ABSTRACT Background The causes of late onset Alzheimer disease (LOAD) are not known but several recent lines of evidence implicate the adaptive immune system. Objective To characterize the adaptive immune system among Midwestern Amish participating in longitudinal studies of aging. Methods We immunosequenced the T‐cell receptor (TCR) beta chain from genomic DNA of 72 participants, including those with clinically diagnosed LOAD ( n = 6), mild cognitive impairment (MCI; n = 16), cognitive impairment but not AD ( n = 3), and 35 cognitively unaffected. For a subset of participants, LOAD pathogenesis plasma biomarkers were available. Results TCR sequence diversity measured as Simpson's clonality was lower among LOAD+MCI compared with non‐LOAD, but these differences were not independent of age. Relatively few clonotypes (exact nucleotide sequences) were shared across participants; of those few shared include the Epstein Barr virus associated clonotype. HLA‐A*03:01 and several HLA‐DRB1 alleles were under‐represented among LOAD+MCI participants compared with cognitively unaffected participants, but these associations were no longer significant in adjusted analyses. Among LOAD+MCI participants, increased p‐tau181 was nominally associated with decreased TCR sequence diversity, and the nominal association was independent of age; however, this association did not remain statistically significant after strict correction for multiple testing and the limited sample size precluded formal tests of heterogeneity. Results In this limited Midwestern Amish sample, the preliminary TCR diversity trends are consistent with the involvement of the adaptive immune system in LOAD.
ABSTRACT Aims Thoracic aortic aneurysms and dissections are major causes of sudden cardiovascular death. We aimed to evaluate the clinical significance of the MYLK c.4079G>A, p.(Gly1360Asp) variant in Finnish families with heritable thoracic aortic disease (HTAD) and to assess evidence for a potential founder effect. Methods We evaluated the clinical significance and potential founder effect of the missense variant MYLK c.4079G>A, p.(Gly1360Asp) in Finnish families. Eight individuals from four unrelated Finnish families carrying the MYLK c.4079G>A heterozygous variant were recruited. Clinical histories, imaging data, and pedigrees were reviewed. Genetic testing included exome‑based gene panel sequencing or targeted familial variant testing. Variant classification followed the American College of Medical Genetics and Genomics 2015 guidelines. Results Thoracic aortic dilatation or aneurysm occurred in 6/8 carriers (75%), with a mean age at diagnosis of 45 years (range 34–67). Ascending aortic diameters ranged from 26–59 mm, most often measured at the aortic root. Aortic dissection occurred in 4/8 (50%) at a mean age of 46 years (range 34–68), including three early‑adult events. Extrathoracic arterial involvement (carotid) was observed in one variant‑positive individual. Conclusion The MYLK c.4079G>A, p.(Gly1360Asp) variant was present in six affected individuals from four unrelated families and is enriched in the Finnish population, supporting a founder effect. The MYLK c.4079G>A, p.(Gly1360Asp) variant is associated with early‑adult‑onset, high‑penetrance thoracic aortic disease and substantial dissection risk, underscoring the need for vigilant surveillance and early intervention in affected individuals and at‑risk relatives.
Background: Hearing impairment is a genetically heterogeneous disorder and represents a significant health concern, particularly in consanguineous populations where autosomal recessive forms are more prevalent. Pakistani families provide an important population for investigating the genetic basis of hereditary hearing impairment. Objective: The current studywas aimed to elucidate the genetic basis of hearing impairment in consanguineous Pakistani families. Material and Methods: Three consanguineous Pakistani families comprising 11 affected individuals presenting bilateral profound hearing loss were investigated using Exome Sequencing (ES). Sanger sequencing was used for segregation analysis of candidate variant(s) in each pedigree. Structural modeling of both wild-type and mutant proteins were performed using bioinformatic tools to assess the functional impact of candidate variants. Results: ES data analysis revealed homozygous missense variants in MSRB3 (c.244T > G; p.Cys82Gly), ESRP1 (c.353T > C; p.Leu118Pro) and TMC1 (c.1749C > G; p.Asn583Lys) in family 1, 2, and 3 respectively. These variants are predicted to be "deleterious" by multiple bioinformatic tools, affecting highly conserved residues of candidate protein, and are absent in homozygous form in public databases. Sanger sequencing validated the co-segregation of the candidate variants within their respective families. Structural modeling of the wild-type and mutant proteins predicted that the candidate variants lead to structural alterations that strengthens the evidence supporting their pathogenicity. Conclusion: This study expands the mutational spectrum of MSRB3, ESRP1 and TMC1 genes associated with hearing loss. Furthermore, carrier screening and genetic counselling can be developed for affected families based on the findings obtained from the current study. The data obtained may also enhance our understanding of the pathophysiology of hearing loss ultimately guiding us in the development of potential therapeutics.
Background Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear.Aims We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers.Materials and Methods We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping.Results A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues.Discussion These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways.Conclusion Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.
Acute myeloid leukemia (AML) cells rely heavily on mitochondrial oxidative phosphorylation (OXPHOS) for energy, making mitochondrial function a promising therapeutic target. TCF12, a transcription factor belonging to the basic helix-loop-helix (bHLH) family, has been implicated in various cancers and is highly expressed in AML, where it may contribute to disease progression. However, the effects of TCF12 on AML progression and the underlying mechanisms remain unclear. This study aimed to elucidate the role of TCF12 in promoting AML cell survival and uncover the underlying mechanism. We found that TCF12 was highly expressed in AML and was associated with poor patient prognosis. Knockdown of TCF12 significantly inhibited AML cell growth, suppressed glycolysis, increased ROS accumulation, and induced mitochondrial dysfunction. Additionally, TCF12 was shown to promote EZH2 transcription, whereas its knockdown increased TXNIP expression, thereby inhibiting AML progression. In summary, TCF12 promotes AML progression by regulating EZH2-mediated suppression of TXNIP, thereby enhancing glycolysis, maintaining mitochondrial function, regulating ROS levels, and promoting cell survival, which underscores its potential as a therapeutic target.
