC1 variant in the Xenopus expression system were performed. The proband showed persistent hypouricemia (67–70 µmol/L; ref. range 120–360 µmol/L) and hyperuricosuria (24–34%; ref. range 7.3 ± 1.3%). The sequencing analysis identified common non-synonymous allelic variants c.73G > A, c.844G > A, c.1049C > T in the SLC2A9 gene and rare variants c.973C > T, c.1300C > T in the SLC22A12 gene. Functional characterization of the novel RHUC associated c.973C > T (p. R325W) variant showed significantly decreased urate uptake, an irregular URAT1 signal on the plasma membrane, and reduced cytoplasmic staining. RHUC is an underdiagnosed disorder and unexplained hypouricemia warrants detailed metabolic and genetic investigations. A greater awareness of URAT1 and GLUT9 deficiency by primary care physicians, nephrologists, and urologists is crucial for identifying the disorder. [ABSTRACT FROM AUTHOR]

The Y chromosome behaves as a single locus. Its genetic information is useful in forensic casework, deficiency kinship testing, and population genetics studies. Continuous increases of loci number within commercial kits forced modification of worldwide reference databases. In Pan American countries, like Argentina, diverse parental ethnic groups contributed to the extant admixed urban populations. We report 509 additional haplotypes of 23 Y-STRs from donors inhabiting urban areas of six Argentinean provinces: Buenos Aires, Santiago del Estero, Santa Cruz, Rio Negro, Santa Fe, and Formosa. To better understand the demographic landscape of the admixed urban paternal lineages, structural analysis was performed using published data from other Argentinean provinces. AMOVA by Rst distance and inferred haplogroups by two predictive online software methods based on haplotypes yielded complementary results with respect to detected population structure, probably due to the different proportions of the Native American Q3-M3 haplogroup in the studied samples. This situation, which is common to most North, Meso, and South American countries, underscores the need for the additional step of typing specific SNPs for haplogroup diagnosis. We propose organizing Y-STR haplotype reference databases according to the most frequent haplogroups detected in a given admixed population. [ABSTRACT FROM AUTHOR]

The identification of genes causing inherited kidney diseases yielded crucial insights in the molecular basis of disease and improved our understanding of physiological processes that operate in the kidney. Monogenic kidney disorders are caused by mutations in genes coding for a large variety of proteins including receptors, channels and transporters, enzymes, transcription factors, and structural components, operating in specialized cell types that perform highly regulated homeostatic functions. Common variants in some of these genes are also associated with complex traits, as evidenced by genome-wide association studies in the general population. In this review, we discuss how the molecular genetics of inherited disorders affecting different tubular segments of the nephron improved our understanding of various transport processes and of their involvement in homeostasis, while providing novel therapeutic targets. These include inherited disorders causing a dysfunction of the proximal tubule (renal Fanconi syndrome), with emphasis on epithelial differentiation and receptor-mediated endocytosis, or affecting the reabsorption of glucose, the handling of uric acid, and the reabsorption of sodium, calcium, and magnesium along the kidney tubule. [ABSTRACT FROM AUTHOR]

Purpose: The role of genetic polymorphisms in the pathogenesis of recurrent pregnancy loss (RPL) has been studied intensively. Complex diseases, including miscarriage, are believed to have a polygenic basis, and gene–gene interactions can play a significant role in the etiology of the disease. This study was conducted to investigate the association of gene–gene interactions with angiogenesis, endothelial dysfunction-related gene polymorphisms, and RPL. Methods: A case–control study was conducted with 253 unrelated RPL patients with 2 or more spontaneous pregnancy losses and 339 healthy women with no history of pregnancy complications. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using real-time polymerase chain reaction (real-time PCR), restriction fragment length polymorphism (RFLP), or allele-specific polymerase chain reaction methods. Results: The genotypes 677TT of the MTHFR gene, 936TT, 936CT, and 634CC, 634GC of the VEGF gene, and allele 894T of the NOS3 gene were associated with a predisposition to RPL in the Russian population. A significant role of additive and epistatic effects in the gene–gene interactions of the SNPs of SERPINE-1, ACE, NOS3, MTHFR, and VEGF genes in RPL was demonstrated. Conclusions: The results showed that gene–gene interactions are important for RPL susceptibility. Additionally, analysis of the genotype combinations of several allelic variants provides more information on RPL risk than analysis of independent polymorphic markers. [ABSTRACT FROM AUTHOR]

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Objective: Chronic myleoid leukemia (CML) is a myeloproliferative disorder characterized with the constitutive activation of Bcr-Abl tyrosine kinase which is a target for imatinib, the first line treatment option for CML. Constitutive activation of NFκB and β-catenin signaling promotes cellular proliferation and survival and resistance to Imatinib therapy in CML. Akirin-2 is a nuclear protein which is required for NFκB dependent gene expression as a cofactor and has been linked to Wnt/beta-catenin pathway. The purpose of this study is to examine Akirin-2, NFκB and β-catenin in imatinib resistance of CML and to test if any direct physical protein-protein interaction exists between NFkB and both β-catenin and Akirin-2. Methods: RT-PCR and western blot were performed to determine Akirin-2, NFκB-p65 and β-catenin gene and protein expressions, Co-immunoprecipitation and chromatin immunoprecipitation analysis were carried out to detect the direct physical interactions and binding of NFκB-p65 and β-catenin proteins to MDR1 promoter region, respectively. Results: β-catenin and NFκB-p65 proteins bound to DNA promoter regions of MDR1 in imatinib-sensitive and resistant CML cells, whereas any direct protein-protein interaction could not be found between NFκB-p65 and Akirin-2 or β-catenin proteins. Nuclear β-catenin and NFκB-p65 levels increased in imatinib resistance. Moreover, increased Akirin-2 protein accumulation in the nucleus was shown for the first time in imatinib resistant CML cells. Discussion: We show for the first time that Akirin-2 can be a novel biomarker in imatinib resistance. Targeting Akirin-2, NFκB and β-catenin genes may provide an opportunity to overcome imatinib resistance in CML. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss is a challenging reproductive problem, and chromosomal anomalies approximately affect 2%-8% of couples with recurrent pregnancy loss. The chromosomal abnormality, especially balanced translocation rearrangement in either parent, is the important cause of recurrent spontaneous abortion. Aims: The aim of this study was to investigate the role and prevalence of chromosomal anomalies in recurrent miscarriages. The results will be helpful for counseling and make the decision for alternative options and precaution for the affected couples and also support to make a national database. Settings and Design: The present retrospective study was carried out in 172 couples (344 individuals) having the history of three or more recurrent spontaneous abortion. The cytogenetic analysis was done in all 344 individuals using G-banding and karyotyping. Results: Out of 172 couples, 17 couples (9.88%) had different types of structural or numerical chromosomal abnormalities. The structural aberrations were observed in 15 (8.72%) couples, and numerical aberrations were seen in 2 (1.16%) couples. Out of 17 couples, 8 (47.05%) had balanced translocations, 2 (11.76%) had the Robertsonian translocation, 5 (29.41%) had the pericentric inversion of chromosome 8, 9, and Y, and only 2 (11.76%) women showed sex chromosome numerical aberrations. Conclusions: Cytogenetic analysis should be an important routine investigation in couples with repeated miscarriages. Cytogenetic analysis is essential and helpful for genetic counseling to take precaution and implementing proper reproductive alternatives. Studies on the genetic basis of pregnancy loss should be taken up to generate data on these issues from different regions. [ABSTRACT FROM AUTHOR]

In the present study, 90 autosomal single nucleotide polymorphisms (SNPs) and 34 Y chromosomal SNPs were sequenced simultaneously using HID-Ion AmpliSeq™ Identity Panel on the Ion PGM™ platform for 125 samples in a southern Chinese population. Raw data were analyzed and forensic parameters were calculated. Haplogrouping concordance was also assessed using alternative methods based on Y-SNP haplotypes and Y-STR haplotypes. The results showed that allelic imbalance occurred more frequently with low coverage while several SNPs with high coverage were also observed with poor allelic balance, including rs214955, rs430046, rs7520386, rs876724, rs9171188, rs16981290, and rs2032631. Totally, 21,261 miscalled reads (0.28%) were observed. The rate of allele-specific miscalled reads (ASMRs) was higher than that of allele nonspecific miscalled reads (ANMRs) and associated with genetic diversity of the SNP. The ASMRs of major allele were lower than that of minor allele while there was no difference for ANMRs. The combined discrimination power (CDP) was 1-4.81 × 10−34 and the combined power of exclusion (CPE) was 0.99989 and 0.99999992 for duo and trio paternity testing, respectively. No significant genetic difference was detected between southern and northern Chinese populations. For haplogroup study, O2 was the predominant haplogroup and 97.01% of samples were assigned consistent haplogoups with Y-SNP and Y-STR haplotypes. In conclusion, the AmpliSeq™ Identity Panel was powerful for individual identification and trio paternity testing. ASMRs were associated with the genetic diversity and allele frequency while neither was related for ANMRs. High concordance of haplogrouping assignment can be obtained with Y-STR and Y-SNP haplotypes. [ABSTRACT FROM AUTHOR]

Aim: (1) To evaluate the prevalence of inherited thrombophilia in pregnant women with adverse pregnancy outcomes: intrauterine growth retardation (IUGR), preeclampsia (PE) and placental abruption. (2) To assess the impact of inherited thrombophilia on the nature of obstetric complications. (3) To assess levels of protein S, protein C, antithrombin III and homocysteine in pregnant women with adverse pregnancy outcomes. Subjects and methods: The study comprised 162 pregnant women. The patients were divided into three test groups and one control group. In all 162 patients the following tests were completed: activated protein C resistance (APC-R), the level of free protein S, activity of protein C, antithrombin III and the level of homocysteine. The data were statistically analyzed via χ2 of independence or homogeneity test. Results: In 32 of 162 patients participating in clinical research thrombophilia was diagnosed (10 patients with APC-R, 21 patients with protein S deficiency, one patient with hyperhomocysteinemia): seven patients belonged to the control group and 25 patients had diagnosed adverse pregnancy outcomes (P=0.04). In 32 patients with diagnosed thrombophilia, level of protein S was decreased (P=0.04). Protein S deficiency was diagnosed, when level of protein S was lower than 30% in the second trimester and lower than 24% in the third trimester. The incidence of activated protein C resistance caused by the mutation of factor V Leiden was in six patients (5.9%) with adverse pregnancy outcomes, and in four patients (6.6%) from the control group. Results were not statistically significant. No protein C deficiency was diagnosed (diagnosis: level<60%), but in 50% of patients with thrombophilia level of protein C was over the norm (P=0.02). The level of antithrombin III was often decreased in patients with preeclampsia – (32.4%), then in the other patients – (17.2%) (P=0.04), but no patient was diagnosed with antithrombin III deficiency (diagnosis: level<60%). Conclusions: Tests for thrombophilia should be carried out in women with adverse pregnancy outcomes in their history, who are planning pregnancy, to start anticoagulant prophylaxis. Our study supports the thesis that tests for thrombophilia should be carried out in women with a history of adverse pregnancy outcomes and who are planning a pregnancy to start anticoagulant prophylaxis. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the phenotypic characteristics of maxillary lateral incisors hypodontia (MLIH) in a Caucasian family in northeastern Romania, and to analyze the dental and occlusal aspects consecutive to tooth agenesis. We constructed family's pedigree and examined clinically and radiographically five of its members. MLIH was transmitted mainly autosomally, with high prevalence in first-degree relatives, incomplete penetrance, variable expressivity and increased risk of recurrence. Additional environmental factors have been suggested as possible mutagens. Common dental (decreased remaining spaces and midline diastema) and occlusal (anterior crossbites) features were observed in the first two cases, and individual features in the third case (persistence of deciduous canine, complete transposition of permanent canines and mandibular anterior dental crowding), consecutive to MLIH. The last two cases - with no MLIH - showed signs common to other related cases. Only one case received complex orthodontic and implant-prosthetic treatment. [ABSTRACT FROM AUTHOR]

Introduction: Urate has been identified as a predictor of amyotrophic lateral sclerosis (ALS) survival in some but not all studies. Here we leverage the recent expansion of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to study the association between urate levels and ALS survival.Methods: Pooled data of 1,736 ALS participants from the PRO-ACT database were analyzed. Cox proportional hazards regression models were used to evaluate associations between urate levels at trial entry and survival.Results: After adjustment for potential confounders (i.e., creatinine and body mass index), there was an 11% reduction in risk of reaching a survival endpoint during the study with each 1-mg/dL increase in uric acid levels (adjusted hazard ratio 0.89, 95% confidence interval 0.82-0.97, P < 0.01).Discussion: Our pooled analysis provides further support for urate as a prognostic factor for survival in ALS and confirms the utility of the PRO-ACT database as a powerful resource for ALS epidemiological research. Muscle Nerve 57: 430-434, 2018. [ABSTRACT FROM AUTHOR]