Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Getting rhythm: how do babies do it?

Objectives To investigate the emergence of biological rhythms in the first months of life in human infants, by measuring age-related changes in core body temperature during night-time sleep, hormones (cortisol and 6-sulfatoxymelatonin) and the expression of a clock-controlled gene H3f3b in oral epithelial cells. Design Observational longitudinal study. Setting We measured overnight core body temperature, actigraphy, day–night urinary cortisol and 6-sulfatoxymelatonin, as well as circadian gene expression, in infants at home from March 2007 to July 2008 in Leicester. Participants We recruited 35 healthy Caucasian infants who were born at term. They were monitored from 6 to 18 weeks of age. Results At 8 weeks of age the day–night rhythm of cortisol secretion was the first to appear followed by 6-sulfatoxymelatonin 1 week later; at the same time that night-time sleep was established. At 10 weeks, the maximum fall in deep body temperature occurred with the onset of night-time sleep, followed at 11 weeks by the rhythmical expression of the H3f3b gene. Conclusions In human infants, there is a clear sequential pattern for the emergence of diurnal biological rhythms between 6 and 18 weeks of postnatal age, led by the secretion of cortisol and linked with the establishment of consolidated night-time sleep. It is likely that this represents part of a maturation and adaption process as infants gain equilibrium with their external environment after birth

Abstract # 3095 Anxiety, pro-inflammatory Cytokines, and RAGE-associated S100A8/A9 levels in breast cancer patients

The link between anxiety and breast cancer outcomes has recently been a topic of interest in behavioral medicine, and threat-associated distress states may be associated with increased inflammation, which is relevant for breast cancer recurrence. The purpose of this study was to examine the relationship between post-surgical anxiety levels, pro-inflammatory cytokines IL-1-β, IL-6, and TNF-α, and ligands associated with the receptor for advanced glycation end-products (RAGE). Activation of RAGE can trigger pathways that promote inflammation. To date, no studies have linked anxiety with RAGE ligands in breast cancer patients. Stage 0-III breast cancer patients (ages 32–69) were recruited 2–10 weeks post-surgery and interviewed with the Hamilton Rating Scale for Anxiety (HRSA) and provided blood samples before initiating adjuvant chemotherapy or radiation. Using linear regression, we found that after controlling for treatment condition, age, stage, body mass index (BMI), time since surgery, and type of surgery, anxiety severity related to significantly greater levels of S100A8/A9 (p = .035) and IL-1-β (p = .022), and marginally with IL-6 (p =.077) and TNF-α (p = .051). Anxiety may relate to markers of inflammation in breast cancer patients at an early point in their treatment. Because inflammatory processes may increase odds of metastasis, addressing anxiety early in the post-surgical period may have future health effects in breast cancer patients