Impact of the COVID-19 Pandemic in Spain in the Successive Pandemic Waves on Hemodialysis Patients and Healthcare Personnel.

(1) Background: The impact of SARS-CoV-2 has been variable over the time course of the pandemic and in different populations. The aim was to analyze the impact of COVID-19 infection in a known population of hemodialysis (HD) patients and professionals in Spain at different times of the pandemic. (2) Methods: We conducted an observational, descriptive study with a follow-up from 3 March 2020 to 23 April 2022 (776 days), using in average of 414 professionals and 1381 patients from 18 HD units in Spain. The data from the positive PCR or the rapid antigen detection test (RADT) subject were analyzed and segmented into six periods (waves). (3) Results: Of 703 positive COVID-19 tests, 524 were HD patients (74.5%), and 179 were HD professionals (25.5%). Overall, 38% of staff and 43% of patients were affected. Differences were observed in regard to incidence (21% vs. 13%), mortality (3.5% vs. 0%), and symptomatology between the patients and professionals and throughout the pandemic. (4) Conclusions: COVID-19 severity varied during different pandemic waves, with a greater impact seen in the first wave. HD professionals and patients had similar infection rates, but patients had higher mortality rates. Community transmission was the primary route of infection.

Exposure to cyan or red light inhibits the axial growth of zebrafish eyes.

Myopia, or nearsightedness, is the most common type of refractive error and is characterized by a mismatch between the optical power and ocular axial length. Light, and more specifically the spectral composition of light, has been known to influence myopic axial growth. In this pilot study, we exposed zebrafish to illuminations that vary in spectral composition and screened for changes in axial length. The illumination spectra included narrow band ultra-violet A (UVA) (peak wavelength 369 nm), violet (425 nm), cyan (483 nm), green/yellow (557 nm), and red (633 nm) light, as well as broad band white light (2700 K and 6500 K), dim white light and broad spectrum (day) light. We found that rearing zebrafish in cyan or red light leads to a reduction of the ocular axial length. The results of this pilot study may contribute to new perspectives on the role of light and lighting as an intervention strategy for myopia control.

Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models.

Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes within these loci. To functionally follow-up on GWAS and characterize the potential role of candidate genes on the development of RE, we prioritized nine genes (TJP2, PDE11A, SHISA6, LAMA2, LRRC4C, KCNQ5, GNB3, RBFOX1, and GRIA4) based on biological and statistical evidence; and used CRISPR/cas9 to generate knock-out zebrafish mutants. These mutant fish were screened for abnormalities in axial length by spectral-domain optical coherence tomography and refractive status by eccentric photorefraction at the juvenile (2 months) and adult (4 months) developmental stage. We found a significantly increased axial length and myopic shift in refractive status in three of our studied mutants, indicating a potential involvement of the human orthologs (LAMA2, LRRC4C, and KCNQ5) in myopia development. Further, in-situ hybridization studies showed that all three genes are expressed throughout the zebrafish retina. Our zebrafish models provide evidence of a functional role of these three genes in refractive error development and offer opportunities to elucidate pathways driving the retina-to-sclera signaling cascade that leads to myopia.

Rare variant analyses across multiethnic cohorts identify novel genes for refractive error.

Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.

Zebrafish: An In Vivo Screening Model to Study Ocular Phenotypes.

Purpose: To establish a set of assays that allow the in vivo screening of candidate genes for ocular diseases in zebrafish, with an emphasis on refractive error. Methods: Our pipeline includes the most relevant ocular screening measurements to assess (1) ocular biometry using spectral domain optical coherence tomography, (2) refractive status using an eccentric photorefractor, (3) intraocular pressure by tonometry, and (4) optokinetic response to study visual capability in zebrafish. To validate our pipeline and to demonstrate the potential of zebrafish as a valid animal model, we chose two well-characterized genes with an ocular phenotype (PRSS56 and FBN1) and generated two mutant zebrafish lines (prss56 and fbn1). Mutant fish were assessed at 2, 4, and 6 months after fertilization. Results: With the proposed phenotyping pipeline, we showed that ocular biometry, refractive status, intraocular pressure, and visual function can be studied in zebrafish. In the prss56 mutant, the pipeline revealed a dramatic decrease in axial length, mainly owing to a decreased vitreous chamber depth, whereas in the fbn1 mutant, ectopia lentis was the most distinctive ocular phenotype observed. Tonometry in both mutant lines showed an increase in intraocular pressure. Conclusions: The proposed pipeline was applied successfully in zebrafish and can be used for future genetic screenings of candidate genes. While validating our pipeline, we found a close resemblance between the ocular manifestations in the zebrafish mutants and patients harboring mutations in PRSS56 and FBN1. Our results support the validity of our pipeline and highlight the potential of zebrafish as an animal model for in vivo screening of candidate genes for ocular diseases.

The Role of GJD2(Cx36) in Refractive Error Development.

Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to severe ocular complications later in life. Genomewide association studies (GWAS) have made considerable contributions to the understanding of the genetic architecture of refractive errors. Among the hundreds of genetic variants identified, common variants near the gap junction delta-2 (GJD2) gene have consistently been reported as one of the top hits. GJD2 encodes the connexin 36 (Cx36) protein, which forms gap junction channels and is highly expressed in the neural retina. In this review, we provide current evidence that links GJD2(Cx36) to the development of myopia. We summarize the gap junctional communication in the eye and the specific role of GJD2(Cx36) in retinal processing of visual signals. Finally, we discuss the pathways involving dopamine and gap junction phosphorylation and coupling as potential mechanisms that may explain the role of GJD2(Cx36) in refractive error development.

Loss of Gap Junction Delta-2 (GJD2) gene orthologs leads to refractive error in zebrafish.

Myopia is the most common developmental disorder of juvenile eyes, and it has become an increasing cause of severe visual impairment. The GJD2 locus has been consistently associated with myopia in multiple independent genome-wide association studies. However, despite the strong genetic evidence, little is known about the functional role of GJD2 in refractive error development. Here, we find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish, cause changes in the biometry and refractive status of the eye. Our immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin and its depletion leads to hyperopia and electrophysiological changes in the retina. These findings support a role for Cx35.5 (gjd2a) in the regulation of ocular biometry. Cx35.1 (gjd2b) has previously been identified in the retina, however, we found an additional lenticular role. Lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. Our results provide functional evidence of a link between gjd2 and refractive error.

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Determining Possible Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma.

Purpose: To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG). Methods: We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method. Results: We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10-3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10-9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 × 10-3), supporting the findings of the PRS approach. Conclusions: Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.

Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes.

PURPOSE: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. DESIGN: Cross-sectional study. METHODS: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines. RESULTS: Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (rg = -0.14; P = .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (rg ≥ 0.45; P ≤ 3.0 × 10-4) and between CDR and POAG were high (rg = 0.57; P = 2.8 × 10-10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (rg range -0.18 to 0.11) and nonsignificant (P ≥ .07). CONCLUSION: These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.

Measurement of Disease Activity in Ecuadorian Patients with Rheumatoid Arthritis: Does RAPID3 Correlate with Traditional Indexes?

OBJECTIVE: The aim of this study is to demonstrate if routine assessment of patient index data 3 has a correlation with disease's activity as much as disease activity score 28, clinical disease activity index, and simplified disease activity index in Ecuadorian patients with rheumatoid arthritis seen in Unidad de Enfermedades Reumáticas y Autoinmunes [UNERA] from December 2016 to December 2017. METHODS: This is a retrospective study in 200 patients that fulfill the American College of Rheumatology 2010 criteria for diagnosis of rheumatoid arthritis. The patients were evaluated from December 2016 to December 2017. Descriptive analyses were carried out, also Pearson correlation was used, and, to give a better clinical significance, a chi-square test was conducted. Whenever assumptions of chi-square test were violated, a Fisher's exact test was reported. RESULTS: RAPID3 correlated best with DAS28 (r.83, p < 0.001), followed by CDAI (r.80, p < 0.001) and then SDAI (r.77, p < 0.001). CONCLUSION: RAPID3 is a questionnaire that only takes 10 seconds to calculate and correlates in a significant way with traditional clinical measures that require more time to perform, saving time in busy health facilities.

Interaction between lifestyle and genetic susceptibility in myopia: the Generation R study.

Myopia is a refractive error of the eye caused by a complex interplay between nature and nurture. The aim of this study was to investigate whether environmental risk factors can influence the genetic effect in children developing myopia. A total of 3422 children participating in the birth-cohort study Generation R underwent an extensive eye examination at 9 years with measurements of refractive error and axial length corneal radius ratio (AL/CR). Environmental risk factors were evaluated using a questionnaire, and environmental risk scores (ERS) were calculated using backward regression analyses. Genetic risk scores (GRS) were calculated based on all currently known risk variants for myopia. Gene-environment interaction (G×E) was investigated using linear and logistic regression analyses. The predictive value of G×E and parental myopia was estimated using receiver operating characteristic curves. Myopia prevalence was 12%. Both GRS (P < 0.01) and ERS (P < 0.01) were significantly associated with myopia and AL/CR, as was G×E interaction (P < 0.01 for myopia; P = 0.07 for AL/CR). The predictive value of parental myopia was 0.67 (95% CI 0.65-0.70), similar to the values of GRS (0.67; 95% CI 0.64-0.70; P = 0.98) and ERS (0.69; 95% CI 0.66-0.72; P = 0.98). Adding G×E interaction significantly improved the predictive value to 0.73 (95% CI 0.70-0.75; P < 0.01). This study provides evidence that nature and nurture are equally important for myopia and AL/CR; however, the combination has the strongest influence. Since myopia genes are common in the population, adjustment of lifestyle should be a major focus in the prevention of myopia.

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

[Characteristics of acute lymphoblastic leukemia and febrile neutropenia in children and adolescents cared for in a hospital in Guayaquil, Ecuador]. / Características de la leucemia linfoblástica aguda y neutropenia febril en niños y adolescentes atendidos en un hospital de Guayaquil, Ecuador.

With the objective of performing a clinical characterization of children and adolescents with acute lymphoblastic leukemia and febrile neutropenia in a hospital in Ecuador, a case series study was carried out, which involved reviewing the clinical records of patients receiving care at "Hospital de la Sociedad de Lucha Contra el Cancer" in Guayaquil between January 2014 and April 2016. Out of the 101 patients, 51.5% were female; mean age was 5.5±2.1 years old; 72.3% were at high risk for invasive bacterial infection; the most common infections were respiratory with 47.5%; 18.8% of bacteria isolated in blood cultures were Gram-positive. Finally, 25.7% of patients died, with chemotherapy resistance as one of the associated factors.

Con el objetivo de caracterizar clínicamente a los niños y adolescentes con leucemia linfoblástica aguda y neutropenia febril en un hospital de Ecuador se realizó un estudio de serie de casos revisando historias clínicas de pacientes atendidos en el Hospital de la Sociedad de Lucha Contra el Cáncer de la ciudad de Guayaquil durante enero 2014 y abril 2016. De los 101 pacientes 51,5% eran mujeres, la edad promedio fue 5,5±2,1 años, el 72,3% tenían riesgo alto de infección bacteriana invasora, el foco de origen infeccioso más frecuente fue el respiratorio con 47,5%, el 18,8% de los microorganismos aislados en hemocultivos fueron Gram-positivos. El 25,7% de los pacientes fallecieron, siendo la refractariedad a la quimioterapia uno de los factores asociados (p<0,001). En conclusión, la mortalidad en niños y adolescentes, con leucemia linfoblástica aguda y neutropenia febril fue elevada; siendo la refractariedad a la quimioterapia uno de los principales factores asociados.

Características de la leucemia linfoblástica aguda y neutropenia febril en niños y adolescentes atendidos en un hospital de Guayaquil, Ecuador / Characteristics of acute lymphoblastic leukemia and febrile neutropenia in children and adolescents cared for in a hospital in Guayaquil, Ecuador

RESUMEN Con el objetivo de caracterizar clínicamente a los niños y adolescentes con leucemia linfoblástica aguda y neutropenia febril en un hospital de Ecuador se realizó un estudio de serie de casos revisando historias clínicas de pacientes atendidos en el Hospital de la Sociedad de Lucha Contra el Cáncer de la ciudad de Guayaquil durante enero 2014 y abril 2016. De los 101 pacientes 51,5% eran mujeres, la edad promedio fue 5,5±2,1 años, el 72,3% tenían riesgo alto de infección bacteriana invasora, el foco de origen infeccioso más frecuente fue el respiratorio con 47,5%, el 18,8% de los microorganismos aislados en hemocultivos fueron Gram-positivos. El 25,7% de los pacientes fallecieron, siendo la refractariedad a la quimioterapia uno de los factores asociados (p<0,001). En conclusión, la mortalidad en niños y adolescentes, con leucemia linfoblástica aguda y neutropenia febril fue elevada; siendo la refractariedad a la quimioterapia uno de los principales factores asociados.

ABSTRACT With the objective of performing a clinical characterization of children and adolescents with acute lymphoblastic leukemia and febrile neutropenia in a hospital in Ecuador, a case series study was carried out, which involved reviewing the clinical records of patients receiving care at "Hospital de la Sociedad de Lucha Contra el Cancer" in Guayaquil between January 2014 and April 2016. Out of the 101 patients, 51.5% were female; mean age was 5.5±2.1 years old; 72.3% were at high risk for invasive bacterial infection; the most common infections were respiratory with 47.5%; 18.8% of bacteria isolated in blood cultures were Gram-positive. Finally, 25.7% of patients died, with chemotherapy resistance as one of the associated factors.

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy.

BACKGROUND: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. METHODS: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. RESULTS: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. CONCLUSIONS: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.