Specific Alleles Research Articles

Two different complement Factor B (Bf) alleles of the orangutan major histocompatibility complex (MHC) are also conserved in chimpanzee and humans showing importance in primate immunity.

MajorHuman Histocompatibility complex (MHC or HLA in humans) has been associated to autoimmune diseases. However, only statistical phenomenological and no pathogenetic description has been reached after decades. This shows that MHC single locus association studies are probably useless for HLA/diseases association. Extended HLA (class I and class II genes) haplotypes should also be studied conjointly with class III or complement alleles (complotypes). Complotypes in humans are defined as alleles belonging to C2, C4 and Bf (Factor B) genes/proteins (class III). Also, the placing of MHC class I and class II genes close together with complement genes from at least birds to humans shows existence of a strong selection to gather conjointly these loci that fight microbes, help self-maintenance and avoid autoimmunity. In this paper we aim to study Bf alleles in primates in order to rise again interest to study the role of Bf alleles together with other MHC genes in their physiopathology and evolution. Orangutan (Pongo pygmaeus, Popy) cell lines RNA from 6 different individuals were retrotranscribed, PCR amplified, cloned and DNA sequenced in order to study Bf alleles. A Bf allele identical to that found in chimpanzee (Patr-Bf*A01) and human (rs641153) was found in two of the six studied orangutans: Popy-Bf*A01 and Popy-Bf*A02. This polymorphism is placed in Factor B codon 32 that defines BF*S and Bf*F proteins in man and produce Leu instead of Arg (Bf*S) or Gln (Bf*F). In addition, each new orangutan allele present synonymous differences with each other at codon 25: Popy-Bf*A01 shows ACG while Popy-Bf*A02 bears ACA, both codifying for Thr. The selection for about 15 million years (time gap of evolutionary appearance between orangutan and hominids) shows the importance of this particular allele conservation in immune and self defense in primates. The complotypes (Bf,C2 and C4 loci) alleles together with other MHC class I and Cass II loci alleles are often transmitted in block to the germinal line: this indicates that all specific alleles from the MHC different loci may work together to accomplish MHC functions. All MHC loci alleles should be studied together to unveil their physiopathology and also maintenance of specific alleles (like the one described in this paper) for so long time in evolution should be further studied in Bf and the other neighbouring complement loci (C2 and C4).

Abstract 4138407: Exome-wide association study of over a million individuals identified effector genes and variants for blood lipids

Background: Inherited hypercholesterolemia is an important Mendelian condition associated with early onset myocardial infarction. However, current genetic diagnostic criteria only partially explain severe clinical hypercholesterolemia. Furthermore, current pathogenicity categorizations do not consistently inform prognosis, but quantification is limited by scarcity of such rare variants. Aim: Exploiting populations scale genotype/phenotype data, to determine the architecture of the genetic variants associating with blood lipid levels with quantitative assessments. Methods: Here, we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease, among over a million individuals combining two large contemporary genetic datasets (Million Veteran Program N = 626,554 and UK Biobank, N = 431,026). Results: Testing 2,869,269 rare (minor allele frequency < 1%), coding variants, we identified 793 exome-wide significant associations ( P < 4.4 × 10 -11 ), including 8 previously undiscovered loci. Associated alleles are highly enriched in functional variant classes; high confidence predicted loss of function, deleterious missense, and cryptic splicing, showed significant and recessive associations, had similar effects across populations. Overall, rare variants contributed to additional > 16% of genetic trait variances on top of common genetic variants. The effect estimates of associated signals confirmed and refined curated pathogenic database, highlighted by the identification of African or South Asian specific pathogenic alleles previously controversial in its pathogenicity. Conclusion: This study provides resources and insights for understanding causal mechanisms and quantifying the expressivity of rare coding alleles for blood lipids by large scale sequencing study. Furthermore, identifying and characterizing population enriched variants, our study underscored the importance of multi-population rare variant study.

Unraveling the protective genetic architecture of COVID-19 in the Brazilian Amazon

Despite all the efforts acquired in four years of the COVID-19 pandemic, the path to a full understanding of the biological mechanisms involved in this disease remains complex. This is partly due to a combination of factors, including the inherent characteristics of the infection, socio-environmental elements, and the variations observed within both the viral and the human genomes. Thus, this study aimed to investigate the correlation between genetic host factors and the severity of COVID-19. We conducted whole exome sequencing (WES) of 124 patients, categorized into severe and non-severe groups. From the whole exome sequencing (WES) association analysis, four variants (rs1770731 in CRYBG1, rs7221209 in DNAH17, rs3826295 in DGKE, and rs7913626 in CFAP46) were identified as potentially linked to a protective effect against the clinical severity of COVID-19, which may explain the less severe impact of COVID-19 on the Northern Region. Our findings underscore the importance of carrying out more genomic studies in populations living in the Amazon, one of the most diverse from the point of view of the presence of rare and specific alleles. To our knowledge, this is the first WES study of admixed individuals from the Brazilian Amazon to investigate genomic variants associated with the clinical severity of COVID-19.

High-Resolution Melting Assay to Detect the Mutations That Cause the Y132F and G458S Substitutions at the ERG11 Gene Involved in Azole Resistance in Candida parapsilosis.

Candida parapsilosis is a pathogenic yeast that has reduced susceptibility to echinocandins and ranks as the second or third leading cause of candidaemia, depending on the geographical region. This yeast often causes nosocomial infections, which are frequently detected as outbreaks. In recent years, resistance to azoles in C. parapsilosis has increased globally, primarily due to the accumulation of mutations in the ERG11 gene. In this study, we have developed an assay based on real-time PCR and high-resolution melting (HRM) curve analysis to detect two of the most prevalent mutations at ERG11 that confer resistance to fluconazole (Y132F and G458S). We designed allele-specific oligonucleotides that selectively bind to either the wild type or mutated sequences and optimised the conditions to ensure amplification of the specific allele, followed by detection via high-resolution melting (HRM) analysis. The designed oligonucleotides to detect the Erg11Y132F and Erg11G458S mutations produced specific amplification of either WT or mutated alleles. We conducted a duplex real-time PCR combining oligonucleotides for the wild-type sequences in one mix, and oligonucleotides for the mutated alleles in another. Following this, we performed an analysis of the HRM curve to identify the amplified allele in each case. This technique was blindly evaluated on a set of 114 C. parapsilosis isolates, all of which were unequivocally identified using our approach. This technique offers a new method for the early detection of azole resistance mechanism in C. parapsilosis.

Genetic and clinical factors influencing CF-associated liver disease: the impact of SERPINA1 variants and CFTR genotypes in Romanian pediatric cystic fibrosis patients.

Hepatic disease represents a significant complication in children with cystic fibrosis (CF), yet its relationship with specific genetic factors, including CFTR (Cystic fibrosis transmembrane conductance regulator) mutations and SERPINA1 alleles, is not well understood. This study aims to clarify these associations within a Romanian pediatric CF population. In this cross-sectional, prospective study, we examined 71 children with CF, comparing those with hepatic disease (n=25) to those without (n=46). We collected comprehensive clinical, biochemical, and genetic data, focusing on CFTR genotypes and SERPINA1 alleles. Key outcomes included the prevalence of hepatic disease in relation to specific genotypes, fibrosis markers, and liver function tests. The DF508/DF508 genotype was the most prevalent, occurring in 49% of the cohort. No significant associations were found between hepatic disease and specific CFTR genotypes or SERPINA1 alleles. However, children with hepatic disease exhibited significantly higher fibrosis scores (APRI and FIB-4), suggesting more advanced liver involvement. Additionally, a slight delay in CF diagnosis was observed in those with hepatic disease, though this difference did not reach statistical significance. This pioneering study in Romania underscores the complexity of hepatic disease in CF. While specific CFTR genotypes and SERPINA1 alleles were not significantly associated with hepatic complications, the findings emphasize the importance of early diagnosis and monitoring using fibrosis markers to identify children at risk for liver involvement.

Inbreeding accelerates reproductive senescence, but not survival senescence, in a precocial bird.

Inbreeding depression is predicted to increase with age, because natural selection is less efficient at purging deleterious alleles that are only expressed later in life. However, empirical results are scarce, and equivocal between studies. Here we performed controlled matings between related and unrelated individuals of domesticated Japanese quail (Coturnix japonica), and monitored the performance of their offspring for all fitness components over their complete life course. We found rapid senescence in adult survival and egg laying performance, and inbreeding depression at all life stages (reduced embryo viability, increased age at maturity, as well as reduced adult survival and reproduction). Inbreeding depression did not increase at later ages for survival, but did so for egg laying, thereby accelerating reproductive senescence. Moreover, the effect of inbreeding on egg laying persisted after correcting for lifespan, indicating that both survival and reproduction were independently affected by inbreeding. We suggest that in heterogeneous populations intra-generational purging may at earlier ages already select out the individuals that are homozygous for the specific alleles responsible for depressed survival, preventing the appearance of increased inbreeding depression in survival with age. Given that inbreeding affects reproduction independent of survival this should not apply to reproductive senescence or homogeneous populations, which may explain equivocal results between traits and studies.

CLINICAL-IMMUNOGENETIC RELATIONSHIP IN CHILDREN WITH CHRONIC TONSILLITIS AND ASSOCIATED DISEASES

General Background: Chronic tonsillitis is a prevalent condition in children, often linked to various immunogenetic factors that influence its pathogenesis and associated diseases. Specific Background: The role of HLA (Human Leukocyte Antigen) system A and B loci in chronic tonsillitis remains inadequately understood, particularly regarding their clinical significance and the immunogenetic correlations with related conditions. Knowledge Gap: While prior studies have examined the genetic factors associated with chronic tonsillitis, there is a lack of comprehensive research focusing on the specific HLA loci and their implications for clinical outcomes in affected children. Aims: This study aims to determine the indicators of HLA A and B loci in children with chronic tonsillitis and to explore the clinical-immunogenetic correlations with associated diseases. Results: The findings demonstrate significant associations between specific HLA alleles and the severity of chronic tonsillitis, highlighting potential immunogenetic predispositions that influence disease progression and comorbidities. Novelty: This research introduces a novel perspective by linking HLA system indicators directly to clinical outcomes, thereby providing new insights into the immunogenetic mechanisms underlying chronic tonsillitis in children. Implications: The identification of these immunogenetic factors could enhance the understanding of chronic tonsillitis pathophysiology and inform personalized treatment strategies, ultimately improving patient management and outcomes in pediatric populations.

Genetic alteration of class I HLA in cutaneous T-cell lymphoma

AbstractAbnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCLs). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides or Sézary syndrome. Targeted DNA sequencing, including coverage of HLA loci, revealed at least 1 HLA abnormality in 26 of 65 patients (40%). Twelve unique somatic HLA mutations were identified across 9 patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with a decrease in the total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presenting greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated that HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed that disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient who received pembrolizumab and in whom resistance to pembrolizumab was associated with the elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.

The Putative Role of TIM-3 Variants in Polyendocrine Autoimmunity: Insights from a WES Investigation.

Autoimmune polyglandular syndrome (APS) comprises a complex association of autoimmune pathological conditions. APS Type 1 originates from loss-of-function mutations in the autoimmune regulator (AIRE) gene. APS2, APS3 and APS4 are linked to specific HLA alleles within the major histocompatibility complex, with single-nucleotide polymorphisms (SNPs) in non-HLA genes also contributing to disease. In general, variability in the AIRE locus and the presence of heterozygous loss-of-function mutations can impact self-antigen presentation in the thymus. In this study, whole-exome sequencing (WES) was performed on a sixteen-year-old female APS3A/B patient to investigate the genetic basis of her complex phenotype. The analysis identified two variants (p.Arg111Trp and p.Thr101Ile) of the hepatitis A virus cell receptor 2 gene (HAVCR2) encoding for the TIM-3 (T cell immunoglobulin and mucin domain 3) protein. These variants were predicted, through in silico analysis, to impact protein structure and stability, potentially influencing the patient's autoimmune phenotype. While confocal microscopy analysis revealed no alteration in TIM-3 fluorescence intensity between the PBMCs isolated from the patient and those of a healthy donor, RT-qPCR showed reduced TIM-3 expression in the patient's unfractionated PBMCs. A screening conducted on a cohort of thirty APS patients indicated that the p.Thr101Ile and p.Arg111Trp mutations were unique to the proband. This study opens the pathway for the search of TIM-3 variants possibly linked to complex autoimmune phenotypes, highlighting the potential of novel variant discovery in contributing to APS classification and diagnosis.

Precise identification and tracking of HMGCR-reactive CD4+ T cells in the target tissue of patients with anti-HMGCR immune-mediated necrotising myopathy

BackgroundAnti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune-mediated necrotising myopathy (IMNM) is characterised by the presence of IgG autoantibodies against HMGCR and a strong association with specific HLA-DR alleles. Although these findings...

Genetic Variants ε2 and ε4 of APOE Predict Mortality and Poor Outcome Independently in Spontaneous Intracerebral Hemorrhage Within the Chinese Han Population.

The heightened mortality and disability rates, coupled with restricted neurological recovery post intracerebral hemorrhage (ICH), have sparked considerable attention toward its treatment and results. Simultaneously, the influence of the APOE gene on ICH prognosis has been well-documented. This research aimed to explore the relationship between specific APOE alleles in the present cohort and the incidences of mortality, recurrence, and adverse prognosis, as determined by neurological function assessments in ICH patients. Data on patients diagnosed with ICH and hospitalized in the Department of Neurology at our institution from October 2021 to March 2022 were collected, including determining their APOE genotypes. A 1-year follow-up was conducted to evaluate mortality, ICH recurrence, and modified Rankin Scale (mRS) scores at 3 and 12 months. Poor prognosis was defined as an mRS score of ≥ 3. Initially, we analyzed the relationships between different APOE alleles and mortality, recurrence, and poor prognosis. Subsequently, we explored additional factors influencing each prognostic outcome and conducted multivariate analysis to identify independent risk factors. An analysis was conducted on 289 patients diagnosed with ICH. The presence of the ε2 allele was found to be a significant independent predictor for unfavorable outcomes at both 3 months (p = 0.022, OR = 2.138, 95% CI [2.041, 3.470]) and 1 year (p = 0.020, OR = 5.116, 95% CI [5.044, 5.307]). Moreover, the ε4 allele was established as an independent risk factor for ICH recurrence within 1 year (p = 0.025, OR = 2.326, 95% CI [1.163, 2.652]), as well as for mortality at 3 months (p = 0.037, OR = 4.250, 95% CI [4.068, 4.920]) and 1 year (p = 0.023, OR = 4.109, 95% CI [4.016, 4.739]). In conclusions, Both APOE ε2 and ε4 variants independently heighten mortality risk, recurrence, and poor prognosis after ICH. The substantial influence underscores the need for additional investigation into the impact of APOE genotype on ICH prognosis.

Evaluation of oxidative stress, biochemical parameters and in silico markers in different pea accessions in response to drought stress.

ARG6 and ARG10 pea accessions exhibited better tolerance to drought by keeping drought-associated attributes stable and higher, that is, stable chlorophyll content, high antioxidant activity, and the presence of polymorphic bands with stress-responsive EST-SSR markers. Each year, a significant portion of crops is lost due to various abiotic stresses, and even pea (Pisum sativum) crop growth and yield are severely affected by the challenges posed by drought stress. Drought is a critical factor that limits crop growth and development, and its impact is exacerbated by changes in the magnitude of climatic conditions. Drought induces oxidative stress in plants, leading to the accumulation of high concentrations of reactive oxygen species that damage cell structures and vital functioning of cells. The primary objective was to identify stress-tolerant plants by evaluating different morphological and biochemical attributes, such as biomass, chlorophyll content, relative water content, ascorbate peroxidase (APX), superoxide dismutase (SOD), and DPPH scavenging activity, as well as protein, proline, and phenolic content. Our study revealed that pea accessions (ARG6 and ARG10) were more resilient to drought stress as their chlorophyll, relative water, protein, and proline contents increased under drought conditions. Antioxidant enzymes, such as SOD, APX, and DPPH activities, also increased under drought stress in ARG10 and ARG6, suggesting that these accessions could bolster the antioxidant defense system in response to drought stress. Based on putative (cellular, biological, and metabolic) functions, ten EST-SSR primers were selected for the amplification study. Three EST-SSR primers, AUMP06_110, AUMP18_300, and AUMP31_250, were used for ARG6 and ARG10. Based on the correlation between the presence or absence of specific EST-SSR alleles, various physiological and morphological traits, and DPPH scavenging activity, both ARG10 and ARG6 demonstrated resistance to drought stress.

Conserved allomorphs of MR1 drive the specificity of MR1-restricted TCRs.

Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, was until recently considered to be monomorphic. MR1 presents metabolites in the context of host responses to bacterial infection. MR1-restricted TCRs specific to tumor cells have been described, raising interest in their potential therapeutic application for cancer treatment. The diversity of MR1-ligand biology has broadened with the observation that single nucleotide variants (SNVs) exist within MR1 and that allelic variants can impact host immunity. The TCR from a MR1-restricted T-cell clone, MC.7.G5, with reported cancer specificity and pan-cancer activity, was cloned and expressed in Jurkat E6.1 TCRαβ- β2M- CD8+ NF-κB:CFP NFAT:eGFP AP-1:mCherry cells or in human donor T cells. Functional activity of 7G5.TCR-T was demonstrated using cytotoxicity assays and by measuring cytokine release after co-culture with cancer cell lines with or without loading of previously described MR1 ligands. MR1 allele sequencing was undertaken after the amplification of the MR1 gene region by PCR. In vivo studies were undertaken at Labcorp Drug Development (Ann Arbor, MI, USA) or Epistem Ltd (Manchester, UK). The TCR cloned from MC.7.G5 retained MR1-restricted functional cytotoxicity as 7G5.TCR-T. However, activity was not pan-cancer, as initially reported with the clone MC.7.G5. Recognition was restricted to cells expressing a SNV of MR1 (MR1*04) and was not cancer-specific. 7G5.TCR-T and 7G5-like TCR-T cells reacted to both cancer and healthy cells endogenously expressing MR1*04 SNVs, which encode R9H and H17R substitutions. This allelic specificity could be overcome by expressing supraphysiological levels of the wild-type MR1 (MR1*01) in cell lines. Healthy individuals harbor T cells reactive to MR1 variants displaying self-ligands expressed in cancer and benign tissues. Described "cancer-specific" MR1-restricted TCRs need further validation, covering conserved allomorphs of MR1. Ligands require identification to ensure targeting MR1 is restricted to those specific to cancer and not normal tissues. For the wider field of immunology and transplant biology, the observation that MR1*04 may behave as an alloantigen warrants further study. .

Trend of N86Y and Y184F Mutations in Pfmdr1 Gene in Children Under Seasonal Malaria Chemoprevention Coverage in Nanoro, Burkina Faso

BackgroundSeasonal malaria chemoprevention (SMC) is an effective malaria preventive intervention in sub-Sahara Africa. However, as with any other drug-based intervention, the large-scale deployment of this strategy could lead to Amodiaquine plus Sulfadoxine-Pyrimethamine (AQSP) drug pressure on the circulating parasites population with selection for specific alleles that could compromise the impact of the intervention in the near future. This study aimed to assess the distribution of the Pfmdr1 mutation involved in resistance to AQ before and after the annual campaign of SMC in the health district of Nanoro.MethodsRandomly selected dried blood spots collected prior (n = 100) and after (n = 100) the 2021 SMC campaign were used for the detection of mutation in codons 86 and 184 of the Pfmdr1 gene using a nested PCR with restriction fragment length polymorphism approach.ResultsNo significant change in the prevalence of Pfmdr1 N86Y mutation was observed before and after the SMC campaign (p = 0.28). The mutant allele 86Y was observed at low prevalences, representing only 2.17% and 6.12%, respectively, before and after the SMC campaign. Patients harboring the mutant Pfmdr1 86Y allele exhibited higher parasite densities compared to patients with the wild-type Pfmdr1 N86 allele (p = 0.04). A significant increase in the prevalence of the mutant allele 184 F was observed in the period before and after the SMC campaign (p = 0.03).ConclusionThis selective pressure needs to be closely monitored in order to preserve the efficacy of this intervention for a long-term period in Burkina Faso.

Characterization of Intsia spp. from Indonesia using microsatellite markers

Microsatellite DNA markers are known to have a high level of genetic diversity and can be used for various purposes. These include population genetic analysis, gene flow assessment, pollen distribution, parent analysis, and accurate distinction between types and varieties. Despite the potential application of microsatellite markers, their development process often requires high costs, energy, and time. To overcome the limitations, several studies have proposed the use of cross-species amplification, which has proven to be a cost and time-efficient method for obtaining species-specific DNA markers. Therefore, this study aimed to identify three species of Merbau in Indonesia, namely Intsia bijuga, I. palembanica, and I. acuminata using cross-species amplification. The three species are known to exhibit similarities in all taxonomical characteristics except for minor differences in the number of leaf pairs per twig and the tip shape of the leaflets. These species also have different levels of economic value and conservation status due to variations in the type of wood produced. Several studies have shown that identification errors can affect the economic value of their wood and logging mistakes can lead to a decrease in the genetic diversity. To address the concerns, Intsia bijuga and I. acuminata from Indonesia were selected as test samples for the cross-amplification of microsatellite markers created for I. palembanica. Due to their taxonomical similarities, the diagnostic characteristics of each Intsia species were assessed based on microsatellite markers. Leaf samples were obtained from three species of Intsia that had been verified and identified based on morphological characteristics by taxonomists from the Bogor Botanical Garden Indonesia. In addition, a total of 10 polymorphic I. palembanica microsatellite markers from the previous literature were used in this study. The results showed that the cross-species amplification of microsatellite locus was successful in all markers. Certain alleles were also observed to be shared by the three species of Intsia, while some were specific to a particular species. These specific alleles could also serve as a diagnostics characteristic for Intsia spp. In addition, a set of polymorphic microsatellites showing a successful transfer across species of Intsia could serve as a valuable tool for comparative studies among related taxa species and breeding and conservation programs.

Associations of classical HLA alleles with sleep behaviours.

Immune dysregulation has been observed in individuals with sleep disturbance, with HLA molecules play a crucial role in the immune response. This study aimed to investigate the associations between HLA alleles and sleep behaviours, considering several environmental factors. Data were sourced from the UK Biobank. Logistic regression analyses were performed to explore the associations between 359 HLA alleles and 4 sleep behaviours, including chronotype (n = 204,636), insomnia (n = 227,553), snoring (n = 214,350) and daytime dozing (n = 227,197). Furthermore, gene-environmental interaction studies (GEIS) were conducted to evaluate the interactions of HLA alleles with environmental factors on sleep behaviours. This study analysed a total sample and subgroups stratified by sex to elucidate the impact of HLA alleles on sleep behaviours. Our findings revealed several associations between specific HLA alleles and sleep behaviours. Notably, HLA-A*23:01 was associated with evening chronotype in the total sample (OR = 0.918, 95%CI: 0.872-0.965), while HLA-A*32:01 was associated with evening chronotype in males (OR = 1.089, 95%CI: 1.037-1.144). Furthermore, GEIS identified multiple sets of interactions associated with sleep behaviours. For example, the interaction of HLA-DPA1*01:04 with alcohol consumption was associated with daytime dozing in the total sample (OR = 1.993, 95%CI: 1.351-2.941), while the interaction of HLA-DQB1*05:04 with ever suffered mental distress preventing usual activities was associated with insomnia in males (OR = 0.409, 95%CI: 0.254-0.658). Our findings highlight the involvement of HLA in sleep regulation and underscore the potential interactions between HLA alleles and environmental factors in modulating susceptibility to sleep behaviours.

Elevated serum angiotensin converting enzyme correlates with specific HLA-DRB1 alleles and extrapulmonary manifestations in sarcoidosis

BackgroundGenetics influence the clinical picture in sarcoidosis, a granulomatous heterogeneous disease often accompanied by elevated serum angiotensin converting enzyme (s-ACE). We aimed to investigate if certain HLA-DRB1 alleles correlate with the levels of s-ACE, known as a marker of the granuloma burden. MethodsMedical journals of patients with sarcoidosis from a Swedish clinical registry were retrospectively examined to extract the highest recorded s-ACE value and analysed in relation to patient characteristics including phenotype [Löfgren syndrome (LS)/ non-LS], chest X-ray staging according to Scadding, treatment with immunosuppressants, presence of extrapulmonary manifestations (EPM), HLA-DRB1 alleles and prognosis (resolving vs. non-resolving disease within 2 years). Data were analysed with Fisher's exact test and Bonferroni correction was applied for HLA analyses. ResultsOf 1204 patients included, 40% had s-ACE levels above reference value. In comparison with patients with normal s-ACE, those with elevated levels were more often classified into non-LS (78% vs 59%, p < 0.001), and Scadding stage II (50% vs 38%, p < 0.001) but less often Scadding stage I (33% vs 46%, p < 0.001) and had more often EPM (45% vs 23%, p < 0.001). The patients with HLA-DRB1×04 had more often elevated s-ACE (p < 0.01) while those with HLA-DRB1×03 commonly had normal levels (p < 0.001). ConclusionsIn this retrospective study, HLA alleles associated with s-ACE levels in sarcoidosis patients, which in turn correlated with occurrence of EPM. These findings shed some new light on possible mechanisms behind differences in s-ACE levels.

Advancing pharmacogenomic research in US Hmong populations: prevalence of key single nucleotide variations in California Hmong.

In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population. Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations. In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans. These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong.

Genotypic Variations Associated with Changes in Body Mass in Response to Endurance Training

ABSTRACT This study investigates the extent to which different genotypes can explain changes in body mass following an 8-week running program, in a UK population. Participants were randomly assigned to either a training (n = 17) or control group (n = 21). Participants’ diets were not altered, only the exercise regime was manipulated to isolate effects. The exercise group completed a periodized running program consisting of 20–30 min, over an agreed route, three times per-week, whilst the control groups refrained from daily exercise. Participants were screened at the end of the study for 1,000 gene variants using a DNA test kit. Results demonstrated a significant reduction in body mass, within the exercise, compared to the control group (p = .002). This reduction in body mass varied significantly (p = .024) between individuals within the exercise group. Moreover, genetic analysis identified 17 single nucleotide polymorphisms (SNPs) associated with this variation (r2 = .74; p < .001). These findings indicate that individuals with specific alleles are better predisposed to weight-management, compared to their counterparts, following an exercise program. This study helps to bridge the gap between population health and exercise science and can inform research in the application of genetics to help develop individually tailored health interventions.

High-resolution functional mapping of RAD51C by saturation genome editing

Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses.