Citations

Summary Asthma genetic architecture varies according to age at onset and biological sex. Medication‐defined severity showed limited common variant genetic heterogeneity compared with age at onset and sex.

Abstract Background Sarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined. Methods We performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV₁% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis. Results Compared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion (∼2.6%) of this association. Conclusions. The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

Abstract Telomere length variation is a hallmark of genomic instability, however, its role in shaping the structural variant (SV) landscape of diffuse astrocytoma remains poorly understood. In this study, we employed Oxford Nanopore long-read sequencing to investigate the association between SVs and chromosome arm-specific telomere length in a clinical patient cohort consisting of n = 20 individuals diagnosed with an IDH mutant astrocytoma. Oxford Nanopore long-read sequencing was performed to a depth of ~20-40× coverage. SVs were identified using Sniffles, copy number alterations were assessed using DNAcopy and chromosome arm-specific telomere length was estimated with Telogator. Statistical analyses were conducted to assess associations between telomere dynamics, structural variation, and copy number changes. Astrocytoma genomes exhibited a broad spectrum of structural variants, including deletions and insertions, with significant enrichment in the short arms of acrocentric chromosomes. A subset of samples demonstrated markedly shorter telomeres relative to the overall cohort, accompanied by an increased burden of structural variants, particularly duplications and inversions, suggesting enhanced genomic instability. Notably, a prominent accumulation of deletion and insertion SVs was observed near chromosome ends and centromeres, highlighting the (sub)telomeric and peri(centromeric) regions as SV hotspots. Statistical modeling revealed a significant association between telomere length and arm-specific variation, including telomeric deletions, inversions, and copy number losses. In summary, our findings reveal a previously underappreciated link between SVs and telomere length in astrocytomas. Genomic rearrangements caused by telomere shortening may represent critical drivers of genome instability and could serve as novel biomarkers for disease progression.