CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.

BACKGROUND: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). METHODS: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed ß-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. RESULTS: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. CONCLUSIONS: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

Genetic structure of Iranian indigenous sheep breeds: insights for conservation.

Genetic structure and genetic diversity levels of indigenous Iranian sheep breeds are not clear, despite the interest this region has in itself as an important center for domestication of livestock. Early population genetic studies have reported high levels of diversity among Iranian sheep breeds until recently, when high admixture levels and genetic homogeneity have been detected. The rapid reduction of diversity observed in Iranian breeds might be due to an increasing trend of intensive crossbreeding practices or even total replacement of native breeds by highly specialized and productive ones. From a conservative perspective, this situation is highly concerning; thus, it might be wise to consider a conservation program in Iran to preserve the original genetic diversity in native sheep breeds. In this study, a total of 1065 animals with the purest morphological features representing 24 Iranian indigenous sheep breeds were sampled, corresponding to ancestral breed diversity. These samples were genotyped for 17 microsatellite loci in order to (1) determine the native ancestral diversity of Iranian breeds, (2) define the degree of genetic relationship among studied breeds, and (3) assess conservation priorities among defined groups. Our results showed no recent loss of diversity, but high genetic diversity levels for indigenous sheep breeds in Iran. Indeed, the analysis of conservation priorities pointed out the importance of 8 breeds for maintaining Iranian sheep breeds' maximum genetic diversity. Thus, under a genetic perspective, these 8 breeds should be the ones included into conservation programs for restocking endangered areas.

Genomic selection signatures in sheep from the Western Pyrenees.

BACKGROUND: The current large spectrum of sheep phenotypic diversity results from the combined product of sheep selection for different production traits such as wool, milk and meat, and its natural adaptation to new environments. In this study, we scanned the genome of 25 Sasi Ardi and 75 Latxa sheep from the Western Pyrenees for three types of regions under selection: (1) regions underlying local adaptation of Sasi Ardi semi-feral sheep, (2) regions related to a long traditional dairy selection pressure in Latxa sheep, and (3) regions experiencing the specific effect of the modern genetic improvement program established for the Latxa breed during the last three decades. RESULTS: Thirty-two selected candidate regions including 147 annotated genes were detected by using three statistical parameters: pooled heterozygosity H, Tajima's D, and Wright's fixation index Fst. For Sasi Ardi sheep, chromosomes Ovis aries (OAR)4, 6, and 22 showed the strongest signals and harbored several candidate genes related to energy metabolism and morphology (BBS9, ELOVL3 and LDB1), immunity (NFKB2), and reproduction (H2AFZ). The major genomic difference between Sasi Ardi and Latxa sheep was on OAR6, which is known to affect milk production, with highly selected regions around the ABCG2, SPP1, LAP3, NCAPG, LCORL, and MEPE genes in Latxa sheep. The effect of the modern genetic improvement program on Latxa sheep was also evident on OAR15, on which several olfactory genes are located. We also detected several genes involved in reproduction such as ESR1 and ZNF366 that were affected by this selection program. CONCLUSIONS: Natural and artificial selection have shaped the genome of both Sasi Ardi and Latxa sheep. Our results suggest that Sasi Ardi traits related to energy metabolism, morphological, reproductive, and immunological features have been under positive selection to adapt this semi-feral sheep to its particular environment. The highly selected Latxa sheep for dairy production showed clear signatures of selection in genomic regions related to milk production. Furthermore, our data indicate that the selection criteria applied in the modern genetic improvement program affect immunity and reproduction traits.

Genetic variants associated with rheumatoid arthritis patients and serotypes in European populations.

OBJECTIVES: To replicate the association of rheumatoid arthritis (RA) susceptibility loci in an independent European sample and to assess their specificity with anti-citrullinated protein antibodies (ACPA) status. METHODS: A selection of 64 SNP previously associated with RA have been typed in a cohort of 267 RA patients (169 ACPA-positive and 98 ACPA-negative) and 152 controls from the Rheumatology Units of the University Hospital of Pisa (Italy) and the University of Pécs Medical Center (Hungary). Regression analyses were performed first considering overall RA patients and secondly, taking both serotype subgroups as different disease entities. The results have been adjusted for age, gender and origin of individuals. RESULTS: The well-known CD2, REL, TNFAIP3, IRF5, PTPRC, and CCR6 have been confirmed as RA disease associated loci together with recently discovered BACH2, RASGRP1, and IKZF3 loci, taking all RA patients as a unique phenotype. Results from both serological subgroups separately reflect the specificity of these susceptibility loci and show additional ACPA-positive specific associations for variants at IL6R, IL2RA, BLK, DDX6, IL6, and TLE3 genes. CONCLUSIONS: The results from GAPAID project are consistent with previously established RA disease associations for CD2, PTPRC, REL, CCR6, TNFAIP3, IRF5, BLK, IL2RA, and DDX6 loci. In addition, IL6R, BACH2, RASGRP1, TLE3, and IKZF3 are replicated for the first time in an independent European population and IL6 appears to be a suggestive new RA associated locus. The stratified analysis based on ACPA status provides further support for distinct genetic aetiologies of RA subsets, which might have therapeutic implications.

The Effects of the Exogenous Melatonin on Shift Work Sleep Disorder in Health Personnel: A Systematic Review.

(1) Background: To know the medical documentation related to exogenous melatonin in sleep disorders caused by shift work in health personnel; (2) Methods: Systematic and critical review. Data were obtained by looking up the bibliographic data base: MEDLINE (via Pubmed), Embase, Cochrane Library, Scopus, Web of Science, Latin American and Caribbean literature in Health Sciences (LILACS) and Medicine in Spanish (MEDES). The used terms, as descriptors and text in the title and abstract record fields, were "Health Personnel", "Melatonin" and "Sleep Disorders", Circadian Rhythm, by using the following filters: "Humans", "Adult: 19+ years" and "Clinical Trial". The search update was in December 2021. The documentary quality of the articles was assessed using the CONSORT questionnaire. (3) Results: Having applied the inclusion and exclusion criteria, 10 clinical essays were selected out of 98 retrieved references. CONSORT scores ranged from a minimum of 6.0 to a maximum of 13. 7 with a median of 10.2. According to the SIGN criteria, this review presented "1-"evidence with a grade of recommendation B. The intervention dose via administration of exogenous melatonin ranged between 1 and 10 mg. It was not mentioned whether the route of administration was by fast or slow absorption. The outcomes showed decreased daytime sleepiness, lessened sleep onset latency, diminished night-time awakenings, increased total sleep period and improved daytime attention in the melatonin-treated group; (4) Conclusions: Exogenously administered melatonin is effective in shift worker health personnel that are suffering from sleep disorders, and given its low adverse effects and tolerability, it might be recommended. A great disparity was evidenced in terms of dose, follow-up periods and type of melatonin, small participant population, same age ranges and young age. Therefore, new trials would be needed to amend these observations in order to have full evidence that is able to ensure the efficacy of exogenous melatonin in the studied population.

Association between combinations of genetic polymorphisms and epidemiopathogenic forms of bovine paratuberculosis.

Control of major mycobacterial diseases affecting livestock is a challenging issue that requires different approaches. The use of genetic markers for improving resistance to Mycobacterium avium subsp. paratuberculosis infection in cattle has been explored as a promising population strategy We performed paratuberculosis epidemiopathogenic phenotypic and genotypic characterization involving 24 SNPs in six candidate genes (NOD2, CD209, SLC11A1, SP110, TLR2 and TLR4) on 502 slaughtered Friesian cows. In the current study, we investigate whether recently proposed paratuberculosis (PTB) epidemiopathogenic (EP) forms (apparently free-AF, latent-LAT and patent-PAT) could be associated with some combination of these 24 SNPs. Best EP form grouping was obtained using a combination of 5 SNPs in four genes (CD209: rs210748127; SLC11A1: rs110090506; SP110: rs136859213 and rs110480812; and TLR2: rs41830058). These groups were defined according to the level of infection progression risk to patent epidemiopathogenic forms and showed the following distributions: LOWIN (low) with 39 (8%) cases (94.9% AF/5.1% LAT/0% PAT); LATIN (low) with 17 (3%) cases (5.9% AF/94.1% LAT/0% PAT); AVERIN (average) with 413 (82%) cases (52.1% AF/38.5% LAT/9.4% PAT) and PATIN (patent) with 33 (7%) cases (36.4% AF/24.2% LAT/39.4% PAT). Age of slaughter was significantly higher for LATIN (88.3 months) compared to AVERIN (65.3 months; p = 0.0007) and PATIN (59.1 months; p = 0.0004), and for LOWIN (73.9 months) compared to PATIN (p = 0.0233), and nearly significant compared to AVERIN (p = 0.0572) These results suggest that some selected genetic polymorphisms have a potential use as markers of PTB EP forms and thus add a new tool for the control of this widespread infection.

Reduced Single Nucleotide Polymorphism Panels for Assigning Atlantic Albacore and Bay of Biscay Anchovy Individuals to Their Geographic Origin: Toward Sustainable Fishery Management.

There is an increasing trend upon adding a detailed description of the origin of seafood products driven by a general interest in the implementation of sustainable fishery management plans for the conservation of marine ecosystems. North Atlantic albacore ("Bonito del Norte con Eusko Label") and Bay of Biscay anchovy ("Anchoa del Cantábrico") are two commercially important fish populations with high economical value and vulnerable to commercial fraud. This fact, together with the overexploited situation of these two populations, makes it necessary to develop a tool to identify individual origin and to detect commercial fraud. In the present study, we have developed and validated a traceability tool consisting of reduced panels of gene-associated single nucleotide polymorphisms (SNPs) suitable for assigning individuals of two species to their origin with unprecedented accuracy levels. Only 48 SNPs are necessary to assign 81.1% albacore and 93.4% anchovy individuals with 100% accuracy to their geographic origin. The total accuracy of the results demonstrates how gene-associated SNPs can revolutionize food traceability. Gene-associated SNP panels are not of mere commercial interest, but they also can result in a positive impact on sustainability of marine ecosystems through conservation of fish populations through establishing a more effective and sustainable fishery management framework and contributing to the prevention of falsified labeling.

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers.

INTRODUCTION: The identification of the genetic risk factors that could discriminate non- thrombotic from thrombotic antiphospholipid antibodies (aPLA) carriers will improve prognosis of these patients. Several human studies have shown the presence of aPLAs associated with atherosclerotic plaque, which is a known risk factor for thrombosis. Hence, in order to determine the implication of atherosclerosis in the risk of developing thrombosis in aPLA positive patients, we performed a genetic association study with 3 candidate genes, APOH, LDLR and PCSK9. MATERIAL & METHODS: For genetic association study we analyzed 190 aPLA carriers -100 with non-thrombotic events and 90 with thrombotic events- and 557 healthy controls. Analyses were performed by χ2 test and were corrected by false discovery rate. To evaluate the functional implication of the newly established susceptibility loci, we performed expression analyses in 86 aPLA carrier individuals (43 with thrombotic manifestations and 43 without it) and in 45 healthy controls. RESULTS: Our results revealed significant associations after correction in SNPs located in LDLR gene with aPLA carriers and thrombotic aPLA carriers, when compared with healthy controls. The most significant association in LDLR gene was found between SNP rs129083082 and aPLA carriers in recessive model (adjusted P-value = 2.55 x 10-3; OR = 2.18; 95%CI = 1.49-3.21). Furthermore, our work detected significant allelic association after correction between thrombotic aPLA carriers and healthy controls in SNP rs562556 located in PCSK9 gene (adjusted P-value = 1.03 x 10-2; OR = 1.60; 95%CI = 1.24-2.06). Expression level study showed significantly decreased expression level of LDLR gene in aPLA carriers (P-value <0.0001; 95%CI 0.16-2.10; SE 0.38-1.27) in comparison to the control group. DISCUSSION: Our work has identified LDLR gene as a new susceptibility gene associated with the development of thrombosis in aPLA carriers, describing for the first time the deregulation of LDLR expression in individuals with aPLAs. Besides, thrombotic aPLA carriers also showed significant association with PCSK9 gene, a regulator of LDLR plasma levels. These results highlight the importance of atherosclerotic processes in the development of thrombosis in patients with aPLA.

Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations.

Epidemiological studies suggest a strong contribution of genetic factors in the pathogenesis of systemic lupus erythematosus (SLE). In the last decades, many risk loci have been identified in several genetic association studies following both candidate gene and genome-wide approaches. The present work was conducted by GAPAID (Genes And Proteins for AutoImmunity Diagnostics) consortium with a dual aim: to replicate the association of several previously reported SLE susceptibility loci in an independent European sample and to explore their relation with some disease subphenotypes. A total of 48 single nucleotide polymorphisms (SNP) from 40 associated loci were typed in a cohort of 208 SLE patients and 152 controls from Rheumatology Units of the University Hospital of Pisa (Italy) and University of Pécs Medical Center (Hungary). Regression analyses were performed to detect disease susceptibility loci and to identify genes affecting specific disease manifestations (renal, neurological, or skin involvement; arthritis; secondary Sjögren syndrome; and secondary antiphospholipid syndrome). Association of previously described risk alleles from HLA locus has been replicated, while IRF5, BLK, ITGAM, and IRF8 loci have been found to be consistent with previous published results. In addition, two new subphenotype-specific associations have been detected: SNP rs5754217 (UBE2L3) with skin involvement and rs3093030 (ICAM1-ICAM4-ICAM5) with hematological disorders. Overall, results from GAPAID project are consistent with previously established associations for HLA, IRF5, BLK, ITGAM, and IRF8 SLE susceptibility loci and report for the first time two subphenotype-specific associations.

New Nuclear SNP Markers Unravel the Genetic Structure and Effective Population Size of Albacore Tuna (Thunnus alalunga).

In the present study we have investigated the population genetic structure of albacore (Thunnus alalunga, Bonnaterre 1788) and assessed the loss of genetic diversity, likely due to overfishing, of albacore population in the North Atlantic Ocean. For this purpose, 1,331 individuals from 26 worldwide locations were analyzed by genotyping 75 novel nuclear SNPs. Our results indicated the existence of four genetically homogeneous populations delimited within the Mediterranean Sea, the Atlantic Ocean, the Indian Ocean and the Pacific Ocean. Current definition of stocks allows the sustainable management of albacore since no stock includes more than one genetic entity. In addition, short- and long-term effective population sizes were estimated for the North Atlantic Ocean albacore population, and results showed no historical decline for this population. Therefore, the genetic diversity and, consequently, the adaptive potential of this population have not been significantly affected by overfishing.

Genetic association analysis of paratuberculosis forms in holstein-friesian cattle.

A genetic susceptibility to Mycobacterium avium subsp. paratuberculosis (MAP) infections in ruminants has been longtime suspected to exist. Recently, natural infections in cattle have been reclassified into latent and patent forms based on histopathological findings and their associations with immunological and microbiological variables. This study aims to explore whether these newly defined phenotypes are associated with twenty-four single-nucleotide polymorphisms (SNPs) in six bovine candidate genes: nucleotide-binding oligomerization domain 2 (NOD2), solute carrier family 11 member A1 (SLC11A1), nuclear body protein SP110 (SP110), toll-like receptors (TLRs) 2 and 4, and CD209 (also known as DC-SIGN, dendritic cell-specific ICAM3-grabbing nonintegrin). SNPs were genotyped for 772 Holstein-Friesian animals (52.6% apparently free; 38.1% latent; 9.3% patent) by TaqMan OpenArray technology. Genotypic-phenotypic associations were assessed by logistic regression analysis adjusted for age at slaughter, under five models (codominant, dominant, recessive, overdominant, and log-additive), and corrected for multiple testing. The rs208222804 C allele (CD209 gene) was found to be associated with latent paratuberculosis (log-additive model: P < 0.0034 after permutation procedure; OR = 0.64, 95% CI = 0.48-0.86). No significant association was detected between any SNP and the patent phenotype. Consequently, CD209 gene may play a key role in the pathogenesis of bovine paratuberculosis.

Multiple SNP markers reveal fine-scale population and deep phylogeographic structure in European anchovy (Engraulis encrasicolus L.).

Geographic surveys of allozymes, microsatellites, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) have detected several genetic subdivisions among European anchovy populations. However, these studies have been limited in their power to detect some aspects of population structure by the use of a single or a few molecular markers, or by limited geographic sampling. We use a multi-marker approach, 47 nDNA and 15 mtDNA single nucleotide polymorphisms (SNPs), to analyze 626 European anchovies from the whole range of the species to resolve shallow and deep levels of population structure. Nuclear SNPs define 10 genetic entities within two larger genetically distinctive groups associated with oceanic variables and different life-history traits. MtDNA SNPs define two deep phylogroups that reflect ancient dispersals and colonizations. These markers define two ecological groups. One major group of Iberian-Atlantic populations is associated with upwelling areas on narrow continental shelves and includes populations spawning and overwintering in coastal areas. A second major group includes northern populations in the North East (NE) Atlantic (including the Bay of Biscay) and the Mediterranean and is associated with wide continental shelves with local larval retention currents. This group tends to spawn and overwinter in oceanic areas. These two groups encompass ten populations that differ from previously defined management stocks in the Alboran Sea, Iberian-Atlantic and Bay of Biscay regions. In addition, a new North Sea-English Channel stock is defined. SNPs indicate that some populations in the Bay of Biscay are genetically closer to North Western (NW) Mediterranean populations than to other populations in the NE Atlantic, likely due to colonizations of the Bay of Biscay and NW Mediterranean by migrants from a common ancestral population. Northern NE Atlantic populations were subsequently established by migrants from the Bay of Biscay. Populations along the Iberian-Atlantic coast appear to have been founded by secondary waves of migrants from a southern refuge.

Microsatellite based ovine parentage testing to identify the source responsible for the killing of an endangered species.

In this study, we present an animal forensic genetics case in which we applied ovine microsatellite based parentage testing to the resolution of an act against protected wildlife. The aim was to identify the origin of the animal responsible for the death of an Egyptian vulture (Neophron percnopterus) that had been poisoned through consumption of a Latxa Blond Face breed lamb. Thus, we carried out a 22 microsatellite based parentage test in order to identify the parents of the lamb in the flock which grazes in the same place where the vulture's remains were found. Multiple parentage analysis revealed two possible parents, one ewe and one ram, with a combined paternity/maternity index (PI) higher than 9.09E9 and a likelihood (W) value of 99.9999%, assuming 50% probability a priori. This result confirmed the flock of origin of the poisoned lamb and shows that the microsatellite panel described herein is a potentially useful tool for the resolution of animal forensic cases.

Evolution of vegetation size in left-sided endocarditis. Is it a prognostic factor during hospitalization?

The objective was to describe the vegetation changes in patients with endocarditis and evaluate their prognostic importance during hospitalization. We selected patients with left-sided endocarditis and two transesophageal echocardiograms separated by at least 8 days. Patients who required surgery or died during the first week after diagnosis of the disease were excluded. Patients were classified into three groups: I, patients whose vegetation increased in size (n=34); II, patients with vegetations that did not vary in size (n=62); and III, patients whose vegetation decreased in size (n=59). Patients whose vegetation increased in size more frequently required surgery. Multivariate analysis showed that the increase in the vegetation is independently associated with increased mortality: adjusted odds ratio, 4.12 (95% confidence interval, 1.14-14.9; P=.031).

Identification of horse chestnut coat color genotype using SNaPshot.

BACKGROUND: The Cantabrian Coast horse breeds of the Iberian Peninsula have mainly black or bay colored coats, but alleles responsible for a chestnut coat color run in these breeds and occasionally, chestnut horses are born. Chestnut coat color is caused by two recessive alleles, e and e(a), of the melanocortin-1 receptor gene, whereas the presence of the dominant, wild-type E allele produces black or bay coat horses. Because black or bay colored coats are considered as the purebred phenotype for most of the breeds from this region, it is important to have a fast and reliable method to detect alleles causing chestnut coat color in horses. FINDINGS: In order to assess coat color genotype in reproductive animals with a view to avoiding those bearing chestnut alleles, we have developed a reliable, fast and cost-effective screening device which involves Single Nucleotide Polymorphism (SNP) detection based on SNaPshot((R) )(Applied Biosystems) methodology. We have applied this method to four native breeds from the Iberian Cantabrian Coast: Pottoka and Jaca Navarra pony breeds, in which only black or bay coats are acceptable, and Euskal Herriko Mendiko Zaldia and Burguete heavy breeds, in which chestnut coats are acceptable. The frequency of the chestnut alleles ranged between f = 0.156-0.322 in pony breeds and between f = 0.604-0.716 in heavy breeds. CONCLUSIONS: This study demonstrates the usefulness of the DNA methodology reported herein as a device for identifying chestnut alleles; the methodology constitutes a valuable tool for breeders to decrease the incidence of chestnut animals among Cantabrian Coast pony breeds.

Evolución del tamaño de la vegetación en la endocarditis izquierda. ¿Es un marcador pronóstico intrahospitalario? / Evolution of vegetation size in left-sided endocarditis. Is it a prognostic factor during hospitalization

El objetivo es describir la evolución de la vegetación en enfermos con endocarditis y evaluar su importancia pronóstica durante la hospitalización. Se seleccionó a pacientes con endocarditis izquierda y dos ecocardiogramas transesofágicos separados al menos 8 días. Se excluyó a los pacientes que precisaron cirugía o fallecieron durante la primera semana siguiente al diagnóstico. Se determinaron tres grupos: grupo I, pacientes cuya vegetación aumentó de tamaño (n=34); grupo II, pacientes con vegetaciones que no variaron (n=62), y grupo III, pacientes cuyas vegetaciones disminuyeron (n=59). Los pacientes del grupo I precisaron cirugía con mayor frecuencia. El incremento del tamaño de la vegetación se asoció de forma independiente a una mayor mortalidad: odds ratio ajustada=4,12 (intervalo de confianza del 95%, 1,14-14,9; p=0,031) (AU)

The objective was to describe the vegetation changes in patients with endocarditis and evaluate their prognostic importance during hospitalization. We selected patients with left-sided endocarditis and two transesophageal echocardiograms separated by at least 8 days. Patients who required surgery or died during the first week after diagnosis of the disease were excluded. Patients were classified into three groups: I, patients whose vegetation increased in size (n=34); II, patients with vegetations that did not vary in size (n=62); and III, patients whose vegetation decreased in size (n=59). Patients whose vegetation increased in size more frequently required surgery. Multivariate analysis showed that the increase in the vegetation is independently associated with increased mortality: adjusted odds ratio, 4.12 (95% confidence interval, 1.14-14.9; P=.031) (AU)