Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study

Methylphenidate (MPH) is the first-line drug for the treatment of children with attention-deficit hyperactivity disorder (ADHD); however, individual curative effects of MPH vary. Many studies have demonstrated that synaptosomal-associated protein 25 (SNAP-25) gene MnlI polymorphisms may be related to the efficacy of MPH. However, the association between SNAP-25MnlI polymorphisms and changes in brain hemodynamic responses after MPH treatment is still unclear. This study used functional near-infrared spectroscopy (fNIRS) to preliminarily investigate the interaction of MPH treatment-related prefrontal inhibitory functional changes with the genotype status of the SNAP-25 gene in children with ADHD. In total, 38 children with ADHD aged 6.76–12.08 years were enrolled in this study and divided into the following two groups based on SNAP-25 gene MnlI polymorphisms: T/T genotype group (wild-type group, 27 children) and G allele carrier group (mutation group, 11 children). The averaged oxygenated hemoglobin concentration changes [Δavg oxy-Hb] and deoxyhemoglobin concentration changes [Δavg deoxy-Hb] in the frontal cortex before MPH treatment and after 1.5 h (post-MPH1.5h) and 4 weeks (post-MPH4w) of MPH treatments were monitored using fNIRS during the go/no-go task. SNAP-IV scores were evaluated both pre-MPH and post-MPH4w treatments. In the T/T genotype group, [Δavg oxy-Hb] in the dorsolateral prefrontal cortex was significantly higher after 4 weeks of MPH (post-MPH4W) treatment than pre-treatment; however, in the G allele group, no significant differences in [Δavg oxy-Hb] were observed between pre- and post-treatments. In the go/no-go task, the accuracy was significantly increased post-MPH4w treatment in the T/T genotype group, while no significant differences were observed in response time and accuracy of the “go” sand no-go task in the G allele group for pre-MPH, post-MPH1.5h, and post-MPH4w treatments. The T/T genotype group exhibited a significant decrease in SNAP-IV scores after MPH treatment, while the G allele group showed no significant difference. In conclusion, fNIRS data combined with SNAP-25 MnlI polymorphism analysis may be a useful biomarker for evaluating the effects of MPH in children with ADHD.

Analysis The Effect of Gene and Platelet Testing Guide Dual Anti-Upgrade Therapy After PCI in Patients With ACS

Objective To analyze whether CYP2C19 gene and platelet testing guide ACS patients PCI benefit from postoperative dual antiplatelet escalation therapy. Methods Selecting ACS patients with 209 routine PCI surgery from January 2018 to January 2019 in Department of Cardiology, Third Affiliated Hospital of Guangzhou Medical University. Preoperative administration of aspirin 300mg and clopidogrel 600mg, and continued administration of clopidogrel 75mg/d and aspirin 100mg/d after operation. Genotype and light transmittance aggregation (LTA) was detected by gene chip 24 h after operation. According to genotype the remaining patients were divided into non loss of function (Non-LOF) alleles group Extensive-metabolisms (EMs) type, loss of function (LOF) alleles group as Intermediate metabolic (IMs) type and Poor-metabolisms (PMs) type. Define the maximum platelet aggregation rate (MPA)≥46% as hyperplatelet reactivity (HPR). The LOF group consisted of 23 patients who had both HPR and proclopidogrel and were upgraded to tigrillo for further treatment.The remaining patients without HPR who continued to be treated with clopidogrel comprised 90 patients in the LOF group without upgrade and 95 patients in the non-LOF group who continued to be treated with clopidogrel.Major adverse cardiovascular events (MACE) were recorded in the follow-up period of 1 year, and the incidence of MACE in the three groups was compared to determine whether gene and platelet detection could guide the benefit of dual anti-platelet upgrade therapy in ACS patients after PCI. Results There were 26 cases occurred during follow-up MACE, among which the incidence of unstable angina recurrence and overall MACE in the LOF allele-not-up group was the highest and significantly different compared with the Non-LOF allele group (P<0.05), there was no significant difference compared with the LOF allele-up group (0.05). while there was no significant difference between the Non-LOF allele and the LOF allele upgrading group (P>0.05). Conclusions Gene is an important factor in the difference of platelet reactivity and is associated with MACE. Upgraded treatments for high-risk patients screened for gene and platelet testing did not benefit.

Burden of cystic fibrosis in children <12 years of age prior to the introduction of CFTR modulator therapies

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF <12 years of age prior to the first approval of CFTR modulators.MethodsData from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to <2 years, 2 to <6 years and 6 to <12 years) and genotype (F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.ResultsThe analysis included 9185 children. Among 6-year-olds to <12-year-olds, mean (SD) per cent predicted FEV1 in 1 s was 92.6% (17.5%). Among all children <12 years of age, the mean (SD) all-cause hospitalisation and pulmonary exacerbation rates in 2011 were 0.4 (1.0) and 0.3 (0.8), respectively. Most (93.6%) had ≥1 positive lung microbiology culture. CF-related medication and nutritional supplementation use was common across all ages and genotypes. More than half (54.7%) had ≥1 CF-related complication. Evidence of disease burden was observed across the age and genotype groups studied.ConclusionsPrior to the approval of the first CFTR modulator therapies in children <12 years of age, CF was associated with substantial BOI from an early age—including respiratory infections, hospitalisations/pulmonary exacerbations, need for supplemental nutrition and pharmacological treatments—irrespective of genotype.

HLA-DQA1*05 Associates with Extensive Ulcerative Colitis at Diagnosis: An Observational Study in Children

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 predisposes to ulcerative colitis (UC) and is associated with the development of antibodies against infliximab in patients with inflammatory bowel disease (IBD). Therefore, we hypothesized that the presence of HLA-DQA1*05 correlates with characteristics of pediatric IBD. Within a multi-center cohort in Poland, the phenotype at diagnosis and worst flare was established and HLA-DQA1*05 status was assessed enabling genotype-phenotype analyses. HLA-DQA1*05 was present in 221 (55.1%) out of 401 children with IBD (UC n = 188, Crohn’s disease n = 213). In UC, the presence of HLA-DQA1*05 was moderately associated with a large extent of colonic inflammation at diagnosis (E4 55% more frequent in HLA-DQA1*05-positive patients, p = 0.012). PUCAI at diagnosis (p = 0.078) and the time from UC diagnosis to the first administration of biologic treatment (p = 0.054) did not differ depending on HLA-DQA1*05 status. The number of days of hospitalization for exacerbation was analyzed in 98 patients for whom sufficient follow-up was available and did not differ depending on HLA-DQA1*05 carriership (p = 0.066). HLA-DQA1*05 carriers with CD were less likely to present with both stenosing and penetrating disease (B2B3, p = 0.048) and to have active disease proximal to the ligament of Treitz (L4a) at the worst flare (p = 0.046). Future research focusing on explaining and preventing anti-TNF immunogenicity should take into account that ADA may develop not only as an isolated reaction to anti-TNF exposure but also as a consequence of intrinsic differences in the early course of UC.

The Genetic Variants of HLA-DRB1 Alleles and the Chance of Developing Rheumatoid Arthritis: Systematic Review and meta-analysis

Rheumatoid arthritis (RA) is more common in those who have special human leukocyte antigen (HLA) genetic types. One of the most important genetic risk factors for RA lies in HLADRB1 locus. The purpose of this meta-analysis was to figure out which HLA-DRB1 allele frequencies are associated with a risk of RA per allele and phenotype group. The statistics data was calculated using RevMan version 5.4.1. This meta-analysis includes nine articles involving 3004 RA patients and 2384 healthy controls. In the allele group, three HLA-DRB1 alleles; HLA-DRB1*10 (OR = 1.88, 95%CI = 1.25-2.83, p = 0.002), HLA-DRB1*04 (OR = 2.38, 95%CI = 1.73-3.29, p < 0.00001), and HLA-DRB1*01 frequencies were shown to be considerably higher in RA patients compared to controls, potentially increasing the chance of disease development. Four HLA-DRB1 alleles among the included studies (*03, *07, *11, *13, and *14) which was observed that these are more prevalent in healthy persons than in RA patients, and may contribute as a protective factor against disease onset. Only the DRB1*04 subtypes DRB1*0401 (OR = 1.37, 95 percent CI = 1.05-1.79, p = 0.02) and DRB1*0404 (OR = 1.73, 95% CI = 1.19-12.53, p = 0.004) show a significant association with the risk of RA in our pooled effect. Moreover, the findings demonstrated a significant relationship between HLA-DRB1 and the risk of disease in various ethnic groups.

Peculiarities of the Presentation of the Encephalitogenic MBP Peptide by HLA-DR Complexes Providing Protection and Predisposition to Multiple Sclerosis

Predisposition to multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system, is due to various factors. The genetic component is considered one of the most important factors. HLA class II genes contribute the most to the development of MS. The HLA-DRB1*15 allele group is considered one of the main genetic risk factors predisposing to MS. The group of HLA-DRB1*01 alleles was shown to have a protective effect against this disease in the Russian population. In this work, we compared the binding of the encephalitogenic fragment of the myelin basic protein (MBP) to two HLA-DR complexes that provide protection against and predisposition to MS: HLA-DR1 (HLA-DRB1*0101) and HLA-DR15 (HLA-DRB1*1501), respectively. We found that the myelin peptide MBP88-100 binds to HLA-DR1 at a rate almost an order of magnitude lower than the viral peptide of hemagglutinin (HA). The same was true for the binding of MBP85-97 to HLA-DR15 in comparison with viral pp65. The structure of the C-terminal part of the peptide plays a key role in the binding to HLA-DR1 for equally high-affinity N-terminal regions of the peptides. The IC50 of the myelin peptide MBP88-100 competing with viral HA for binding to HLA-DR1 is almost an order of magnitude higher than that of HA. As for HA, the same was also true for the binding of MBP85-97 to HLA-DR15 in comparison with viral pp65. Thus, autoantigenic MBP cannot compete with the viral peptide for binding to protective HLA-DR1. However, it is more competitive than viral peptide for HLA-DR15.

Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants

In prior work, we identified a novel gene-by-stress association of EBF1’s common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to “racism/discrimination” (P = 0.036) and “not meeting basic needs” (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e−03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.

HLA allele repertoire in Russian chronic lymphocytic leukemia patients with an unfavorable prognosis

Introduction. An unfavorable prognosis in chronic lymphocytic leukemia (CLL) is associated with unmutated status of rearranged IGHV genes. CLL is also characterized by a narrowing of the repertoire of IGHV genes and the formation of quasiidentical (stereotyped) receptors, which is probably associated with antigenic selection of the tumor B-cell clone in the pathogenesis of the disease. The HLA phenotype plays an important role in antigenic selection of B cells. On the other hand, the association of specifi c HLA alleles with various diseases has been described. Aim. To assess the frequencies of HLA alleles in CLL patients with unmutated IGHV genes and the most common stereotyped receptors (SARs). Materials and methods. The study included 100 CLL patients with unmutated IGHV genes - 50 with the most common stereotyped antigen receptors (SARs) and 50 with non-stereotyped antigenic receptors. Control group of healthy donors was also included. Results. Signifi cant differences in HLA-allele repertoire between this two groups of patients and groups of donors were found. B*18 allele group was found much more common in patients with SARs than in donors and in patients without SARs. HLA-B*39 was more frequent for patients with SARs compared to donors; in patients without SARs these alleles were not found. For all patients, the frequency of HLA-B*52 alleles was higher than for donors. HLA-C*12 allelic group was found more frequent in CLL patients than in donors. HLA-DRB1*15 in CLL patients with SARs was found twice as often as in healthy donors or patients without SARs, while HLA-DRB1*13, oppositely, was found twice as rare. HLA-DRB1*16 was signifi cantly more frequent in patients without SARs, compared with donors and the patients with SARs. No signifi cant differences were found in the HLA-A and HLA-DQB1 loci. Conclusion. The association of two HLA alleles with “unmutated” CLL and two others with CLL bearing prognostically unfavorable SARs was found. HLA typing of expanded samples of CLL patients with different prognosis and course of the disease will provide more information on the mechanisms of antigen selection in the pathogenesis of CLL and improve diagnostic and therapeutic approaches.

Specific amino acid patterns define split specificities of HLA-B15 antigens enabling conversion from DNA-based typing to serological equivalents

The HLA-B15 typing by serological approaches defined the serological subgroups (or splits) B62, B63, B75, B76, B77 and B70 (B71 and B72). The scarcity of sera with specific anti-HLA antibodies makes the serological typing method difficult to discriminate a high variety of HLA antigens, especially between the B15 antigen subgroups. Advancements in DNA-based technologies have led to a switch from serological typing to high-resolution DNA typing methods. DNA sequencing techniques assign B15 specificity to all alleles in the HLA-B*15 allele group, without distinction of the serological split equivalents. However, the presence of antibodies in the patient defined as split B15 antigens urges the identification of HLA-B*15 allele subtypes of the donor, since the presence of donor-specific antibodies is an important contraindication for organ transplantation. Although the HLA dictionary comprises information regarding the serological subtypes of HLA alleles, there are currently 394 B15 antigens out of 516 in the IPD-IMGT/HLA database (3.38.0) without any assigned serological subtype. In this regard, we aimed to identify specific amino acid patterns for each B*15 serological split, in order to facilitate the assignment of B*15 alleles to serological equivalents after high-resolution molecular typing. As a result, serological specificities of 372/394 not yet assigned alleles could be predicted based on amino acid motifs. Furthermore, two new serological types were identified and added, B62-Bw4 and B71-Bw4.