Receptor Genotype Research Articles

Duffy Binding Protein Ligand (PvDBP) gene duplication in Indian P. Vivax Malaria isolates: implication for malaria research.

Plasmodium vivax malaria poses a major global health challenge, fueled by the parasite's ability to establish chronic infections via dormant liver hypnozoites that enable immune evasion and show transmission resilience. A key virulence determinant of P. vivax blood-stage infection is the ligand-receptor interaction of infected erythrocytes mediated by the Duffy Binding Protein (PvDBP) ligand. Gene duplication events leading to increased PvDBP copy numbers have been documented in parasite populations in Cambodia, Brazil, and Sudan, but whether such changes exist in Indian isolates is not known. India shoulders a disproportionately high P. vivax burden in the world. DNA extracted from malaria-positive samples from a multisite survey was subjected to diagnostic PCR to evaluate PvDBP duplication. We identified PvDBP duplication at 18.6% frequency across various regions in India via diagnostic PCR. Both 'Cambodian-type' and 'Malagasy-type' duplication patterns were detected. PvDBP copy number variations associated with specific Duffy antigen receptor genotypes were correlated in the patient cohort. While PvDBP duplication was widespread, its geographic distribution varied, occurring most prevalently in northeastern regions of India. The presence of Duffy binding protein gene duplication in nearly one-fifth of P. vivax isolates in India may have significant epidemiological and clinical implications. This genetic variation could potentially impact, parasite fitness and invasion efficiency, possibly leading to higher parasitemia levels and immune evasion capabilities, which may affect the efficacy of natural immunity and vaccine development efforts and / or transmission dynamics if the duplication confers any advantage in mosquito stages. To fully understand these implications, we propose longitudinal studies tracking patients with and without PvDBP duplications, comparing clinical outcomes, parasitemia levels, and transmission rates. Additionally, spatial and temporal analyses of duplication frequency across India could reveal patterns of spread and potential selective pressures driving this genetic change.

Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicity

Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT.

B-222 Receptor-donor CYP3A5 and CYP3A4 genotype testing in liver transplant patients and its influence in tacrolimus blood levels: a retrospective study

Abstract Background Optimal immunosupression is crucial for transplant success. In orthohepatic transplants, blood target levels of tacrolimus, when coadministred with corticoids and mycophenolic acid, are between 6 and 10 ng/mL during the first three months post-transplant. Notwithstanding, achieving tacrolimus concentrations into this range may be tough because of factors such as liver function status, age, sex, drug-drug interactions, etc. In this way, pharmacogenetic testing of CYP3A5 and CYP3A4 genes have demonstrated to be useful in tacrolimus dosing optimization. Nonetheless, there is no evidence enough for pharmacogenetic based adjusting in liver transplant, specially if receptor and graft’s genotypes differ in these loci. The aim of the present study is to find out how the receptor and donor genotypes in CYP3A5 and CYP3A4 genes affect tacrolimus pharmacokinetics. Methods Genotypic profiling of 108 receptor-donor's pairs biopsies gathered from patients who were underwent hepatic transplant from 2012 to 2019 were carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™). We focused on CYP3A5*3, *6 and *7; and CYP3A4*1B, *3 and *22 alleles. Next to pharmacogenetic testing, each patient was classified as very poor, poor, intermediate, rapid or ultrarapid metabolizer according to their own genotype, graft’s genotype or both of them. Patient’s initial dose, at seven days after treatment start and after discharge of tacrolimus and their trough concentrations (C0) were collected from their electronic health records. Tacrolimus levels were measured by affinity chrome-mediated immunoassay. C0 was normalized by weight-adjusted dosage (C/D ratio); then, median C/D ratios between different metabolic profiles were compared through Kruskal-Wallis test. Results When patients were classified based on donor’s genotype isolated or combined with receptor’s genotype, lower C/D ratios were found as metabolizer ability increases (p=0.045 for donors and p=0.027 for combined genotypes, respectively). No statistically differences were found for C/D ratios at seven days and discharge, though that differences were almost significant for donor’s genotypes (p=0.06 in both cases). Conclusions These results show that previous information about both patient’s and specially donor’s CYP genes genotype may improve initial immunosupression and avoid tacrolimus induced toxicity. Pharmacogenetics has been currently proposed as a guide for tacrolimus treatment of some solid organ transplants as kidney transplanted patients. Better understanding of how receptor and donor’s CYP genotype affects its pharmacokinetics, along with liver’s damage markers and other genetic polymorphisms will allow clinicians, in the era of personalized medicine, to improve immunosupressive management.

Association of alcohol with lung cancer risk in men with different growth hormone receptor genotypes

ObjectiveTo test whether genetic variants of the growth hormone receptor gene (GHR) modulate the effect of lifestyle variables on lung cancer (LC) risk. Materials and methodsThis population-based cohort study involved 6,439 men from the Japan-Hawaii Cancer study drawn from the Kuakini Honolulu Heart Program who were cancer-free at baseline examination (1965–1968; age 45–68 years) and followed-up until December 1999. We determined the association of GHR SNP rs4130113 genotypes GHR-AA (common allele A homozygotes) and GHR-G (minor allele G carriage) with alcohol drinking, BMI, physical activity and cigarette smoking in relation to LC and non-small cell LC (NSCLC). Results were expressed as hazard ratios and 95 % CIs estimated from Cox proportional hazard models. ResultsOver mean 26.7 ± 7.4 SD years follow-up, 190 LC cases, including 133 NSCLC cases, were diagnosed. After adjusting for age, education, alcohol intake, BMI, physical activity, cigarette smoking, green tea consumption and dietary saturated fat, main-effect Cox models showed that compared with GHR-AA, GHR-G was associated with protection against LC: HR = 0.75 (95 % CI, 0.56–1.00). Full Cox models showed GHR-G interacted with alcohol intake only (β = 1.171; p = 0.0003; drinks per week: β = 0.279; P = 0.0025). Stratified analyses showed that for GHR-AA, drinkers had reduced LC risk (HR = 0.53; 95 % CI, 0.34–0.84), and that <2 drinks/week had the strongest protection (HR = 0.39; 95 % CI, 0.18–0.84). In contrast, for GHR-G, alcohol drinkers had increased LC risk (HR = 1.74; 95 % CI, 1.11–2.75) which was dose-dependent (P for trend = 0.003). Results for NSCLC were similar. ConclusionIn men with the GHR-AA genotype, alcohol drinking at a low dose poses significantly less risk of LC compared with non-drinkers and higher alcohol consumption., the overall relationship being U-shaped. In contrast, in GHR minor allele carriers, alcohol posed a progressively greater risk of LC as amount consumed increased

Impact of Human Leukocyte Antigen Allele-Killer Cell Immunoglobulin-like Receptor Partners on Sexually Transmitted Human Immunodeficiency Virus Type 1 Infection.

Human leukocyte antigen (HLA) class I/killer cell immunoglobulin-like receptor (KIR) genotypes influence human immunodeficiency virus type 1 (HIV-1) disease progression and viral load, but their role in primary infection is uncertain. Inconsistent results from previous studies suggest that the inoculum size and transmission route-parenteral versus sexual-may influence this association. We conducted a genome-wide association study in a population of people with HIV-1 and HIV-1-exposed seronegative individuals exposed to the virus through the sexual route. Our data do not support any role of the HLA/KIR system in susceptibility to sexually transmitted HIV-1 infection. The genetics basis of HIV-1 viral load and disease progression are distinct from the genetics of HIV resistance, a paradox worth exploring.

Study of the association between oxytocin receptor gene polymorphism, childhood adversity and negative symptoms of schizophrenia

Is known that the neurohormone oxytocin plays an important role in the pathogenesis of mental illness, and also models the relationship between stress factors, especially those acting in the early stages of development, and the development of mental disorders. Based on these data, we investigated the effects of the interaction of the environmental factor, which was considered the adversity of childhood (ND) and the oxytocin receptor (OXTR) genotypes in the polymorphic sites rs4686302 and rs7632287, on the severity of negative symptoms of schizophrenia. The study involved 592 patients with schizophrenia (headings F20. according to ICD-10). Information about the presence of ND was obtained from case histories and patient interviews. Analysis of covariance (GML) was used for statistical data processing; in post-hoc pairwise comparison, Tukey’s test was used. A significant effect of the interaction between ND and OXTR gene polymorphism rs7632287(G/A) on the severity of negative symptoms in patients with schizophrenia was revealed. In patients without ND, polymorphisms did not have a significant effect on the studied phenotype. Thus, our study showed for the first time that the rs7632287(G/A) polymorphism and ND have a mutual effect on the severity of negative symptoms of schizophrenia.

Efficacy of evinacumab by low-density lipoprotein receptor genotype and function in patients with homozygous familial hypercholesterolaemia: A subanalysis from the ELIPSE open-label extension study

Efficacy of evinacumab by low-density lipoprotein receptor genotype and function in patients with homozygous familial hypercholesterolaemia: A subanalysis from the ELIPSE open-label extension study

TAS2R38 Genotype Does Not Affect SARS-CoV-2 Infection in Primary Ciliary Dyskinesia.

Several chronic respiratory diseases could be risk factors for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunction of the respiratory cilia. In this study, we aimed to investigate whether PCD subjects are more susceptible to infection by SARS-CoV-2 and whether some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms. Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms, and vaccinations; in the case of infection, they also filled out a SNOT-22 questionnaire and ARTIQ. Forty PCD adult patients (mean age, 36.6 ± 16.7 years; 23 females, 17 males) participated in this study, out of which 30% had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistically significant difference (p = 0.03) was observed in body mass index (BMI), which was higher in the COVID-acquired group (23.2 ± 3.3 vs. 20.1 ± 4.1 kg/m2). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI, and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of the PAV allele towards SARS-CoV-2 infection. Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype does not affect SARS-CoV-2 infection.

Orchestrating the Impact of KIR/HLA Interactions on Kidney Transplant.

This study examines the interplay between human leukocyte antigen (HLA) compatibility and killer-cell immunoglobulin-like receptor (KIR) genotypes in influencing kidney transplantation outcomes. Understanding these interactions is crucial for improving graft survival and minimizing rejection risks. We evaluated 84 kidney transplant recipients, dividing them into two groups based on post-transplant outcomes: there were 68 with stable graft function (SGF) and 16 who experienced chronic rejection (CR). Patients were selected based on specific inclusion criteria. HLA mismatches (Class I: HLA-A, -B; Class II: HLA-DR) and KIR genotypes were determined using standard genotyping techniques. Statistical analyses, including logistic regression, were performed to correlate these factors with transplant outcomes. Significant age differences were observed, with younger patients more likely to experience graft rejection, while no significant gender-based differences were noted. A significant correlation was found between Class II mismatches and increased rejection rates, highlighting the importance of HLA-DR compatibility. Further analysis revealed that certain inhibitory KIRs, such as KIR3DL1, were associated with favorable outcomes, suggesting a protective role against graft rejection. These findings were corroborated by evaluating serum creatinine levels over multiple years, serving as a biomarker for renal function post transplant. This study underscores the critical need for meticulous HLA matching and the consideration of KIR genotypes in pre-transplant evaluations to enhance graft survival and minimize rejection risks. Integrating these genetic factors into routine clinical assessments could significantly improve personalized transplant medicine strategies, ultimately enhancing patient outcomes. Further research is needed to explore the underlying mechanisms and validate these findings in larger, diverse populations.

The association of the killer cell immunoglobulin-like receptor (KIR) genotype distribution and HLA-C ligands in colorectal cancer in the eastern region of Saudi Arabia

Colorectal cancer (CRC) is the most common cause of cancer-related mortality globally. It ranks as the most common cancer among men and the third most prevalent among women in Saudi Arabia, especially in the eastern region. The immune system's response to cancer is significantly influenced by natural killer cells through their killer-cell immunoglobulin-like receptors (KIRs) interaction with human leukocyte antigen (HLA) molecules. Our research aimed to target a homogeneous ethnic group in the eastern region of Saudi Arabia, analyzing the distribution of 16 KIR genes and HLA-C1/C2 allotypes in 50 CRC patients and 63 healthy controls using the sequence-specific PCR amplification method. Findings revealed significantly lower frequencies of the 2DL2 and 3DL1 genes in CRC patients compared to controls (OR = 2.21; P = 0.04) and (OR = 7.46; P = 0.00009), respectively. Additionally, a higher prevalence of HLA-C2 was noted in CRC patients (84 %) versus controls (66.7 %) (OR = 2.26; P = 0.04). Conversely, the HLA-C1C2 combination showed a protective effect against CRC (OR = 0.38; P = 0.04). Our combinatorial analysis further identified specific gene combinations correlating with CRC risk or protection. Notably, the absence of KIR2DL2 combined with the presence of KIR2DS2 emerged as a significant risk factor, while various combinations involving KIR2DL2 and/or KIR2DS1 with HLA-C ligands were associated with either increased susceptibility or protection. The study underscores the protective role of KIR2DL2 against CRC in Saudi Arabia's eastern region and suggests that the absence of KIR2DL2, especially when KIR2DS2 is present, might increase CRC risk. This research contributes to understanding genetic influences on CRC susceptibility, emphasizing the potential of KIR and HLA interactions as biomarkers for CRC risk assessment.

Relationship between vitamin D receptor genotypes (FOK1rs2228570) and IL18 gene expression in sample of multiple sclerosis Iraqi patients

BACKGROUND: Multiple Sclerosis known as MS, this chronic inflammatory demyelinating condition affects the nervous system. It is a heterogenic and multifactorial disease. The goal of the current study was to investigate the relationship between MS patients’ IL18 gene expression and the vitamin D receptor gene polymorphism (FOK1rs2228570). OBJECTIVE: The aim of the study to investigate the association of vitamin D receptor (FOK1rs2228570) gene polymorphism and pro inflammatory cytokine (IL18) gene expression among multiple sclerosis Iraqi patients. Detection VDR polymorphism and determine whether this SNP is involved in susceptibility to multiple sclerosis and estimation IL18 gene expression and explore its relation with multiple sclerosis susceptibility. METHODS: Blood samples were taken from 75 MS patients in Iraq (30 men and 45 women), as well as from 75 volunteers who seemed to be in a favorable state of health and fell within the age range of 20 to 50 years. Tetra-ARMS Polymerase Chain Reaction (Tetra-ARMS PCR) was used to find polymorphisms in the vitamin D receptor (VDR) gene, and Real-time Polymerase Chain Reaction (RT-PCR) was used to measure IL18 gene expression. RESULTS: The findings from the analysis of VDR gene polymorphism in patients with MS indicated that the wild-type genotype T/T was present in 8 individuals, accounting for 10.6%, the heterogeneous genotype TC was 36 (48%), and the homogeneous genotype CC was 31 (41.3%), whilst T allele frequency was 52(34.6%) and C allele was 98(65.3%) with (P⩽ 0.01) significant difference and even as in control T/T genotype was 49(65.3%), TC genotype was 21(28%), CC genotype was 5(6.66%), T allele frequency was 119(79.3%) and C allele was 31(20.6%) with significant difference (P⩽ 0.001). While estimation of IL18 expression showed high elevation in patients’ group (2.59 ± 0.51 fold) by significance difference (P⩽ 0.5) when compared to control group (1.35 ± 0.14 fold). The relationship between IL18 gene expression with VDR variant in MS patients demonstrated a significant rise (2.9 ± 0.51 fold) at CC genotype patients in IL18 folding gene expression, followed by (4.6 ± 0.17 fold) in TC genotype patients and finally (1.4 ± 0.08 fold) in TT genotype patients with highly significant (P⩽ 0.01). CONCLUSION: The VDR(FOK1rs2228570) genotype was significantly correlated with IL18 expression in MS patients from Iraq.

Donor KIR genotype based outcome prediction after allogeneic stem cell transplantation: no land in sight.

Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.

Footprints of Stress in Vitiligo: Association of the 5-HTR2C rs6318 Variant

Abstract Vitiligo is a chronic, progressive autoimmune dermatological disease, and stress is known to have an impact on the development of vitiligo. However, the effect of the serotonin pathway and its impact have not been clearly explained for disease progression. Thus, this study aimed to clarify the stress induced serotonin receptor 5-HTR2C rs6318 variant and its association with vitiligo pathogenesis. Case-control study was conducted with 108 vitiligo patients and 107 age-sex matched, unrelated healthy control group. Real Time-PCR analysis was used for genotyping the 5-HTR2C variation. Genotype and allele frequencies, genotype distributions, Hardy-Weinberg Equilibrium (HWE) and vitiligo-related risk measurements were examined. Genotype correlations of the variant were also analyzed based on gender difference, age onset, Koebner phenomenon history, triggered with stress, clinical subgroups, treatment types, the presence of other autoimmune diseases, vitiligo presence in family members and other auto-immune diseases in relatives. Statistical differences in 5HT-R2C receptor genotypes and allele frequencies between patients and controls were not detected. Genotype frequencies were not in agreement with Hardy-Weinberg Equilibrium in the patients’ group (p&lt;0.00001). The frequency of the risk allele (allele C) was not significantly different between the patient and control groups (p=0.1392). However, in the clinical subgroup analysis, the risk allele presence was detected to be significantly higher for early age onset (&lt;40 years) vitiligo development (p=0.035, OR=Infinity, RR=1.391) and lower in Koebner phenomenon history (p=0.0276, OR= 0.219, RR=0.325). In conclusion, although there was no association between the 5-HTR2C variant rs6318 and vitiligo, current results indicate that there is an association between the 5HTR2C rs6318 variant C allele and early onset vitiligo development.

Patterns of neural activity in response to threatening faces are predictive of autistic traits: modulatory effects of oxytocin receptor genotype

Autistic individuals generally demonstrate impaired emotion recognition but it is unclear whether effects are emotion-specific or influenced by oxytocin receptor (OXTR) genotype. Here we implemented a dimensional approach using an implicit emotion recognition task together with functional MRI in a large cohort of neurotypical adult participants (N = 255, male = 131, aged 17–29 years) to establish associations between autistic traits and neural and behavioral responses to specific face emotions, together with modulatory effects of OXTR genotype. A searchlight-based multivariate pattern analysis (MVPA) revealed an extensive network of frontal, basal ganglia, cingulate and limbic regions exhibiting significant predictability for autistic traits from patterns of responses to angry relative to neutral expression faces. Functional connectivity analyses revealed a genotype interaction (OXTR SNPs rs2254298, rs2268491) for coupling between the orbitofrontal cortex and mid-cingulate during angry expression processing, with a negative association between coupling and autistic traits in the risk-allele group and a positive one in the non-risk allele group. Overall, results indicate extensive emotion-specific associations primarily between patterns of neural responses to angry faces and autistic traits in regions processing motivation, reward and salience but not in early visual processing. Functional connections between these identified regions were not only associated with autistic traits but also influenced by OXTR genotype. Thus, altered patterns of neural responses to threatening faces may be a potential biomarker for autistic symptoms although modulatory influences of OXTR genotype need to be taken into account.

Association between vitamin D receptor (APAI rs7975232) genotypes and vitamin D serum levels in Iraqi multiple sclerosis patients

BACKGROUND: Multiple sclerosis (MS) is a long-term condition characterized by chronic inflammation, damage to the myelin sheath, and progressive nerve cell degeneration. It is a heterogeneous and multifactorial disease. The aim of the present investigation was to analyze the connection between variations in the vitamin D receptor gene. (APAI rs7975232) and vitamin D serum levels among MS patients. METHODS: Blood samples were collected from 75 Iraqi patients with MS (33 male, 42 female), and 75 control group volunteers who appeared to be in good health with an age range of 20–50 years. Vitamin D receptor (VDR) gene polymorphism was detected by HRM RT-PCR and vitamin D serum levels were assessed by ELISA. RESULTS: Detection of VDR gene polymorphism in MS patients discovered that the wild genotype was C/C 15 (20%), the heterozygous genotype CA was 27(36%), and the homozygous genotype AA was 33(44%), whilst allele C occurrence was 57(38%) and allele A was 93(62%), compared per control genotype C/C was 40(53.3%), CA genotype was 20(26.6%), AA genotype was 15(20%), C allele frequency was 100(66.6%) and A allele was 50(33.3%) with highly significant difference (P≤0.001). Analysis of vitamin D serum levels showed much higher levels in the control group (43.40±0.85 pg/ml) than in the MS patients group (15.46±0.93 pg/ml; P≤0.001). Result of relationship between Vitamin D serum level with genotype of VDR among individuals with MS was found to be significant decrease (5.3±0.52) at AA genotype of MS patients, followed by (11.79±0.68) in CA genotype and finally (15.52±0.93) in CC genotype, all highly significant (P≤0.01). CONCLUSION: There was a notable correlation observed with VDR (APAI rs7975232) genotypes and Vitamin D serum level in MS Iraqi patients.

Abstract 266: The effects of retinoid agents and retinoic acid receptor genotype on proliferation, differentiation, and stem cells in colorectal cancer

Abstract Understanding how to therapeutically target colonic stem cells (SCs) is important because SC overpopulation drives CRC growth and development. Our goal is to therapeutically sensitize cancer SCs (CSCs) to the differentiation-inducing effects of retinoid agents. We previously found that ALDH specifically marks normal and malignant colonic SCs. We also found that retinoic acid (RA) receptors and other RA signaling components are selectively expressed in ALDH+ SCs, indicating that RA signaling occurs through ALDH+ SCs. Because all-trans retinoic acid (ATRA) is a highly effective treatment for acute promyelocytic leukemia, which is caused by a genetic translocation involving retinoic acid receptor alpha (RARA), we conjecture that the response of RA agents may be effective against solid tumors depending on their pathway genotype. Our bioinformatics analysis on mutations and overexpression of RA signaling component genes in CRC showed that most of the RA pathway genes are altered in human CRCs. Therefore, we hypothesize that the ability of retinoid agents and retinoid metabolism blocking agents to induce differentiation of CSCs depends on the RA pathway genotype of CRC cells.Testing the effect of various retinoid drugs on cell proliferation shows that RA pathway genotype affects the response of RA agents in CRC cell lines. HCT116 and SW480 CRC cell lines, which have RA receptor mutations, displayed resistance to ATRA. In contrast, HT29 CRC cells that have wild-type RA receptors are sensitive to ATRA. All three cell lines however showed similar dose responses to the ATRA metabolizing enzyme, CYP26A1 inhibitor Liarozole. This finding indicates that regardless of RA receptor mutations, inhibition of ATRA metabolism can increase intracellular RA levels in a similar manner on all three cell lines to induce anti-proliferative effects. We used CRISPR-Cas9 gene editing to knock out the RARA gene in HT29 cells and evaluated its response to ATRA compared to HT29 cells. The RARA knockout derived lines showed reduced sensitivity to ATRA treatment and a slower rate of cell division compared to HT29 control cells. Additionally, Nanostring mRNA profiling analysis shows that ATRA treatment of HT29 cells increases expression of RARA, CYP26A1, and KRT20 (differentiation marker); and decreased decreases expression of CSC markers LGR5 and ALDH1A1. Altogether, these findings indicate that upregulated RA signaling can reduce cell proliferation, increase differentiation, and decrease CSC numbers in CRCs. Overall, our findings indicate that colon SCs are regulated by RA signaling mechanisms and dysregulation of RA signaling contributes to the SC overpopulation that drives CRC growth. Thus, therapeutically sensitizing CSCs to differentiation-inducing effects of retinoid agents should provide insight into designing new SC-targeted therapies for CRC. Citation Format: Victoria O. Hunsu, Caroline O. Facey, Bruce M. Boman. The effects of retinoid agents and retinoic acid receptor genotype on proliferation, differentiation, and stem cells in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 266.

Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo

While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for their attachment and entry into splenic B cells. Single-cell RNA sequencing analysis of the transduced cells demonstrated that different pseudotypes transduce distinct B cell subpopulations characterized by specific B cell receptor (BCR) genotypes. Functional analysis of the BCRs of the transduced cells demonstrated that BCRs specific to the pseudotyping envelope proteins mediate viral entry, enabling the vectors to selectively transduce the B cell populations that are capable of producing antibodies specific to their envelope proteins. Lentiviral vector entry via the BCR activated the transduced B cells and induced proliferation and differentiation into mature effectors such as memory B and plasma cells. BCR-mediated viral entry into clonally specific B cell subpopulations raises new concepts for understanding the biodistribution of transgene expression after systemic administration of lentiviral vectors and offers new opportunities for BCR-targeted gene delivery by pseudotyped lentiviral vectors.

Non-invasive molecular biomarkers for monitoring solid organ transplantation: A comprehensive overview.

Solid organ transplantation is a life-saving intervention for individuals with end-stage organ failure. Despite the effectiveness of immunosuppressive therapy, the risk of graft rejection persists in all viable transplants between individuals. The risk of rejection may vary depending on the degree of compatibility between the donor and recipient for both human leucocyte antigen (HLA) and non-HLA gene-encoded products. Monitoring the status of the allograft is a critical aspect of post-transplant management, with invasive biopsies being the standard of care for detecting rejection. Non-invasive biomarkers are increasingly being recognized as valuable tools for aiding in the detection of graft rejection, monitoring graft status and evaluating the efficacy of immunosuppressive therapy. Here, we focus on the importance of molecular biomarkers in solid organ transplantation and their potential role in clinical practice. Conventional molecular biomarkers used in transplantation include HLA typing, detection of anti-HLA antibodies, killer cell immunoglobulin-like receptor genotypes, and anti-MHC class 1-related chain A antibodies, which are important for assessing the compatibility of the donor and recipient. Emerging molecular biomarkers include the detection of donor-derived cell-free DNA, microRNAs (regulation of gene expression), exosomes (small vesicles secreted by cells), and kidney solid organ response test, in the recipient's blood for early signs of rejection. This review highlights the strengths and limitations of these molecular biomarkers and their potential role in improving transplant outcomes.

The trilogy of human musk receptors: linking receptor activation, genotype, and sensory perception.

The scent of musk plays a unique role in the history of perfumery. Musk odorants comprise 6 diverse chemical classes and perception differences in strength and quality among human panelists have long puzzled the field of olfaction research. Three odorant receptors (OR) had recently been described for musk odorants: OR5AN1, OR1N2, and OR5A2. High functional expression of the difficult-to-express human OR5A2 was achieved by a modification of the C-terminal domain and the link between sensory perception and receptor activation for the trilogy of these receptors and their key genetic variants was investigated: All 3 receptors detect only musky smelling compounds among 440 commercial fragrance compounds. OR5A2 is the key receptor for the classes of polycyclic and linear musks and for most macrocylic lactones. A single P172L substitution reduces the sensitivity of OR5A2 by around 50-fold. In parallel, human panelists homozygous for this mutation have around 40-60-fold higher sensory detection threshold for selective OR5A2 ligands. For macrocyclic lactones, OR5A2 could further be proven as the key OR by a strong correlation between in vitro activation and the sensory detection threshold in vivo. OR5AN1 is the dominant receptor for the perception of macrocyclic ketones such as muscone and some nitromusks, as panelists with a mutant OR5A2 are still equally sensitive to these ligands. Finally, OR1N2 appears to be an additional receptor involved in the perception of the natural (E)-ambrettolide. This study for the first time links OR activation to sensory perception and genetic polymorphisms for this unique class of odorants.

Effects of genetics on odor perception: Can a quick smell test effectively screen everyone?

SCENTinel, a rapid smell test designed to screen for olfactory disorders, including anosmia (no ability to smell an odor) and parosmia (distorted sense of smell), measures 4 components of olfactory function: detection, intensity, identification, and pleasantness. Each test card contains one of 9 odorant mixtures. Some people born with genetic insensitivities to specific odorants (i.e. specific anosmia) may fail the test if they cannot smell an odorant but otherwise have a normal sense of smell. However, using odorant mixtures has largely been found to prevent this from happening. To better understand whether genetic differences affect SCENTinel test results, we asked genetically informative adult participants (twins or triplets, N = 630; singletons, N = 370) to complete the SCENTinel test. A subset of twins (n = 304) also provided a saliva sample for genotyping. We examined data for differences between the 9 possible SCENTinel odors; effects of age, sex, and race on SCENTinel performance, test-retest variability; and heritability using both structured equation modeling and SNP-based statistical methods. None of these strategies provided evidence for specific anosmia for any of the odors, but ratings of pleasantness were, in part, genetically determined (h2 = 0.40) and were nominally associated with alleles of odorant receptors (e.g. OR2T33 and OR1G1; P < 0.001). These results provide evidence that using odorant mixtures protected against effects of specific anosmia for ratings of intensity but that ratings of pleasantness showed effects of inheritance, possibly informed by olfactory receptor genotypes.