Associations of Baseline Sleep Microarchitecture with Cognitive Function After 8 Years in Middle-Aged and Older Men from a Community-Based Cohort Study

Published: 24 May 2023. Corrected by: Corrigendum to: Associations of Baseline Sleep Microarchitecture with Cognitive Function After 8 Years in Middle-Aged and Older Men from a Community-Based Cohort Study (Nat Sci Sleep. 2023, 15, 389–406.) In vol. 15 (2023), pp. 433-434. The authors advise that the funding section on page 404 is incorrect.Purpose: Prospective studies examining associations between baseline sleep microarchitecture and future cognitive function recruited from small samples with predominantly short follow-up. This study examined sleep microarchitecture predictors of cognitive function (visual attention, processing speed, and executive function) after 8 years in community-dwelling men. Patients and Methods: Florey Adelaide Male Ageing Study participants (n=477) underwent home-based polysomnography (2010– 2011), with 157 completing baseline (2007– 2010) and follow-up (2018– 2019) cognitive assessments (trail-making tests A [TMT-A] and B [TMT-B] and the standardized mini-mental state examination [SMMSE]). Whole-night F4-M1 sleep EEG recordings were processed following artifact exclusion, and quantitative EEG characteristics were obtained using validated algorithms. Associations between baseline sleep microarchitecture and future cognitive function (visual attention, processing speed, and executive function) were examined using linear regression models adjusted for baseline obstructive sleep apnoea, other risk factors, and cognition. Results: The final sample included men aged (mean [SD]) 58.9 (8.9) years at baseline, overweight (BMI 28.5 [4.2] kg/m2), and well educated (75.2% ≥Bachelor, Certificate, or Trade), with majorly normal baseline cognition. Median (IQR) follow-up was 8.3 (7.9, 8.6) years. In adjusted analyses, NREM and REM sleep EEG spectral power was not associated with TMT-A, TMT-B, or SMMSE performance (all p> 0.05). A significant association of higher N3 sleep fast spindle density with worse TMT-B performance (B=1.06, 95% CI [0.13, 2.00], p=0.026) did not persist following adjustment for baseline TMT-B performance. Conclusion: In this sample of community-dwelling men, sleep microarchitecture was not independently associated with visual attention, processing speed, or executive function after 8 years.Jesse L Parker, Andrew Vakulin, Yohannes Adama Melaku, Gary A Wittert, Sean A Martin, Angela L D, Rozario, Peter G Catcheside, Bastien Lechat, Barbara Toson, Alison J Teare, Sarah L Appleton, Robert J Adam

Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-analysis.

BACKGROUND: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. METHODS: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. RESULTS: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10(-10)). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. CONCLUSION: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke

Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium.

Background The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. Methods We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. Findings Significant dose–response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5–9 years to 89%quit_for_≥ 20 years declined SCLC risk vs. subjects who had quit smoking < 5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. Interpretation This is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study. Abbreviations COPD, chronic obstructive pulmonary disease; CPG, cigarettes per day; ILCCO, International Lung Cancer Consortium; MeSH, medical subject headings; NSCLC, non-small cell lung cancer; OR, odds ratio; SCLC, small cell lung cancer

Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In the current study, we performed a large-scale case-control study with 20,871 lung cancer cases and 15,971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The eQTL (expression quantitative trait loci) analysis and pathway enrichment analysis were performed to identify the possible target genes and pathways. Additionally, we performed motif-based analysis to explore the lung cancer related motifs using sequence kernel association test (SKAT). Two novel variants, rs186332 in 20q13.3 (C>T, OR = 1.17, 95% CI: 1.10-1.24, P = 8.45×10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02×10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1 respectively. What's more, the expression of both MRGBP and SLC16A1 were aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71×10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS related genetic variants for lung cancer

Iam hiQ—a novel pair of accuracy indices for imputed genotypes

Background Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. Results Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). Conclusion We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data

Mendelian randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between SNPs and smoking status (never vs ever smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13,336 NSCLC cases. Candidate SNPs with p-value less than 0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with p-value less than 3.5x10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 NSCLC cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis p-value for these two SNPs were 1.24 with 6.96x10-7 and 1.37 with 3.49x10-7, respectively. Additionally, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and p-value of 8.12x10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease

Determination of Helicobacter pylori vacA allelic types by single-step multiplex PCR

Methods and Results Application of the one-step system to DNA extracts from 22 cultures of known vacA genotype demonstrated that it was highly accurate. Analysis of 15 matched gastric biopsy/culture pairs generated exactly correlating genotype profiles. vacA genotypes were determined from an additional 62/70 gastric biopsies from dyspeptic patients of known H. pylori positive status by the one-step assay, compared with 63/70 by the original two-reaction test. Types s1/m1, s1/m2 and s2/m2 were identified in 51·9%, 31·2% and 16·9% of biopsies, respectively. Conclusions The multiplex PCR system developed enables rapid one-step vacA genotyping that is accurate, easy to interpret and more economical than the alternative multiple-reaction tests. Application of this system to gastric biopsies from patients in South-east England demonstrated that s1/m1 was the most common genotype, while s1/m2 and s2/m2 were less prevalent. Significance and Impact of the Study This simple one-step system can be applied direct to antral gastric biopsies without the need for culture, thereby facilitating rapid surveillance of vacA genotype in relation to geographical location and disease status

Quantitative electroencephalography measures in rapid eye movement and nonrapid eye movement sleep are associated with apnea-hypopnea index and nocturnal hypoxemia in men

Study Objectives: Quantitative electroencephalography (EEG) measures of sleep may identify vulnerability to obstructive sleep apnea (OSA) sequelae, however, small clinical studies of sleep microarchitecture in OSA show inconsistent alterations. We examined relationships between quantitative EEG measures during rapid eye movement (REM) and non-REM (NREM) sleep and OSA severity among a large population-based sample of men while accounting for insomnia. Methods: All-night EEG (F4-M1) recordings from full in-home polysomnography (Embletta X100) in 664 men with no prior OSA diagnosis (age ≥ 40) were processed following exclusion of artifacts. Power spectral analysis included non-REM and REM sleep computed absolute EEG power for delta, theta, alpha, sigma, and beta frequency ranges, total power (0.5-32 Hz) and EEG slowing ratio. Results: Apnea-hypopnea index (AHI) ≥10/h was present in 51.2% (severe OSA [AHI ≥ 30/h] 11.6%). In mixed effects regressions, AHI was positively associated with EEG slowing ratio and EEG power across all frequency bands in REM sleep (all p < 0.05); and with beta power during NREM sleep (p = 0.06). Similar associations were observed with oxygen desaturation index (3%). Percentage total sleep time with oxygen saturation <90% was only significantly associated with increased delta, theta, and alpha EEG power in REM sleep. No associations with subjective sleepiness were observed. Conclusions: In a large sample of community-dwelling men, OSA was significantly associated with increased EEG power and EEG slowing predominantly in REM sleep, independent of insomnia. Further study is required to assess if REM EEG slowing related to nocturnal hypoxemia is more sensitive than standard PSG indices or sleepiness in predicting cognitive decline.Sarah L. Appleton, Andrew Vakulin, Angela D’Rozario, Andrew D. Vincent, Alison Teare, Sean A. Martin, Gary A. Wittert, R. Doug McEvoy, Peter G. Catcheside, and Robert J. Adam