Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3\'G(801)A] for SDF-1 gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02-6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01-7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion.

Large sample datasets have been regarded as the primary basis for innovative discoveries and the solution to missing heritability in genome-wide association studies. However, their computational complexity cannot consider all comprehensive effects and all polygenic backgrounds, which reduces the effectiveness of large datasets. To address these challenges, we included all effects and polygenic backgrounds in a mixed logistic model for binary traits and compressed four variance components into two. The compressed model combined three computational algorithms to develop an innovative method, called FastBiCmrMLM, for large data analysis. These algorithms were tailored to sample size, computational speed, and reduced memory requirements. To mine additional genes, linkage disequilibrium markers were replaced by bin-based haplotypes, which are analyzed by FastBiCmrMLM, named FastBiCmrMLM-Hap. Simulation studies highlighted the superiority of FastBiCmrMLM over GMMAT, SAIGE and fastGWA-GLMM in identifying dominant, small α (allele substitution effect), and rare variants. In the UK Biobank-scale dataset, we demonstrated that FastBiCmrMLM could detect variants as small as 0.03% and with α ≈ 0. In re-analyses of seven diseases in the WTCCC datasets, 29 candidate genes, with both functional and TWAS evidence, around 36 variants identified only by the new methods, strongly validated the new methods. These methods offer a new way to decipher the genetic architecture of binary traits and address the challenges outlined above.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

Age-related hearing loss is a complex disease caused by a combination of genetic and environmental factors, and a study have conducted animal experiments to explore the association between BCL11B heterozygosity and age-related hearing loss. The present study used established genetic models to examine the association between BCL11B gene polymorphisms and age-related hearing loss. A total of 410 older adults from two communities in Qingdao, China, participated in this study. The case group comprised individuals aged ≥ 60 years with age-related hearing loss, and the control group comprised individuals without age-related hearing loss from the same communities. The groups were matched 1:1 for age and sex. The individual characteristics of the participants were analyzed descriptively using the Mann-Whitney U test and the chi-square test. To explore the association between BCL11B gene polymorphisms and age-related hearing loss, conditional logistic regression was performed to construct genetic models for two single-nucleotide-polymorphisms (SNPs) of BCL11B, and haplotype analysis was conducted to construct their haplotype domains. Two SNP sites of the BCL11B gene, four genetic models of rs1152781 (additive, dominant, recessive, and codominant), and five genetic models of rs1152783 (additive, dominant, recessive, codominant, and over dominant) were significantly associated with age-related hearing loss in the models both unadjusted and adjusted for all covariates (P < 0.05). Additionally, a linkage disequilibrium between rs1152781 and rs1152783 was revealed through haplotype analysis. Our study revealed that BCL11B gene polymorphisms were significantly associated with age-related hearing loss.

The symptoms of SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to severe forms marked by acute respiratory distress syndrome, multi-organ damage, and fatalities. Studies indicate a correlation between specific genes and susceptibility to SARS-CoV-2 infection and disease severity, particularly involving variants in genes linked to inflammation and immune responses. The objective of this study is to investigate the association between rs1800795 (- 174 G > C) and rs1800797 (- 597 A > G) variants in the interleukin-6 (IL-6) promoter region and susceptibility to SARS-CoV-2 infection. Additionally, we aim to explore their correlation with COVID-19 severity in a Moroccan population. In this case-control study, we enrolled 270 unvaccinated COVID-19 patients, consisting of 132 with severe COVID-19 and 138 with asymptomatic-moderate COVID-19. Additionally, we included 339 SARS-CoV-2-negative group. Genotyping of rs1800795 and rs1800797 polymorphisms of the IL-6 gene was performed using predesigned TaqMan SNP genotyping. The median age of SARS-CoV-2-negative controls was 50 years, while severe COVID-19 cases exhibited a median age of 61 years. Additionally, individuals with asymptomatic to moderate COVID-19 had a median age of 36 years. We observed a significant age difference between severe and mild COVID-19 patients (p < 0.0001), and an association was noted between gender and the severity of COVID-19 (p = 0.011). The allele and genotype frequencies of the IL-6 - 597G > A and - 174G > C variants did not show significant associations with susceptibility to SARS-CoV-2 infection (p > 0.05). However, further analysis revealed that the linkage disequilibrium between rs1800797 and rs1800795 indicated that individuals with the GC* haplotype (OR = 0.04, 95% CI 0.01-0.30, p = 0.001) and AG* haplotype (OR = 0.11, 95% CI 0.03-0.46, p = 0.002) were significantly associated with protection against SARS-CoV-2 infection. Moreover, in the overdominant model, the IL-6 - 174 G/C genotype was found to be protective against the development of severe disease compared to those with the G/G-C/C genotypes (p = 0.03; OR = 0.41, 95% CI 0.18-0.96). However, correlations between complete blood count markers, hematological markers, D-dimer, C-reactive protein, and ferritin levels according to - 597 A > G and - 174G > C genotypes showed no significant differences (all p > 0.05). Our findings provide valuable insights into the pathogenesis of COVID-19, suggesting that genetic variations at the IL-6 gene may contribute to the susceptibility to severe SARS-CoV-2 infection within the Moroccan population.

To assess whether Casitas B-lineage lymphoma (CBL) gene polymorphism influences the risk of microscopic polyangiitis (MPA) in Chinese populations.
In total, 266 MPA patients and 297 healthy controls were recruited for a case-control study. Five CBL SNPs were genotyped using multiplex polymerase chain reaction and high-throughput sequencing. The relationship between SNPs and the risk of MPA under different genetic models was evaluated by SNPstats. SNP-SNP interaction was analyzed by generalized multifactor dimensionality reduction (GMDR). Finally, the association between CBL SNPs and treatment effects were assessed.
The results showed that CBL rs2276083 was associated with decreasing MPA risk under dominant (OR: 0.53; p = 0.014) and recessive models (OR: 0.52; p = 0.0034). Stratification analysis indicated that rs2276083 and rs2509671 in age < 60 years, rs2276083 in female or in Han population were protective factors for MPA. The CBL haplotype (A-A-G-C-T) was associated with an increased risk of MPA. GMDR suggested that CBL rs2276083, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) rs1607237, and autophagy-related gene 7 (ATG7) rs7549008 might interact with each other in MPA development (p = 0.0107). CBL rs1047417 with AG genotype and rs11217234 with AG genotype had better clinical treatment effects than other two genotypes (p = 0.048 and p = 0.025, respectively).
The genetic polymorphism of CBL had a potential association with the risk of MPA and clinical treatment effects in Guangxi population in China.

BACKGROUND: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B.
OBJECTIVE: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers.
METHODS: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique.
RESULTS: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather.
CONCLUSIONS: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.

OBJECTIVE: To explore the clinical application of preimplantation genetic testing for monogenic disorders (PGT-M) in an unique case with Spinal muscular atrophy (SMA) type 2+0.
METHODS: A special SMA family presented at the Third Affiliated Hospital of Guangzhou Medical University on October 19, 2020 was selected as the study subject. Multiple ligation-dependent probe amplification (MLPA) and molecular tagging linkage analysis were carried out to identify the SMN1 genotype of the couple and their fetus. Subsequently, next-generation sequencing (NGS), molecular tagging linkage analysis, and chromosomal microarray analysis were employed to determine the haplotypes and validate the result of PGT-M on the 11 embryos derived for the couple.
RESULTS: The female partner was identified as a carrier of the rare SMN1[2+0] variant, and prenatal diagnosis confirmed the fetus to be affected by SMA. Ultimately, PGT-M has successfully selected four embryos free from the pathogenic SMN1 variants and X chromosome deletion.
CONCLUSIONS: PGT-M can effectively prevent the transmission of rare genetic variants such as the SMA 2+0 subtype in the families. Above finding has provided guidance for genetic counseling and family planning for the couple.

To evaluate the relationship between genetic haplotypes associated with celiac disease (Human Leucocyte Antigen [HLA] DQ2 and DQ8) with the diagnosis, clinical presentation, and location of endometriosis in Brazilian women.
A retrospective cross-sectional study, was conducted in a Tertiary hospital.
Women aged 18-50 years who underwent HLA-DQ2 and HLA-DQ8 haplotype analysis.
The patients were divided into endometriosis and control groups and evaluated for symptoms; endometriosis location, American Society for Reproductive Medicine (ASRM) stage, and the presence of anti-tissue transglutaminase IgA (anti-TgA), HLA-DQ2, and HLA-DQ8 markers.
A total of 434 consecutive patients with (n = 315) and without (n = 119) endometriosis were included. Pain and infertility were more frequent in the endometriosis group than in the control group. The presence of HLA-DQ2, HLA-DQ8, and anti-TgA was similar between both groups. The presence of HLA-DQ2 and HLA-DQ8 markers did not differ based on age, pain symptoms, ASRM stage, or endometriosis location.
Although there are similarities in inflammatory markers and pathophysiology between celiac disease and endometriosis, this study found no significant associations in the presence of HLA-DQ2 or HLA-DQ8 haplotypes and endometriosis.

BACKGROUND: As an emerging pandemic disease, COVID-19 encompasses a spectrum of clinical diagnoses, from the common cold to severe respiratory syndrome. Considering the shreds of evidence demonstrating the relationship between human leukocyte antigen (HLA) allele diversity and infectious disease susceptibility, this study was conducted to determine the association of HLA alleles with COVID-19 severity in Iranian subjects.
METHODS: In this case-control study, a total of 200 unrelated individuals (consisting of 100 people with severe COVID-19 and an average age of 55.54 as the case group, and 100 patients with mild COVID-19 with an average age of 48.97 as the control group) were recruited, and HLA typing (Locus A, B, and DR) was performed using the Olerup sequence-specific oligonucleotide (SSO) HLA-typing kit.
RESULTS: Our results showed that HLA-A*11 and HLA-DRB1*14 alleles were more frequently observed in severe COVID-19 cases, while HLA-B*52 was more common in mild cases, which was in agreement with some previous studies.
CONCLUSIONS: Our results confirmed the evidence for the association of HLA alleles with COVID-19 outcomes. We found that HLA-A*11 and HLA-DRB1*14 alleles may be susceptibility factors for severe COVID-19, while HLA-B*52 may be a protective factor. These findings provide new insight into the pathogenesis of COVID-19 and help patient management.