Receptor Genotype Research Articles

DNMT3A mutation is associated with increased age and adverse outcome in adult T-cell acute lymphoblastic leukemia.

The prognostic implications of DNMT3A genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute lymphoblastic leukemia patients with DNMT3A mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had DNMT3A alterations. Two patients also had DNMT3A mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia. DNMT3A mutation was associated with older age (median 43.9 years vs. 29.4 years, P<0.001), immature T-cell receptor genotype (53.3% vs. 24.4%, P=0.016) and lower remission rates (72.2% mutated vs. 94.4% non-mutated, P=0.006). DNMT3A alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (HR 2.33, 95% CI: 1.05-5.16, P=0.037) and markedly poorer event-free survival (HR 3.22, 95% CI: 1.81-5.72, P<0.001) and overall survival (HR 2.91, 95% CI: 1.56-5.43, P=0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of DNMT3A-mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, DNMT3A mutation was significantly associated with shorter event-free survival (HR 2.33, 95% CI: 1.06 – 4.04, P=0.02). Altogether, these results identify DNMT3A genotype as a predictor of aggressive T-cell acute lymphoblastic leukemia biology. The GRAALL-2003 and -2005 studies were registered at http://www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678, respectively.

Pathways To Precision Medicine In Smoking Cessation Treatments

Introduction: Cigarette smoking is highly addictive and prevalent among individuals with mental illness. Modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. MethodsWe investigated the significant genetic variants that predict nicotine dependence, smoking cessation, and response to cessation pharmacotherapy using both large cohort studies of smokers and randomized controlled trials. ResultsWe find that genetic risks may predict prognosis and response to pharmacological treatments. For prognosis, the nicotinic receptor genotypes predict delayed quitting and earlier lung cancer diagnoses after adjusting for smoking quantity in large meta-analyses of studies of lung cancer and nicotine dependence. For treatment response, some pharmacogenetic findings have been replicated in meta-analyses or multiple smoking cessation trials for both pharmacodynamic markers (e.g., CHRNA5) and pharmacokinetic marker (e.g., CYP2A6). The variation in efficacy between smokers with different genetic markers supports the notion that personalized smoking cessation intervention based upon genotype could maximize the efficiency of such treatment while minimizing side effects, thus influencing the number needed to treat (NNT) and the number needed to harm. ConclusionCurrent evidence strongly suggests that cessation failure and cessation pharmacotherapy effectiveness are modulated by biomarkers such as nicotinic receptor genotypes, nicotine metabolism ratio (NMR), or polygenic risk scores for nicotine dependence. These findings strengthen the case for further research on genetics of smoking cessation success, and the development and rigorous testing of treatments for smokers with different genetic risk profiles. Learning Objectives1) human genetic studies can inform the biological mechanisms of nicotine dependence and health consequences such as lung cancer, 2) pharmacogenetic studies may inform personalized treatments for tobacco use disorder, possibly increasing efficacy and reducing risk of side effects.

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.

Explore new approaches to prevent and treat type 2 diabetes with vitamin D and its active analogues——From somewhat disappointing clinical trials results to promising basic researches

The prevalence of diabetes is increasing rapidly which becomes a serious economic burden to society. The effects of vitamin D beyond bone are increasingly recognized. Circulating level of vitamin D is associated with the development of obesity and type 2 diabetes in cross-sectional human studies. However, as to the therapeutic efficacy of vitamin D supplementation on the prevention of diabetes, the results derived from randomized controlled clinical trials were disappointing, probably due to variations in the vitamin D receptor genotypes, the dosages and courses of vitamin D treatments. However, two recent basic studies found that central administration of active vitamin D can improve glucose metabolism in diet induced obesity rats; and the combining use of active vitamin D analogue and BRD9 inhibitor rendered the chromatin of vitamin D response elements more accessible, thus more efficiently exerted its anti-inflammatory efficacy and protected islet β cell function in obese and diabetic mice models. Thus it is paramount important to explore some new approaches to prevent and treat diabetes with vitamin D and its active analogues. (Chin J Endocrinol Metab, 2018, 34: 992-996) Key words: Vitamin D; Vitamin D receptor; Diabetes mellitus, type 2

Genetic variation in the TAS2R38 taste receptor contributes to the oral microbiota in North and South European locations: a pilot study

BackgroundMicrobial communities are influenced by environmental factors including host genetics. We investigated the relationship between host bitter taste receptor genotype hTAS2R38 and oral microbiota, together with the influence of geographical location.MethodshTAS2R38 polymorphisms and 16S bacterial gene sequencing from oral samples were analyzed from a total of 45 healthy volunteers from different geographical locations.ResultsGenetic variation in the bitter taste receptor TAS2R38 reflected in the microbial composition of oral mucosa in Finnish and Spanish subjects. Multivariate analysis showed significant differences in the microbial composition between country and also dependent on taste genotype. Oral microbiota was shown to be more stable to the geographical location impact among AVI-homozygotes than PAV-homozygotes or heterozygotes (PAV/AVI).ConclusionGeographical location and genetic variation in the hTAS2R38 taste receptor impact oral mucosa microbial composition. These findings provide an advance in the knowledge regarding the interactions between taste receptor genes and oral microbiota. This study suggests the role of host-microbiota interactions on the food taste perception in food choices, nutrition, and eating behavior.

Donor KIR3DL1/Receptor HLA-Bw4-80I Combination Reduce Acute Leukemia Relapse after Umbilical Cord Blood Transplantation without in Vitro T-Cell Depletion

Objective: How to reduce relapse is still a puzzle in the treatment of acute leukemia patients with allogeneic umbilical cord blood hematopoietic cell transplantation (UCBT). Donor natural killer (NK) cell alloreactivity in UCBT can control leukemic relapse, However, NK cell function is calibrated through education, that is governed by human leukocyte antigens (HLAs), our study aim to investigate the Graft-resistant leukemia effect after transplantation of KIR3DL1 and its different ligand HLA-B subtypes(BW6, Bw4-80T, Bw4-80I).Design and method: we retrospectivly analysed single center of 232 acute leukemia patients who underwent UCBT(myeloablative conditioning without ATG). The killer immunoglobulin-like receptor (KIR) genotype of cord blood donors was detected by SSP method, they all contains KIR3DL1. There were 104 cases of acute lymphoblastic leukemia, 112 cases of acute myeloid leukemia, 16 cases of myelodysplastic syndrome. 168 cases of transplant patients in remission period, and 64 cases of non-remission. There were 122 males and 110 females with a median age of 13 years (2-45 years). The patients were divided into three groups according to HLA-B locus, 1.patients had BW6 in both two HLA-B locus(group 1, N=86) , which means uneducated; 2.patients had HLA-Bw4-80T in the HLA-B locus(group 2, N=68), which means educated; 3.patients had HLA- Bw4-80I in the HLA-B locus(group 3, N=77), which means highly educated. The receptors were followed-up from July 31, 2012 to December 30,2017, in graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse, overall survival (OS), and leukemia free survival (LFS).Results: In group 3 patients, donor KIR3DL1 and receptor HLA-Bw4-80I combinations that were predictive of highly educated were associated with significantly lower relapse (hazard ratio [HR], HR = 0.49; P =0 .004) and better LFS (HR = 0.68, p = 0.014), compared with the educated(group2) and uneducated (group3) group, with no significant increase in aGVHD and cGVHD incidence. While no difference was observed in the other index in the three group.Conclusion : Alloreactivity of NK cells demonstrated reproducible patterns of strong or weak graft-versus-leukemia (GVL) effect against leukemia blast, which is depend on donor KIR3DL1/receptor HLA-B subtype combinations. Our data suggests that donor KIR3DL1/receptor HLA-Bw4-80I combination in UCBT may achieve superior graft versus leukemia effects, lower risk for relapse among patients with acute leukemia.Keywords: KIR, Umbilical Cord Blood Transplantation, UCBT, GVL DisclosuresNo relevant conflicts of interest to declare.

Classification of Donor KIR-Genotype Information to Predict Outcome after Unrelated Hematopoietic Stell Cell Transplantation: The Jury Is Still out

Introduction:A series of studies suggest that harnessing natural killer (NK) cell reactivity by killer cell immunoglobulin-like receptor (KIR) genotype based unrelated donor selection could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). A Receptor-Ligand model has been proposed for donor selection which aims at augmenting NK cell activation while minimizing inhibition. Information on education of KIR2DS1-positive NK cells (Venstrom et al, NEJM 2012) and the predicted Receptor-Ligand interaction of KIR3DL1-positive NK cells is utilized for this algorithm. By combining this information donors can be classified as KIR-advantageous or disadvantageous. Patients with donors, characterized by activating KIR2DS1 and weak/non-inhibiting KIR3DL1, experienced less relapse and improved survival compared to patients with donors, characterized by lacking an activating KIR2DS1 but presence of strong-inhibiting KIR3DL1. This study aimed at validating this predictor in an independent cohort of patients.Methods:Donor samples were retrieved from the Collaborative Biobank (Dresden, Germany) and mapped to patient outcome data extracted from the German Registry for Stem Cell transplantation. KIR typing was performed using a high resolution amplicon-based next generation sequencing method. KIR typing at the allele level was based on sequencing of exons 3, 4, 5, 7, 8, and 9. The patient population was restricted to patients with AML or MDS. Donor and patient mapping was cross-checked by HLA-typing of the donor sample. The impact of the predictor on overall survival was tested in a Cox regression model adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex match, CMV match, conditioning intensity, type of T-cell depletion and graft type.Results:Clinical data from 2314 patients were analyzed. The median age at alloHCT was 59.4 years (range, 18.1 to 79.6 years). The indication for alloHCT was AML for 80% of patients and MDS for 20% of patients. Disease risk was assessed as low, intermediate, high or very high in 1%, 52%, 42%, and 5%, respectively. Patient and donor were 10/10 matched in 78% of pairs, whereas a one locus mismatch was reported for 21% of pairs. Myeloablative, reduced-intensity and non-myeloablative conditioning regimens were used in 29%, 67%, and 4% of patients, respectively. ATG was administered in 77% and alemtuzumab in 3% of patients. Twenty percent of patients received no T-cell depletion.In total, 535 patients experienced relapse and 945 patients died. This number of events translated into a power of the confirmatory analysis for the predictor of KIR2DS1 and KIR3DL1 of 67%. Two-year overall and event-free survival for the whole cohort was 51% (95%-CI 48% to 53%) and 44% (95%-CI 42% to 47%) and the 2-year incidence of relapse and non-relapse mortality was 28% (95%-CI 26% to 30%) for both endpoints. In univariate analysis, overall survival (54% versus 56%) and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with KIR-disadvantageous donors. The adjusted hazard ratio from the multivariable Cox regression model for the comparison of patients with KIR-advantageous versus KIR-disadvantageous donors was 0.99 (Wald-test, p=0.95) for overall survival and 1.12 (Wald-test, p=0.41) for relapse incidence.When evaluated separately, the two components of the predictor (degree of inhibition by KIR3DL1 & presence of activating KIR2DS1) did not have an impact on overall survival or the incidence of relapse (see Figure). Also, evaluation of the combined predictor in subsets of patients by disease, type of T-cell depletion and HLA-compatibility did not allow prediction of these outcomes.Conclusions:Relapse incidence and overall survival after unrelated donor alloHCT could not be predicted using information on activating KIR2DS1 and inhibiting KIR3DL1 donor genes in an independent cohort of predominantly Caucasian patients. The predictor had been developed in a cohort of patients with AML who were younger and predominantly had received myeloablative conditioning based on total-body irradiation, ATG was administered less often, but donors often were only partially HLA-compatible. The different outcome in the current analysis thus points at potential interactions between NK-cell mediated allo-reactivity and procedural variations of alloHCT. [Display omitted] DisclosuresSchetelig:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Roche: Honoraria; Abbvie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Stelljes:Novartis: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; JAZZ: Honoraria; Amgen: Honoraria. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Bethge:Neovii GmbH: Honoraria, Research Funding; Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding. Bug:Neovii: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Janssen: Other: Travel Grant; Celgene: Honoraria; Amgen: Honoraria; Astellas Pharma: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant. Kobbe:Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding; Amgen: Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Fleischhauer:GENDX: Research Funding.

Killer immunoglobulin-like receptor genotype did not correlate with response to anti-PD-1 antibody treatment in a Japanese cohort

Immune checkpoint blockade (ICB) induces a remarkable response in patients with certain cancers. However, the response rate is not yet satisfactory. Biomarkers that help physicians identify patients who would benefit from ICB need to be developed. Killer immunoglobulin-like receptors (KIRs) are a class of receptors that are mainly expressed by natural killer cells. KIR genotypes have been shown to influence the outcomes of patients with neuroblastoma and hematopoietic malignancies. KIRs may thus influence the clinical outcomes of melanoma patients receiving nivolumab. We aimed to identify the KIR genotype, or KIR/KIR-ligand combinations, which influence the outcomes of melanoma patients receiving nivolumab. We genotyped 112 melanoma patients who were treated with nivolumab for KIR and human leukocyte antigen. The clinical records of the patients were analyzed to determine if they showed a response to nivolumab, and whether or not they experienced adverse events. Our analysis showed that no KIR gene was associated with a response to nivolumab. The KIR/KIR-ligand combination did not correlate with a response to nivolumab. KIR genes were not predictive of experiencing adverse events of grade 2 or greater. We conclude that the KIR genotype or KIR/KIR-ligand genotype do not show predictive value in melanoma patients receiving nivolumab.

Association of KIR Genotypes and Haplotypes in HBeAg-positive Chronic Hepatitis B Patients Treated with Entecavir

ABSTRACTBackground:A large proportion of patients with chronic hepatitis B (CHB) in China do not respond to entecavir (ETV) treatment. It remains unclear whether the Killer immunoglobulin-like receptor (KIR) genotypes and haplotypes were associated with the advantage of seroconversion in phepatitis B e-Antigen (HBeAg) positive CHB patients treated with ETV.Methods: Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to analyze KIR genes in a Chinese Han population of 198 ETV-treated HBeAg-positive CHB patients and 200 healthy controls. Of the 198 patients, 59 were complete response group (CRG) and 139 were null or partial response group (NPRG) to the treatment with ETV.Results: The frequencies of KIR genotype M, and haplotype 8 were significantly higher(P = 0.017, OR = 2.497，95%CI = 5.39–1.16 and P = 0.034, OR = 1.905，95%CI = 3.48–1.04, respectively), while the frequencies of genotype AH and haplotype 5 were significantly lower (P = 0.039, OR = 0.504, 95%CI = 0.97–0.26 and P = 0.031, OR = 0.601, 95%CI = 0.96–0.38, respectively) in HBeAg-positive CHB patient group than those in healthy group. Of note, the frequencies of KIR genotype AF and haplotype 1 were significantly higher (P = 0.022, OR = 2.860, 95%CI = 7.24–1.13 and P = 0.001, OR = 3.261, 95%CI = 6.47–1.64, respectively), while the frequencies of genotype AH and haplotype 5 were significantly lower (P = 0.038, OR = 0.338, 95%CI = 0.98–0.12 and P = 0.004, OR = 0.354, 95%CI = 0.73–0.17, respectively) in NPRG than those in CRG.Conclusions: The patients with KIR genotype AF and haplotype 1 might be negative, while genotype AH and haplotype 5 might be of advantage to the therapy with ETV, which are useful for improving novel personalized precise therapy strategy in HBeAg-positive CHB patients.

The association between perinatal hypoxia exposure and externalizing symptoms and children's decision making in conditions of uncertainty is moderated by DRD2 genotype.

Variants of the DRD2 Taq1A polymorphism, which have been shown to result in functional differences in dopamine D2 receptors (D2R), have been linked to various externalizing outcomes in adults. However, the neurobiological processes that contribute to these associations are not well understood. The current study investigates gene×environment effects on teacher-rated externalizing behaviors and probabilistic decision making in a sample of 333 children (age 9) enrolled in an ongoing longitudinal study. Findings indicate that externalizing behaviors increased as a function of hypoxic exposure only among individuals carrying the A1 (A1+) allele. Results also indicate that willingness to pursue reward under conditions of maximum uncertainty (50% probability) decreased as a function of hypoxic exposure only among A1- individuals. Among A1 carriers, no association between probability decision making and hypoxic exposure emerged. These findings suggest that hypoxia could influence neural development through different biological pathways depending on D2 receptor genotype, and provide insight into the development of individual differences in behavior and decision making.

The late positive potential and subjective arousal ratings evoked by negative images vary as a function of oxytocin receptor genotype SNP rs53576.

In the central nervous system the neuropeptide oxytocin mediates a range of behaviors related primarily to emotionality. One factor that influences oxytocinergic communication in the human brain and correlates with emotional behaviors is the single nucleotide polymorphism rs53576 on the oxytocin receptor gene (OXTR). For example, variations in this OXTR genotype are related to parental, altruistic, and other prosocial behaviors. Electroencephalographic waveforms of visually evoked response potentials recorded at the midline parietal electrode site display a prominent component putatively involved with attention allocation called the late positive potential. The magnitude of the late positive potential was found to be significantly higher in homozygous G allele individuals compared with A allele carriers when viewing negative emotionally charged images. Inversely, A allele carriers rated these negative images as more arousing, when measured by the Self-Assessment Manikin rating scale. These data suggest that OXTR functioning contributes to visual processing and subjective experience of negative stimuli.

Impact of Genetic Variability on Physiological Responses to Caffeine in Humans: A Systematic Review.

Emerging research has demonstrated that genetic variation may impact physiological responses to caffeine consumption. The purpose of the present review was to systematically recognize how select single nucleotide polymorphisms (SNPs) impact habitual use of caffeine as well as the ergogenic and anxiogenic consequences of caffeine. Two databases (PubMed and EBSCO) were independently searched using the same algorithm. Selected studies involved human participants and met at least one of the following inclusion criteria: (a) genetic analysis of individuals who habitually consume caffeine; (b) genetic analysis of individuals who underwent measurements of physical performance with the consumption of caffeine; (c) genetic analysis of individuals who underwent measurements of mood with the consumption of caffeine. We included 26 studies (10 randomized controlled trials, five controlled trials, seven cross-sectional studies, three single-group interventional studies and one case-control study). Single nucleotide polymorphisms in or near the cytochrome P450 (CYP1A2) and aryl hydrocarbon receptor (AHR) genes were consistently associated with caffeine consumption. Several studies demonstrated that the anxiogenic consequences of caffeine differed across adenosine 2a receptor (ADORA2A) genotypes, and the studies that investigated the effects of genetic variation on the ergogenic benefit of caffeine reported equivocal findings (CYP1A2) or warrant replication (ADORA2A).

P006 NK KIR receptor genotypes are associated with relapse in mexican HLA matched sibling patients with acute lymphoblastic leukemia (ALL)

Aim The outcome of Hematopoietic Stem Cell Transplantation (HSCT) is strongly associated with the HLA identity of donor/recipient, and GVHD remains the most frequent associated factor with mortality and impact on the quality of life. A successful HSCT depends also on T-cell mediated graft vs. leukemia (GvL) effect. Relapse is a major important challenge. NK cells, KIR and their HLA ligands are involved with an increase in overall survival, as well as better engraftment and reduced incidence of GVHD in patients with AML. The aim of the study was to determine the KIR gene content, their HLA ligands and their association on the outcome of ALL patients transplanted with HLA-identical sibling donors. Methods Twenty-seven Mexican patients with their HLA-identical siblings were included. Of these, 20 had ALL and 7 AML. KIR gene content was determined with the LinkSēq™ KIR kit and was run on an ABI 7500 Real-Time PCR instrument. Analysis was done with SureTyper 5. HLA intermediate resolution typing was performed by SSOP on a Luminex. HLA alleles were analyzed with the Match it DNA 1.2.0 software. KIR haplotypes and HLA ligands were assessed using https://www.ebi.ac.uk/ipd/kir/ligand.html . Allele Frequency (AF) and multiple parameter comparison analysis was performed using the SPSS17 software. Results We looked if activating or inhibitory KIR genes had any effect on relapse, long term disease free survival (DFS), GVHD or mortality. An association with relapse was observed in ALL patients, when the matched sibling donor carried the 3DL1 -Bw4 ligand (50% of ALL patients were carriers); (Chi2 = 5.93; p = 0.03) with no differences in Bw4 80I and 80T ligand. The AA and Bx haplotypes did not have any association with mortality, GVHD, relapse or DFS. Conclusions The results in ALL regarding relapse show that the presence of 3DL1 -Bw4, conveys higher susceptibility for relapse, as shown for AML. Contrary to AML, no effect was detected with 80I or 80T with intermediate relapse and mortality, implying a non benefit of education and sensitivity to inhibition as reported for AML. More cases of ALL are being analyzed to confirm if HLA and KIR allele typing in donor selection, enables the antileukemic benefits of NK alloreactivity in HSCT, in ALL, as it has been pointed out in AML, since the affected cell population in ALL, is totally different of the latter.

Vitamin D receptor genotype influences risk of upper respiratory infection.

SNP in the vitamin D receptor (VDR) gene is associated with risk of lower respiratory infections. The influence of genetic variation in the vitamin D pathway resulting in susceptibility to upper respiratory infections (URI) has not been investigated. We evaluated the influence of thirty-three SNP in eleven vitamin D pathway genes (DBP, DHCR7, RXRA, CYP2R1, CYP27B1, CYP24A1, CYP3A4, CYP27A1, LRP2, CUBN and VDR) resulting in URI risk in 725 adults in London, UK, using an additive model with adjustment for potential confounders and correction for multiple comparisons. Significant associations in this cohort were investigated in a validation cohort of 737 children in Manchester, UK. In all, three SNP in VDR (rs4334089, rs11568820 and rs7970314) and one SNP in CYP3A4 (rs2740574) were associated with risk of URI in the discovery cohort after adjusting for potential confounders and correcting for multiple comparisons (adjusted incidence rate ratio per additional minor allele ≥1·15, P for trend ≤0·030). This association was replicated for rs4334089 in the validation cohort (P for trend=0·048) but not for rs11568820, rs7970314 or rs2740574. Carriage of the minor allele of the rs4334089 SNP in VDR was associated with increased susceptibility to URI in children and adult cohorts in the United Kingdom.

Taste Exam: A Brief and Validated Test.

The emerging importance of taste in medicine and biomedical research, and new knowledge about its genetic underpinnings, has motivated us to supplement classic taste-testing methods in two ways. First, we explain how to do a brief assessment of the mouth, including the tongue, to ensure that taste papillae are present and to note evidence of relevant disease. Second, we draw on genetics to validate taste test data by comparing reports of perceived bitterness intensity and inborn receptor genotypes. Discordance between objective measures of genotype and subjective reports of taste experience can identify data collection errors, distracted subjects or those who have not understood or followed instructions. Our expectation is that fast and valid taste tests may persuade researchers and clinicians to assess taste regularly, making taste testing as common as testing for hearing and vision. Finally, because many tissues of the body express taste receptors, taste responses may provide a proxy for tissue sensitivity elsewhere in the body and, thereby, serve as a rapid, point-of-care test to guide diagnosis and a research tool to evaluate taste receptor protein function.

Serum vitamin D level and vitamin D receptor genotypes may be associated with tuberculosis clinical characteristics: A case-control study.

Vitamin D is associated with the susceptibility of tuberculosis and might have an adjunctive effect on anti-tuberculosis treatment. This study aims to investigate the association of vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms with susceptibility and severity to multidrug-resistant tuberculosis (MDR-TB) in comparison with drug-sensitive tuberculosis (DS-TB) and health controls in China.A total of 180 patients with pulmonary TB (128 DS-TB, 52 MDR-TB) and 59 healthy controls were enrolled into 3 groups. Vitamin D levels and VDR genotypes at FokI, BsmI, ApaI, and TaqI sites of all the participants and clinical characteristics of patients with TB were measured and collected.Statistical analysis revealed that vitamin D levels were lower in both TB groups. Patients with TB with bilateral lesions and patients with MDR-TB with extrapulmonary TB had lower vitamin D levels. The frequencies of ff genotype and f allele were higher in both TB groups. Patients with Ff genotype and ff genotype had lower proportion of extrapulmonary TB. Patients with ff genotype had higher proportion of retreatment. Male patients with ff genotype had higher proportion of cavity formation. Patients with DS-TB with AA genotype had higher proportion of cavity formation.Our findings demonstrate that vitamin D deficiency and ff genotype may be the risk factors of TB in Chinese population. In addition, patients with TB with lower level of vitamin D may have a greater risk of bilateral lesions and extrapulmonary TB. VDR genotypes may be associated with TB clinical characteristics.

Killer cell immunoglobulin-like receptor genotypes in a Chilean population from Talca

Ninety healthy and unrelated volunteers were randomly selected to study the gene frequencies of Killer-cell immunoglobulin-like receptors (KIRs) in a Chilean (Talca) population. KIR typing was resolved by PCR-single specific primer (SSP), and their gene frequencies were calculated by direct counting of the number of positive and negative loci. The KIR genotype data is publicly available in the Allele Frequencies Net Database under the name “Chile Talca KIR”.

Vitamin D receptor gene polymorphisms modify the association of serum 25-hydroxyvitamin D levels with handgrip strength in the elderly in Northern China.

The aim of this cross-sectional study was to investigate the association of serum 25-hydroxyvitamin D (25[OH]D) levels and vitamin D receptor (VDR) genotypes with skeletal muscle mass and function in elderly subjects in northern China. A total of 275 men and 510 women, ages 63.1 to 72.5 y, in two randomly selected communities in Beijing were investigated. The investigation included a questionnaire, physical measurements, muscle mass and function measurements, serum 25(OH)D levels, and VDR gene polymorphisms analysis. In the group with 25(OH)D levels <10.0 ng/mL, the proportion with low handgrip strength was 3.04 times higher than that in the group with 25(OH)D levels >20.0 ng/mL for men (odds ratio: 3.04; 95% confidence interval, 1.13-8.20) but not for women. The general linear model showed that higher 25(OH)D levels and having T allele of Fok1 and the bb genotype of Bsm1 were significantly associated with more handgrip strength. The regression coefficients (β) were 1.80 (P < 0.01), 1.26 (P < 0.01), and 2.90 (P < 0.01), respectively. There was a significant interaction between 25(OH)D and VDR gene polymorphisms for handgrip strength for both Fok1 (β = 2.86; P < 0.01) and Bsm1 (β = 3.14; P = 0.02) after adjustment for potential confounders (sex, age, body mass index, fat mass, physical activity, sun exposure, energy, and protein intake). 25(OH)D levels are associated with handgrip strength for men and this relationship could be modified with the interaction between 25(OH)D and VDR gene polymorphisms (Fok1 and Bsm1).

Adoptive immunotherapy with haploidentical natural killer cells and Anti-GD2 monoclonal antibody m3F8 for resistant neuroblastoma: Results of a phase I study

ABSTRACTNatural killer (NK) cell-mediated antibody-dependent toxicity is a potent mechanism of action of the anti-GD2 murine monoclonal antibody 3F8 (m3F8). Killer immunoglobulin-like receptor (KIR) and HLA genotypes modulate NK activity and are key prognostic markers in m3F8-treated patients with neuroblastoma. Endogenous NK-cells are suppressed in the setting of high tumor burden and chemotherapy. Allogeneic NK-cells however, demonstrate potent anti-neuroblastoma activity. We report on the results of a phase I clinical trial of haploidentical NK-cells plus m3F8 administered to patients with high-risk neuroblastoma after conditioning chemotherapy. The primary objective was to determine the maximum tolerated NK-cell dose (MTD). Secondary objectives included assessing anti-neuroblastoma activity and its relationship to donor-recipient KIR/HLA genotypes, NK function, and donor NK chimerism. Patients received a lymphodepleting regimen prior to infusion of haploidentical CD3-CD56+ NK-cells, followed by m3F8. Overall and progression free survival (PFS) were assessed from the time of first NK-cell dose. Univariate Cox regression assessed relationship between dose and outcomes. Thirty-five patients received NK-cells at one of five dose levels ranging from <1×106 to 50×106 CD3-CD56+cells/kg. One patient experienced grade 3 hypertension and grade 4 pneumonitis. MTD was not reached. Ten patients (29%) had complete or partial response; 17 (47%) had no response; and eight (23%) had progressive disease. No relationship was found between response and KIR/HLA genotype or between response and FcγRIII receptor polymorphisms. Patients receiving >10×106 CD56+cells/kg had improved PFS (HR: 0.36, 95%CI: 0.15–0.87, p = 0.022). Patient NK-cells displayed high NKG2A expression, leading to inhibition by HLA-E-expressing neuroblastoma cells. Adoptive NK-cell therapy in combination with m3F8 is safe and has anti-neuroblastoma activity at higher cell doses.

Review article: the prevention of hepatitis B-related hepatocellular carcinoma.

Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure.