Biology subjects

Mook-Kanamori, D. O.

Publications and source records attributed to Mook-Kanamori, D. O..

6 recordsLinked to original sources

bioRxiv2026

Ageing of the Upper Airway Epithelial Niche Limits Tissue-Resident T Cell Immunity

Respiratory tract infections are a major cause of morbidity and mortality among older adults worldwide. Yet, how ageing shapes protective immunity within the upper respiratory tract (URT) remains poorly understood. Here, we profiled the nasal immune landscape of young adults and older adults with and without frailty, using high-dimensional cytometry, proteomics, single-cell transcriptomics and T cell receptor (TCR) sequencing. Ageing was associated with a selective reduction of tissue-resident memory T (Trm) cells, independent of effector T cell numbers, inflammageing levels or frailty and was accompanied by a decline in T cell receptor repertoire stability. Trm cells from older adults also showed decreased steady-state IFN{gamma} expression, accompanied by reduced antiviral transcriptional programs in the mucosa. Mechanistically, in vitro PBMC-epithelium co-culture models revealed that older adults have a reduced capacity for Trm differentiation, which was associated with a diminished epithelial TGF-{beta} secretion, driven by reduced expression in ciliated epithelial cells. Together, these findings reveal that URT immunity deteriorates with age due to disrupted epithelial-immune crosstalk. This identifies the epithelial niche as a key regulator of mucosal immune ageing and suggests that enhancing TGF{beta} signaling may improve the effectiveness of mucosal airway vaccination strategies in older populations.

immunology↗

bioRxiv2024

Associations between common genetic variants and income provide insights about the socioeconomic health gradient

We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic index captures 1 - 4% of income variance, with only one-fourth attributed to direct genetic effects. A phenome-wide association study using this polygenic index showed reduced risks for a broad spectrum of diseases, including hypertension, obesity, type 2 diabetes, coronary atherosclerosis, depression, asthma, and back pain. The income factor showed a substantial genetic correlation (0.92, s.e. = .006) with educational attainment (EA). Accounting for EAs genetic overlap with income revealed that the remaining genetic signal for higher income related to better mental health but reduced physical health benefits and increased participation in risky behaviours such as drinking and smoking.

genetics↗

bioRxiv2019

Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts

Context: Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. Objective: We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics. Design: meta-analysis of two cross-sectional studies. Setting: Two population-based European cohort studies. Patients or other participants: Non-diabetic individuals from the Oxford BioBank (OBB; N=6,368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N=5,916; mean age 55.6 years, males 43%) studies. Intervention(s): Data on mean outdoor bright sunlight and temperature collected from local weather stations in the week prior to blood sampling. Main Outcome Measure(s): Serum levels of 148 metabolites measured using NMR spectroscopy, including 14 lipoprotein subclasses. Statistical analyses: Multivariable linear regression analyses adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. Summary statistics from the OBB and NEO cohorts were combined using fixed-effect meta-analyses. Results: A higher mean outdoor temperature was associated with increased concentrations of lipoprotein (sub)particles and certain amino acids such as phenylalanine and leucine. In contrast, longer mean hours of bright sunlight were specifically associated with lower concentrations of very low density lipoprotein (sub)particles. The direction of effects was consistent between the OBB and NEO, although effect sizes were generally larger in the OBB. Conclusions: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.

physiology↗

bioRxiv2019

Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

BackgroundAlcohol intake influences plasma lipid levels and such effects may be modulated by genetic variants. ObjectiveWe aimed to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. DesignIn the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 34,153 European Americans from five discovery studies and 32,275 individuals from six replication studies. Rare and low-frequency protein coding variants (minor allele frequency [≤] 5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction (GxE) test and a joint test of genetic main and GxE interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least two drinks per week, were considered. ResultsWe discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3 and CD300LG) remained significant after conditioning on the common index single nucleotide polymorphism (SNP) identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on TG was discovered at a Bonferroni corrected significance level (p-value <5x10-5) and replicated (p-value <0.013 for the interaction test) in SMC5. ConclusionsIn conclusion, this study applied new gene-based statistical approaches to uncover the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels.

epidemiology↗

bioRxiv2019

Multi-ancestry analysis of gene-sleep interactions in 126,926 individuals identifies multiple novel blood lipid loci that contribute to our understanding of sleep-associated adverse blood lipid profile

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To provide new insights in the biology of sleep-associated adverse lipid profile, we conducted multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identified 49 novel lipid loci, and 10 additional novel lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identified new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The novel gene-sleep interactions had a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explained 4.25% of the variance in triglyceride concentration. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

genomics↗

bioRxiv2016

Connecting genetic risk to disease endpoints through the human blood plasma proteome

Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence for mapping disease associations and translating them into clinical applications. However, although hundreds of genetic risk variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits across multiple chromosome locations are key in establishing functional links between GWAS-identified risk-variants and disease endpoints. Here, we describe a GWAS performed with a highly multiplexed aptamer-based affinity proteomics platform. We quantified associations between protein level changes and gene variants in a German cohort and replicated this GWAS in an Arab/Asian cohort. We identified many independent, SNP-protein associations, which represent novel, inter-chromosomal links, related to autoimmune disorders, Alzheimer's disease, cardiovascular disease, cancer, and many other disease endpoints. We integrated this information into a genome-proteome network, and created an interactive web-tool for interrogations. Our results provide a basis for new approaches to pharmaceutical and diagnostic applications.

genetics↗