Frequency In Population Research Articles

Identification of Three POMCa Genotypes in Largemouth Bass (Micropterus salmoides) and Their Differential Physiological Responses to Feed Domestication

Diverse feeding habits in teleosts involve a wide range of appetite-regulating factors. As an appetite-suppressing gene, the polymorphisms of POMCa in largemouth bass (Micropterus salmoides) were validated via sequencing and high-resolution melting (HRM). The frequency distribution of different POMCa genotypes were analyzed in two populations, and physiological responses of different POMCa genotypes to feed domestication were investigated. The indel of an 18 bp AU-rich element (ARE) in the 3′ UTR and four interlocked SNP loci in the ORF of 1828 bp of POMCa cDNA sequence were identified in largemouth bass and constituted three genotypes of POMC-A I, II, and III, respectively. POMC-A I and Allele I had increased frequencies in the selection population than in the non-selection population (p < 0.01), 63.55% vs. 43.33% and 0.7850 vs. 0.6778, respectively. POMC-A I possessed the lowest value of POMCa mRNA during fasting (p < 0.05) and exhibited growth and physiological advantages under food deprivation and refeeding according to the levels of body mass and four physiological indicators, i.e., cortisol (Cor), growth hormone (GH), insulin-like growth factor-1 (IGF-1), and glucose (Glu). The identification of three POMCa genotypes, alongside their varying physiological responses during feed domestication, suggests a selective advantage that could be leveraged in molecular marker-assisted breeding of largemouth bass that are adapted to feeding on formula diet.

INVOLVEMENT OF HLA-DRB1*11 AND HLA-DRB1*12 ALLELES IN THE OCCURRENCE OF DENGUE FEVER IN BURKINA FASO

Introduction: Dengue has become the world's most common arbovirosis. In some individuals, genetic factors can increase the risk of developing severe dengue fever. Human leukocyte antigen (HLA) genes are one of the most extensively studied gene groups in human disease. The present study investigated HLA DRB1*11 and HLA DRB1*12 polymorphisms in dengue cases and their susceptibilities in the development of dengue in a population in Ouagadougou, Burkina Faso. Methodology: This was a case-control study involving 56 patients with clinically and biologically confirmed dengue fever and 65 others who had never been in contact with DENV, for a total of 121 individuals. A blood sample was taken from each study participant. After extraction of genomic DNA using the salting-out technique, characterisation of carriage of the HLA-DRB1*11 and 1*12 alleles was carried out using multiplex polymerase chain reaction (PCR). The χ² test, odds ratio (OR), and confidence interval (CI) were calculated using SPSS software to estimate associations and assess the level of risk. Results: Allele frequencies in the general population were 64.4% and 62.8% for HLA DRB1*11 and HLA DRB1*12, respectively. The HLA-DRB1*12 allele was present in 28.9% of cases and 33.9% of controls. The HLA-DRB1*11 allele was present in 32.2% of both cases and controls. In this study, no direct association was found between the presence of the HLA-DRB1*11 and HLA-DRB1*12 alleles and the surveillance of dengue infection. Furthermore, the absence of the HLA-DRB1*11 allele was associated with protection against the development of severe disease (OR = 0.03; 95% CI [0.11 - 0.80]; and p = 0.01). Conclusion: No risk of developing severe dengue fever was found in individuals carrying the HLA-DRB1*11 and HLA-DRB 1*12 alleles. However, further study of other HLA alleles involved in the development of severe dengue may provide more information.

Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy.

Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data. Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM. This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

Experimental investigation on the effect of concentration on the resonance frequency of lipid coated ultrasonically excited microbubbles

This study presents an experimental investigation of the influence of MB concentration on the resonance frequency of lipid-coated microbubbles (MBs). Expanding on theoretical models and numerical simulations from previous research, this work experimentally investigates the effect of MB size on the rate of resonance frequency increase with concentration, a phenomenon observed across MBs with two different lipid compositions: propylene glycol (PG) and propylene glycol and glycerol (PGG). Employing a custom-designed ultrasound attenuation measurement setup, we measured the frequency-dependent attenuation of MBs, isolating MBs based on size to generate distinct monodisperse sub-populations for analysis. The resonance frequency of MBs was determined by identifying the attenuation peak in the broadband attenuation ultrasound attenuation measurements. Our experimental findings confirm that larger MBs (≈2.1μm) demonstrate a more significant shift in resonance frequency (≈ 5 MHz, ≈ 40%) as a function of MB concentration. In contrast, smaller MBs (≈1.3μm) show a minor shift in the resonant frequency (≈ 1.8MHz, ≈ 8%), underlining the importance of size in determining acoustic behavior compared to changes in the lipid shell properties. Additionally, we observed that resonance frequency increase with concentration reaching a saturation point at higher concentrations. This plateau occurs at higher concentrations for larger MBs (≈2.1μm), while smaller MBs (≈1.6μm and ≈1.3μm) reach this saturation point at lower concentrations. Furthermore, the study highlights the small effect of bubble-bubble interactions on the resonance frequency of MB populations, particularly at lower MB concentrations and for smaller MBs. This insight is important for applications utilizing MB clusters, such as contrast-enhanced ultrasound imaging and MB-mediated therapies. While both size and lipid shell composition influence resonance frequency, MB size has a more significant effect. In conclusion, our findings affirm the need to consider both MB size and concentration when utilizing MBs for clinical and industrial ultrasonic applications.

Patterns of herbicide resistance in Raphanus raphanistrum revealed by comprehensive testing and statistical analysis.

Raphanus raphanistrum causes $40 million total revenue losses annually in Western Australia partly due to its historically-documented ability to evolve herbicide resistance to multiple modes of action. In this study, 376 field-sampled populations of R. raphanistrum were tested for resistance to 21 herbicides applied at the recommended label rate. Eight treatments were herbicide mixtures with two, three or four modes of action. A total of 7199 individual resistance tests were conducted across 4 years by screening approximately 104 000 individual seeds and seedlings. The mean survival of individuals within a population for all standalone herbicides was 9%, whereas survival was significantly decreased to 3.5% with a herbicide mixture. Some herbicides such as triasulfuron (herbicide Group 2), 2,4-D (Group 4) or diflufenican (Group 12) were highly impacted by resistance, with frequencies of resistant populations being > 50%. Conversely, there was negligible resistance to glyphosate (Group 9) or protoporphyrinogen oxidase (PPO) inhibitors (tiafenacil, saflufenacil + trifludimoxazin, fomesafen: Group 14), and pre-emergence herbicides (i.e., atrazine or mesotrione: Groups 5 and 27, respectively) remained largely effective. Binary, ternary or quaternary mixtures of Groups 4, 6, 12 and 27 herbicides reduced the frequency of high-level resistant populations to 7.1%, 3.8% or 0%, respectively. The cost-effective control of R. raphanistrum remains a challenge due to herbicide resistance. Raphanus raphanistrum management relies heavily on herbicide uses not yet compromised by resistance, such as pre-emergence herbicides (atrazine, fomesafen, mesotrione), glyphosate, and mixtures of two, three or four modes of action including bromoxynil, diflufenican, MCPA, picolinafen, pyrasulfotole and topramezone. Strategies that integrate effective herbicide use patterns, novel modes of action and efficiently-mechanized non-chemical weed control options (i.e., seed destructors) can completely constrain the selection of herbicide resistance in this highly adaptable species. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Three Fields Allelic Haplotype Frequencies of HLA‐DPA1 and ‐DPB1 Typed by Next Generation Sequencing of 563 Families in Chinese Han Population

ABSTRACTThe present study investigated the HLA‐DPA1 and ‐DPB1 allele and haplotype frequencies in the Chinese Han population. A total of 563 families, which have been typed for the purpose of haematopoietic stem cell transplantation, were included, and three‐field allelic resolution typing of HLA‐DPA1 and ‐DPB1 of all individuals were defined by the next‐generation sequencing method. HLA‐DPA1~DPB1 haplotypes were determined by allele segregation within a nuclear family. A total of 9 HLA‐DPA1 and 39 HLA‐DPB1 alleles, and 62 HLA‐DPA1~DPB1 haplotypes were identified. The three most frequent alleles at HLA‐DPA1 locus are HLA‐DPA1*02:02:02 (46.581%), HLA‐DPA1*01:03:01 (36.456%) and HLA‐DPA1*02:01:01 (12.167%); and the three most frequent HLA‐DPB1 alleles are HLA‐DPB1*05:01:01 (34.014%), HLA‐DPB1*02:01:02 (18.428%) and HLA‐DPB1*04:01:01 (10.124%). The three most frequent haplotypes are HLA‐DPA1*02:02:02~DPB1*05:01:01 (32.327%), HLA‐DPA1*01:03:01 ~ DPB1*02:01:02 (14.654%) and HLA‐DPA1*01:03:01~DPB1*04:01:01 (9.458%). The HLA‐DPA1*02:01~DPB1*02:02 and HLA‐DPA1*04:01~DPB1*05:01 haplotypes appear to be unique in Han Chinese. Strong global linkage disequilibrium (LD) between HLA‐DPA1 and ‐DPB1 was confirmed (D′ = 0.848, Wn = 0.684). Moreover, the haplotype frequencies based on the family study were compared with the frequencies estimated by the expectation–maximisation algorithm, and the equivalent results were obtained except for haplotypes with very low frequencies. Our data provide a solid base for HLA‐DP dimer association studies and useful information for transplantation and disease association studies.

Single-cell analyses reveal that monocyte gene expression profiles influence HIV-1 reservoir size in acutely treated cohorts.

Elimination of latent HIV-1 is a major goal of AIDS research but the host factors determining the size of these reservoirs are poorly understood. Here, we investigated whether differences in host gene expression modulate the size of the HIV-1 reservoir during suppressive ART. Peripheral blood mononuclear cells (PBMC) from fourteen individuals initiating ART during acute infection who demonstrated effective viral suppression but varying magnitude of total HIV-1 DNA were characterized by single-cell RNA sequencing (scRNA-seq). Differentially expressed genes and enriched pathways demonstrated increased monocyte activity in participants with undetectable HIV-1 reservoirs. IL1B expression in CD14+ monocytes showed the greatest fold difference. The inverse association of IL1B with reservoir size was validated in an independent cohort comprised of 38 participants with different genetic backgrounds and HIV-1 subtype infections, and further confirmed with intact proviral DNA assay (IPDA ® ) measurements of intact HIV-1 proviruses in a subset of the samples. Modeling interactions with cell population frequencies showed that monocyte IL1B expression associated inversely with reservoir size in the context of higher frequencies of central memory CD4+ T cells, implicating an indirect effect of IL1B via the cell type well established to be a reservoir for persistent HIV-1. Signatures consisting of co-expressed genes including IL1B were highly enriched in the "TNFα signaling via NF-κB" geneset. Functional analyses in cell culture revealed that IL1B activates NF-κB, thereby promoting productive HIV-1 infection while simultaneously suppressing viral spread, suggesting a natural latency reversing activity to deplete the reservoir in ART treated individuals. Altogether, unbiased high throughput scRNA-seq analyses revealed that monocyte IL1B variation could decrease HIV-1 proviral reservoirs in individuals initiating ART during acute infection.

Genome-wide copy number variation association study in anorexia nervosa.

This study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wide association study (GWAS) array data from the Anorexia Nervosa Genetics Initiative (ANGI), which included 7414 AN case and 5044 controls, we investigated the association of 67 well-established syndromic CNVs and 178 pleiotropic disease-risk dosage-sensitive CNVs with AN. To identify novel CNV regions (CNVRs) that increase the risk of AN, we conducted genome-wide association studies with a focus on rare CNV-breakpoints (CNV-GWAS). We found no net enrichment of rare CNVs, either deletions or duplications, in AN, and none of the well-established syndromic or pleiotropic CNVs had a significant association with AN status. However, the CNV-GWAS found 21 nominally associated CNVRs that contribute to AN risk, covering protein-coding genes implicated in synaptic function, metabolic/mitochondrial factors, and lipid characteristics, like the CD36 (7q21.11) gene, which transports long-chain fatty acids into cells. CNVRs intersecting genes previously related to neurodevelopmental traits include deletions of NRXN1 intron 5 (2p16.3), IMMP2L (7q31.1), and PTPRD (9p23). Overall, given that our study is well powered to detect the CNV burden level reported for schizophrenia, we can conclude that rare CNVs have a limited role in the etiology of AN, as reported for bipolar disorder. Our nominal associations for the 21 discovered CNVRs are consistent with AN being a metabo-psychiatric trait, as demonstrated by the common genetic architecture of AN, and we provide association results to allow for replication in future research.

Abstract 4136581: Shared Genetic Burden of Ischemic and Non-Ischemic Dilated Cardiomyopathy

Introduction: Ischemic dilated cardiomyopathy (IDCM) is defined as DCM caused by severe stenosis of one or more coronary arteries. Patients with non-ischemic dilated cardiomyopathy (NIDCM) have normal coronary arteries and may possess rare disease-causing variants in cardiac proteins such as TTN . However, IDCM and NIDCM share echocardiographic and pathologic features, possibly suggesting a shared etiology. Hypothesis: There is a similar prevalence of pathogenic (P)/likely pathogenic (LP) variants in patients with IDCM compared to patients with NIDCM. Aims: We compared the prevalence of P/LP genetic variants in DCM-associated genes in a cohort of patients with NIDCM or IDCM who received a heart transplant. Methods: We conducted a retrospective cohort study of patients who received a heart transplant between May 2017 and October 2023 at Cedars Sinai Medical Center in Los Angeles, CA. All subjects had LVEF ≤ 50% and LVEDD ≥ 95 th percentile for sex and height. Whole exome sequencing was performed on explanted heart tissue. We assessed for rare variants (minor allele frequency &lt;0.1%) in genes with a definite, strong, or moderate rating in the ClinGen DCM Gene Curation Expert Panel. Variant pathogenicity was interpreted using the American College of Genetics and Genomics criteria for DCM. Ischemic cardiomyopathy was defined by the Felker criteria (Felker et al., JACC 2002). Results: We included 60 subjects: 16 with IDCM and 44 with NIDCM. There was no difference in LVEF or LVEDD between groups (TABLE). 2/16 (12.5%) patients with IDCM carried a P/LP variant, both of which were in TTN . 11/44 (25.0%) patients with NIDCM carried a P/LP variant: 6 in TTN and 1 each in FLNC, ILK, LMNA, MYH7 , and RBM20 . The prevalence of TTN variants in each group was similar (12.5% in IDCM vs. 13.6% in NIDCM) and higher than the expected frequency in the general population (0.2%). There was no significant difference in the prevalence of P/LP variants between the groups (chi-squared p-value 0.493, Bayes factor 0.45). Conclusion: Patients with IDCM exhibited a similar prevalence of P/LP variants to NIDCM patients, which suggests a shared genetic burden. If further studies confirm our findings, genetic testing for individuals with IDCM may be warranted.

Toll-like receptors polymorphisms and COVID-19: a systematic review.

COVID-19 is a disease caused by SARS-CoV-2. It became a health problem affecting the lives of millions of people. Toll-like receptors are responsible for recognizing viral particles and activating the innate immune system. The genetic factors associated with COVID-19 remain unclear. Thus, this study aims to assess the association between the polymorphism in Toll-like receptors and susceptibility to COVID-19. We searched the electronic databases (Science Direct, PUBMED, Web of Science, and Scopus) for studies assessing the association between Toll-like receptor polymorphisms and susceptibility to COVID-19. The quality of the studies was assessed using the Q-Genie tool. Thirteen studies were included in this systematic review. The studies analyzed polymorphisms in TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9. We used SNP2TFBS bioinformatic analysis to identify the variants influencing transcription factor binding sites. The Ensembl Genome Browser was used to assess the allele and genotype frequencies in different populations. The bioinformatic analysis revealed that the variant rs5743836 of TLR9 affects the transcription factor binding sites NFKB1 and RELA. The genotype frequency of the variants rs3775291, rs3853839, rs3764880 were higher in East Asian population compared to the other populations. The frequency of the rs3775290 variant was higher in East and South Asian populations. The rs179008 variant was higher in the European population, and the rs5743836 was higher in the African population. Toll-like receptors play an important role in COVID-19 susceptibility. Further studies in different populations are necessary to elucidate the role of Toll-like receptors polymorphisms in SARS-CoV-2 infection.

Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis.

Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.

Pharmacogenetics of colorectal cancer in a third-level hospital in Valencia

Abstract Objectives Genetic variants with associated pharmacokinetic and pharmacodynamic effects have an impact on the development of adverse drug reactions and survival of patients with colorectal cancer. Methods A selection of genetic variants was performed according to the established chemotherapy and the pharmacogenetic databases. Genotyping was performed using MassArray technology (Agena Bioscience). Variant-toxicity and survival-genotype correlations were assessed using logistic regression (SPSS v.28.0.1.1). Results Genotyping of 25 SNPs was performed in 96 patients. In relation to the DPYD gene, 3.5 % had the rs75017182 mutation; 4.7 % the rs1801158 mutation and 7.1 % the rs1801160 mutation. Genotypic frequencies in the UGT1A1 gene were 39.4 % (*1/*1); 37.9 % (*1/*28); 19.7 % (*28/*28); and 3 % (*1/*36). The genotypes CT of the rs1801160 variant, AT of the rs67376798 variant (DPYD) and *1/*36 (UGT1A1) were associated with low survival (p-value: 0.006, &lt;0.001, and 0.052, respectively). The most frequent adverse reactions were gastrointestinal disorders, followed by neurotoxicity. The CC genotype (rs1801160, DPYD) was associated with a lower risk for developing severe gastrointestinal events, whereas CC (rs1801158, DPYD) was associated with a lower risk of developing severe general hematologic toxicity. Conclusions The population frequencies obtained in our study for rs1801160 and rs75017182 (DPYD); and for *1/*28, *28/*, and *1/*36 (UGT1A1) were inconsistent with the frequencies reported for the Spanish population in the literature. The genotypes CT of rs1801160, AT of rs67376798 (DPYD), and 1/*36 (UGT1A1) were associated with lower survival rates.

ERRα is dispensable for hematopoietic stem cell function in the bone marrow

Hematopoietic stem cells (HSCs) have the ability to self-renew, differentiate into various blood cell types, and reside in the bone marrow (BM) niche. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has a role in mitochondrial biogenesis and metabolic regulation. Previous research has shown that ERRα contributes to the development of acute myeloid leukemia (AML) by acting as a key regulator of mitochondrial processes, though its role in HSC regulation remains mostly unknown. Flow cytometric analysis determined the population of the hematopoietic stem and progenitor cells (HSPC) using Errα knockout (KO) and conditional KO (cKO) mice. Furthermore, we investigated reconstitution with BM transplantation assay. Here, the ablation of Errα in the BM demonstrated that the production of mature blood cells, lineage distribution within hematopoietic organs, and frequencies of the HSPC populations were similar to those of controls. In addition, the ablation of Errα did not perturb HSC function under the stress of transplantation. Collectively, ERRα is not necessary for the control of HSPC populations, as well as for the maintenance of HSC characteristics and functions within the BM.

Carrier frequency and incidence estimation of deficiency of adenosine deaminase 2 in the Chinese population based on massive exome sequencing data

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease characterised by early onset stroke, recurrent fever, and diverse vascular pathologies, caused by loss-of-function homozygous or compound heterozygous variants of ADA2. This research aimed to determine the carrier frequency and expected incidence of DADA2 in China, using massive exome sequencing (ES) data. A total of 50 likely pathogenic/pathogenic variants (LP/PVs) were identified among 69,413 Chinese individuals, including 20 novel and rare variants (<0.0022 % allele frequency), expanding the known spectrum of PVs in ADA2. The overall carrier frequency in the Chinese population was 1.05 % (732/69,413) and the estimated incidence of DADA2 was approximately one in 92,251 individuals. The present study provides an accurate estimation of the prevalence of DADA2 in China, supporting genetic counseling, early diagnosis treatment, and prognostic evaluation.

Characterization of Y chromosome diversity in newfoundland and labrador: evidence for a structured founding population.

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700s-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL-based cohort were analyzed using 5,761 Y-specific SNPs. We identified 160 distinct terminal haplogroups, the majority of which (71.4%) belong to the R1b haplogroup. When compared with global reference populations, the NL population haplogroup composition and frequencies primarily resemble those observed in English and Irish ancestral source populations. There is also evidence of genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers who frequented NL. Interestingly, the observed population structure shows geographical and religious clustering that can be associated with the settlement of the ancestral source populations from predominantly Protestant, England, and Catholic, Ireland respectively. For example, the R1b-M222 haplogroup, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplogroups in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation, and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population.

Hereditary transthyretin amyloidosis caused by Val142Ile variant in Spain: phenotypic characteristics, geographic distribution and population frequency

Abstract Background During recent years, several cases of hereditary transthyretin amyloidosis (ATTRv) due to p.Val142Ile have been described in patients without African ancestry in countries like Japan, Spain or Italy (1,2,3,4). All this evidence suggests that p.Val142Ile might be more prevalent than expected worldwide. Objectives The aim of this study was to analyze the impact of ATTRv caused p.Val142Ile in Spain to define its phenotypic characteristics, to explore endemic geographical areas and define its population frequency. Methods Patients diagnosed with ATTRv caused by p.Val142Ile and carriers irrespective of their phenotype were recruited from 16 centers in Spain. Baseline characteristics and events during follow-up were retrieved. Population frequency was assessed through the Spanish National DNA bank (N=3,569) and the Catalan Health Databank (N=790). Results The cohort included information regarding 164 subjects (75 probands [45.7%] and 89 relatives [54.3%]). Among probands, mean age was 73.9 ± 8.5 years and 47 (62.7%) were males. 67 probands (89.3%) had self-declared European ancestry and only 6 cases (8%) referred African or Afro-American ancestry. Cardiac symptoms were the most frequent reason leading to ATTRv diagnosis (N=64, 85.3%) followed by incidental finding (N=8, 10.7%) and neurologic symptoms (N=3, 4%). (Figure 1). Median follow-up was 1.6 years (Interquartile range 0.6-3.2). Neurologic involvement was observed in 35 probands (46.7%) at first evaluation or during follow-up. Overall penetrance at 65, 75 and 85 years was 12.8%, 44.3% and 94.2% respectively. Male sex was associated with earlier penetrance than women (P = 0.02). 38 patients initiated treatment with tafamidis during follow-up (28 [73.7%] 20 mg and 10 [26.3%] 61 mg), despite treatment, disease progression at 1 year (cardiovascular death or 30% increase of NTProBNP) was observed in 10 patients (40%). Population frequency was estimated between 0.0% and 0.12% based on the Spanish and Catalan databases respectively. Birthplace of probands suggests a higher prevalence in the Mediterranean basin. (Figure 2) Conclusions Our data suggests that ATTRv caused by p.Val142Ile has a significant prevalence in Spain, mostly in some specific regions. Phenotypic features are defined by late onset, male predominance, and cardiac involvement although a significant proportion develop neuropathy. Disease progression was observed in 40% of patients despite disease-modifying therapies.

Increased risk for thoracic and abdominal aortic aneurysm in the relatives of abdominal aorta aneurysm patients

Abstract Introduction Genetic susceptibilities in aneurysm genes are risk factors for developing aneurysms of the aorta. This translates to a high aneurysm prevalence in relatives of aortic aneurysm patients. For relatives of abdominal aorta aneurysm (AAA) patients, guidelines recommend abdominal ultrasound screening for early detection and management, while for relatives of thoracic aorta aneurysm patients (TAA), transthoracic ultrasound of the ascending aorta and aortic root is recommended. Neither of these guidelines are designed to detect aneurysms in the whole aorta. The incidence of TAA in relatives of AAA index-patients is unknown and may determine whether abdominal ultrasound screening is sufficient for relatives of AAA patients or whether whole aorta screening should be recommended. Furthermore, focused screening of high risk relatives of aneurysm patients may improve the yield of aneurysm detection now that population frequencies are declining. Methods Whole aorta non-contrast CTs of relatives of AAA index-patients were collected retrospectively in a tertiary referral (2016 to 2021). Family history and DNA testing of AAA index-patients were used to classify relatives into high genetic risk (familial disease and/or pathogenic/likely pathogenic variant (P/LP) in an aneurysm gene) or unknown genetic risk (no familial disease or no P/LP detected). TAA were defined as ascending diameters ≥ 45mm or descending diameters ≥ 40mm. Thoracic aortic dilatations (TAD) were defined as ascending diameters of 40-45 mm or descending diameters of 35-40 mm. Abdominal diameters ≥30mm were classified as AAA and diameters between 25-29 mm as abdominal dilatations (AAD). References 1-3. Results CT scans (n=301 relatives, 47% male, age 58(50-65)) showed 34% aortic aneurysms and/or dilatations versus 14% in the general population (age adjusted, p&amp;lt;0.001). TAA was 28-times more frequent (2%, p&amp;lt;0001) and AAA 3 times more frequent (8%, p&amp;lt;0.001) than in the general population. Thoracic and abdominal dilatations occurred in 18% and 17% of relatives. Overall, males were 4 times more likely to have an aneurysm than females (p&amp;lt;0.05). Aneurysms and dilatations occurred at the same rate in relatives with or without a family history or a P/LP in an aneurysm gene. These results endorse total aorta screening for relatives of all AAA patients rather than restricting screening to the abdominal aorta. Conclusions Relatives of AAA patients had a high risk for thoracic and abdominal aneurysms as well as dilatations. This indicates that imaging of the whole aorta will improve early detection of aortic aneurysms in relatives both with and without a family history of aneurysms.

Epidemiological analysis of pediculosis and the distribution of kdr mutation frequency in head lice populations in Torbat Heydarieh city of Khorasan Razavi Province, Northeastern Iran

Head lice infestations are the most prominent ectoparasitic infection in the world, including Iran, particularly among school children. Recently, numerous cases of infestation have been reported in various provinces of the country. This study aimed to investigate the prevalence of head louse infestations and analyze kdr gene sequences in terms of resistance mutations in the Torbat-e Heydarieh, Mahvelat, and Zaveh cities of Khorasan Razavi Province, Northeast Iran. The data related to the epidemiological and demographic history of head lice populations were extracted from their medical records and analyzed in Excel software. After extracting the genomic DNA, the kdr fragment was amplified using specific primers. The sequences were also analyzed using bioinformatics software. The prevalence of head louse infestations was 1.59% and 1.7% during 2016 and 2017, respectively. Sequence analysis revealed the frequency distribution of two kdr haplotypes, I and V, in the study areas. The increase in head louse infestations in recent years and the simultaneous presence of kdr mutations indicate the need for new treatments and monitoring/controlling resistance to head louse insecticides.

Genetic analysis of preaxial polydactyly: identification of novel variants and the role of ZRS duplications in a Chinese cohort of 102 cases.

Preaxial polydactyly (PPD) is a congenital limb malformation, previously reported to be caused primarily by variants in the ZRS and upstream preZRS regions. This study investigated genetic variations associated with PPD, focusing on point variants and copy number variations (CNVs) in the ZRS and preZRS regions. Comprehensive genetic analyses were conducted on 102 patients with PPD, including detailed clinical examinations and Sanger sequencing of the ZRS and preZRS regions. Additionally, real-time quantitative PCR (qPCR) was used to detect CNVs in the ZRS region. The evolutionary conservation and population frequencies of identified variants were also evaluated. Six point variants were identified, among which four are likely pathogenic novel variants: 93G > T (g.156584477G > T), 106G > A (g.156584464G > A), 278G > A (g.156584292G > A), and 409A > C (g.156585378A > C). Additionally, qPCR analysis revealed that 66.67% of patients exhibited ZRS duplications. Notably, these duplications were also present in cases with newly identified potential pathogenic point variants. These findings suggest the possible interaction of point variants in ZRS and preZRS through a common pathogenic mechanism, leading jointly to PPD. The findings expand the variant spectrum associated with non-syndromic polydactyly and highlight that, despite different classifications, anterior polydactyly caused by variants in ZRS and nearby regions may share common pathogenic mechanisms. The incorporation of various variant types in genetic screening can effectively enhance the rate of pathogenic variant detection and contribute to the cost-effectiveness of genetic testing for limb developmental defects, thereby promoting healthy births.

Strong association of single nucleotide polymorphisms in BRCA1, ATM, and CHEK2 with breast cancer susceptibility in a sub-population of Iranian women.

Breast cancer (BC) is the most prevalent malignancy in females worldwide. Mutations in the DNA repair pathway genes contribute to a significant increase in BC risk. The present study aimed to assess the frequency of polymorphisms in BRCA1, ATM, and CHEK2 genes and their association with BC susceptibility in the Kurdish population from the West of Iran. In the present case-control study, the distribution of single nucleotide polymorphisms (SNPs) in CHEK2 (rs17879961), ATM (rs28904921), and BRCA1 (rs80357906, rs1555576855, rs1555576858, and rs397509247) genes were investigated in 335 BC cases and 354 healthy-matched controls by Taqman allelic discrimination assay. The chi-square goodness-of-fit test was employed for the assessment of Hardy-Weinberg Equation. Relative risk and odds ratios were calculated based on the Koopman asymptotic score and the Baptista-Pike method, respectively. Also, the sensitivity and specificity of each polymorphism were assessed using the Wilson-Brown test and a P-value < 0.05 indicating significant differences between the two groups in all assessments. Data showed there was a strong association between rs397509247 (OR = 7.53, 95% CI 1.88-90.91, p = 0.004), rs1555576858 (OR = 10.53, 95% CI 0.01-0.51, p = 0.0005), and rs80357906 (OR = 6.33, 95% CI 0.05-0.043, p < 0.0001) in BRCA1 gene and rs17879961 (OR = 3.52, 95% CI 0.084-0.946, p = 0.02) in CHEK2 gene, with BC risk in the population of interest. Among these, rs28904921 in ATM gene demonstrated the strongest association (OR = 72.66, 95% CI 0.007-0.214, p < 0.0001). This suggests that these SNPs, particularly rs28904921, are significantly associated with an increased risk of BC in the studied population. Our results indicated that BRCA1, ATM, and CHEK2 polymorphisms have a high frequency in the Iranian breast cancer population, with some mutant allele frequencies being much higher than those reported in other populations. We have also provided a simple, multiplex, rapid, and accurate genotyping assay that is useful in clinical settings.