OBJECTIVE: Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism.
METHODS: We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms.
RESULTS: Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression.
CONCLUSIONS: These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.

OBJECTIVE: Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP.
METHODS: A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher\'s exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity.
RESULTS: All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity.
CONCLUSIONS: The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.

MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I-related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon-based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA-genes, sub-stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA-matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA-B mismatches have to be accepted.

HIV-1 protease inhibitors are an essential component of antiretroviral therapy. However, drug resistance is a pervasive issue motivating a persistent search for novel therapies. Recent reports found that when protease activates within the host cell\'s cytosol, it facilitates the pyroptotic killing of infected cells. This has led to speculation that promoting protease activation, rather than inhibiting it, could help to eradicate infected cells and potentially cure HIV-1 infection. Here, we used a nanoscale flow cytometry-based assay to characterize protease resistance mutations and polymorphisms. We quantified protease activity, viral concentration, and premature protease activation and confirmed previous findings that major resistance mutations generally destabilize the protease structure. Intriguingly, we found evidence that common polymorphisms in the hinge domain of protease can influence its susceptibility to premature activation. This suggests that viral heterogeneity could pose a considerable challenge for therapeutic strategies aimed at inducing premature protease activation in the future.

Previous studies have reported that TT genotype carriers of the adenosine A2a receptor (ADORA2A) gene rs5751876 polymorphism have better ergogenic and anti-inflammatory responses to caffeine intake compared to C allele carriers. The aim of the present study was twofold: (1) to investigate the association of the ADORA2A rs5751876 polymorphism with acute caffeine supplementation on hormonal (growth hormone and testosterone) response to resistance exercise (RE); (2) to examine the relationship between the rs5751876 polymorphism and the resting levels of growth hormone and testosterone in athletes who are light caffeine consumers. A double-blind, crossover, placebo-controlled study involving 30 resistance-trained men (age 21.7 ± 4.1) was conducted to assess the impact of caffeine supplementation on serum growth hormone (GH) and testosterone (TS) levels before, immediately after, and 15 min post-RE. One hour before engaging in resistance exercise, subjects were randomly administered 6 mg of caffeine per kg of body mass or a placebo (maltodextrin). After a 7-day washout period, the same protocol was repeated. Resting testosterone and growth hormone levels were examined in the sera of 94 elite athletes (31 females, age 21.4 ± 2.8; 63 males, age 22.9 ± 3.8). Caffeine consumption led to significantly greater increases in GH and TS in men with the TT genotype compared to C allele carriers. Furthermore, in the group of athletes, carriers of the TT genotype had significantly higher testosterone (p = 0.0125) and growth hormone (p = 0.0365) levels compared to C allele carriers. In conclusion, the ADORA2A gene rs5751876 polymorphism may modify the effect of caffeine intake on the hormonal response to exercise.

Background: Apolipoprotein E (APOE) gene polymorphism has been implicated in the pathogenesis of various metabolic disorders, including type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, including in Pakistan. Cardiovascular problems linked with T2DM have a significant impact on individuals and society. The goal of this study is to investigate the relationship between Apolipoprotein E (ApoE) genotypes, dyslipidemia, and cardiovascular complications such as ischemic heart disease (IHD) and stroke. Methods: This study was carried out on 260 subjects divided into controls and diabetics. The diabetics were further divided into four subgroups such as D1: diabetics without cardiovascular issues, D2: diabetics with heart disease, D3: diabetics with stroke, and D4: diabetics with both heart disease and stroke. Anthropometric parameters (age, BMI) and risk factors (smoking, diabetes duration, hypertension) were assessed in all groups. Serum levels of TC, TG, LDL, HDL, VLDL, creatinine, BSF, and HbA1c were also measured. Apolipoprotein E gene polymorphism was determined using PCR-RFLP. Results: Hypertension, BMI, and dyslipidemia are defined as elevated levels of total cholesterol, triglycerides, LDL, and VLDL, and decreased levels of HDL. Uncontrolled hyperglycemia (elevated fasting blood sugar and glycated hemoglobin) in T2DM was linked to vascular complications such as IHD and stroke. Hypertension was prevalent in 79.3% of the population. Stage 2 hypertension was more prevalent in all age groups. It was also noted that common genotypes in the Pakistani population are 3/3, 4/4, 2/3, and 3/4. The frequency of genotypes 3/4 and 2/3 is highest in diabetics with stroke. Genotype 3/3 is present frequently in diabetics with IHD/stroke and patients with both these complications. However, genotype 4/4 is most frequently found in diabetics with IHD. Conclusions: It is concluded that BMI, hypertension, hyperglycemia, atherosclerosis, and dyslipidemia are linked with cardiovascular complications of type 2 diabetes. Apolipoprotein E gene polymorphism is associated with cardiovascular disease in patients with diabetes by affecting the lipid profile.

Background: Preeclampsia (PE) is a critical condition affecting pregnancies worldwide. Understanding its etiology, particularly the genetic factors, is vital. This study aims to investigate the association between ACE gene polymorphisms, specifically the ACE G2350A (rs4343) variant, and the predisposition to PE, offering insights into the genetic predisposition towards this complex condition. Methods: A case-control study was conducted with 140 participants without PE (Control Group) and 128 participants diagnosed with PE (PE Group). The study focused on comparing the prevalence of the rs4343 polymorphism between the groups. Results: The analysis identified a significantly reduced risk associated with the AG genotype and an insignificant increase in risk with the AA genotype. Statistically significant differences in demographic and clinical characteristics, such as BMI and marital status, were observed between the groups, suggesting a multifaceted risk profile for PE that includes genetic, environmental, and socio-economic factors. Conclusions: The study highlight the significant role of genetic variations, specifically the ACE G2350A (rs4343) polymorphism, in influencing PE predisposition. It highlights the intricate interplay between genetic predispositions and other risk factors in the development of PE. Further research is encouraged to expand on these findings and explore a wider range of genetic polymorphisms and their interactions with environmental factors.

Deficits in theory of mind (ToM), known as the ability to understand the other\'s mind, have been associated with several psychopathological outcomes. The present systematic review aims to summarize the results of genetic studies that investigated gene polymorphisms associated with mentalization performance tasks in children and adults. The systematic review was carried out following PRISMA guidelines, and the literature search was conducted in PubMed and EBSCOhost using the following keywords: \'theory of mind, mentalizing, mindreading\' and \'gene, genetic basis\'. Nineteen studies met the eligibility criteria for inclusion. Most of the literature focused on the role of DRD4, DAT1, OXTR, OXT, COMT, ZNF804A, AVP, AVPR, SCL6A4, EFHC2, MAO-A, and the family of GTF2I genes in influencing ToM. However, controversial results emerged in sustaining the link between specific genetic polymorphisms and mentalization abilities in children and adults. Available data show heterogeneous outcomes, with studies reporting an association between the same family genes in subjects of the same age and other studies reporting no correlation. This does not allow us to draw any solid conclusions but paves the way for exploring genes involved in ToM tasks.

BACKGROUND: Chayote is a high economic crop in the Cucurbitaceae family, playing an important role in food production, disease treatment and the production of degradable materials in industries. Due to the harsh environment, such as high temperature, drought and frost, some chayote resources are gradually disappearing. It is crucial to collect, characterize, and conserve chayote resources. However, the genetic diversity of chayote resources in China has not been studied so far.
RESULTS: In this study, we collected 35 individuals of chayote from 14 provinces in China. Subsequently, we found 363,156 SSR motifs from the chayote genome and designed 57 pairs of SSR primers for validation. Out of these, 48 primer pairs successfully amplified bands, with 42 of them showing polymorphism. These 42 primer pairs detected a total of 153 alleles, averaging 3.64 alleles per locus. The polymorphic information content ranged from 0.03 to 0.78, with an average value of 0.41, indicating a high level of polymorphism. Based on the analysis using STRUCTURE, PCoA, and UPGMA methods, the 35 chayote individuals were divided into two major clusters. Through further association analysis, 7 significantly associated SSR markers were identified, including four related to peel color and three related to spine.
CONCLUSIONS: These molecular markers will contribute to the analysis of genetic diversity and genetic breeding improvement of chayote in the future.

Two novel MICB alleles with coding polymorphisms in exon 3 were detected by next generation sequencing.