Salt sensitivity of blood pressure and aldosterone: interaction between Lysine-specific demethylase 1 gene, sex, and age

Context Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular risk, especially in individuals of African descent, although underlying mechanisms remain obscure. Lysine-specific demethylase 1 (LSD1) is a salt-sensitive epigenetic regulator associated with SSBP and aldosterone dysfunction. An LSD1 risk allele in humans is associated with SSBP and lower aldosterone levels in hypertensive African but not European descent. Heterozygous knockout LSD1 mice display SSBP and aldosterone dysregulation, but this effect is modified by age and biological sex. This might explain differences in cardiovascular risk with aging and biological sex in humans. Objective To determine if LSD1 risk allele (rs587618) carriers of African descent display a sex-by-age interaction with SSBP and aldosterone regulation. Methods We analyzed 297 individuals of African and European descent from the HyperPATH cohort. We performed multiple regression analyses for outcome variables related to SSBP and aldosterone. Results LSD1 risk allele carriers of African (but not European) descent had greater SSBP than non-risk homozygotes. Female LSD1 risk allele carriers of African descent had greater SSBP, mainly relationship-driven by women of low estrogen (postmenopausal). There was a significant LSD1 genotype-sex interaction in aldosterone response to angiotensin II stimulation in individuals ≤50 years, with female carriers displaying decreased aldosterone responsiveness. Conclusions SSBP associated with LSD1 risk allele status is driven by women of deplete estrogen state. Mechanisms related to a resistance to develop SSBP in females are uncertain but may relate to an estrogen modulating effect on mineralocorticoid receptor activation and/or LSD1 epigenetic regulation of the mineralocorticoid receptor.

Host Genetic Liability for Severe COVID-19 Associates with Alcohol Drinking Behavior and Diabetic Outcomes in Participants of European Descent

Risk factors and long-term consequences of COVID-19 infection are unclear but can be investigated with large-scale genomic data. To distinguish correlation from causation, we performed in-silico analyses of three COVID-19 outcomes (N > 1,000,000). We show genetic correlation and putative causality with depressive symptoms, metformin use (genetic causality proportion (gĉp) with severe respiratory COVID-19 = 0.576, p = 1.07 × 10−5 and hospitalized COVID-19 = 0.713, p = 0.003), and alcohol drinking status (gĉp with severe respiratory COVID-19 = 0.633, p = 7.04 × 10−5 and hospitalized COVID-19 = 0.848, p = 4.13 × 10−13). COVID-19 risk loci associated with several hematologic biomarkers. Comprehensive findings inform genetic contributions to COVID-19 epidemiology, molecular mechanisms, and risk factors and potential long-term health effects of severe response to infection.

On Rehumanizing Pleistocene People of the Western Hemisphere

Since the emergence of the niche in Folsom, New Mexico, in the late 1920s, peopling archaeology has sought to understand the earliest human occupants of the Western Hemisphere. Three generations of practitioners have made great strides in the techno-environmental arena. However, we have largely failed to tap into PaleoIndigenous intellectual, emotional, and social lives—the very domains that made Ice Age people as fully human as we are. As a result, our interpretations of those pioneering populations could often apply as readily to a colony of ants or a herd of wildebeest as they do to living, breathing, thinking, dreaming, loving, striving human ancestors. This article first explores the reasons for our failure to fully actualize First Peoples, identifying and implicating a feedback loop that includes practitioner homogeneity (we have always been and continue to be disproportionately white men of European descent); our predominantly positivist worldview; our language, training, and practice; and even the limited nature of the material record we study. This article also, however, highlights the ways that an important minority of peopling scholars have sought to access the humanity of PaleoIndigenous people. By more consistently mobilizing our own human capacity to creatively interrogate the deep past, we will produce scholarship that more consistently recognizes the capacity of the people who lived it and, just as importantly, respects those living today.

An Overview of Strategies for Detecting Genotype-Phenotype Associations Across Ancestrally Diverse Populations

Genome-wide association studies (GWAS) have been very successful at identifying genetic variants influencing a large number of traits. Although the great majority of these studies have been performed in European-descent individuals, it has been recognised that including populations with differing ancestries enhances the potential for identifying causal SNPs due to their differing patterns of linkage disequilibrium. However, when individuals from distinct ethnicities are included in a GWAS, it is necessary to implement a number of control steps to ensure that the identified associations are real genotype-phenotype relationships. In this Review, we discuss the analyses that are required when performing multi-ethnic studies, including methods for determining ancestry at the global and local level for sample exclusion, controlling for ancestry in association testing, and post-GWAS interrogation methods such as genomic control and meta-analysis. We hope that this overview provides a primer for those researchers interested in including distinct populations in their studies.

Comprehensive Profile of Young and Elderly Chronic Lymphocytic Leukemia Patients in China: The Younger Population Compared with Western Countries

Introduction The epidemiological features of chronic lymphocytic leukemia (CLL) are different in the United States (US) and China. In addition to variant incidence rates, the median age at diagnosis of CLL patients in the Shandong Provincial Hospital CLL (SPHCLL) database is younger than the Surveillance, Epidemiology, and End Results (SEER) database. However, investigations on the association between age at onset and other clinical characteristics of Chinese patients with CLL remain unclear. Hence, the aim of this study was to explore the clinical-pathological parameters and prognosis of Chinese patients with CLL which were divided into the young (<60 years) group and the elderly (≥60 years) group. Methods The clinical data of 510 Chinese CLL patients diagnosed between October 2010 and June 2020 were obtained from the SPHCLL database. Meanwhile, the survival data of 2580 CLL patients diagnosed between 2010 and 2018 were obtained with SEER*Stat 8.1.5 from the SEER database. Patients <60 years were divided into the young group and patients ≥60 years were divided into the elderly group. Clinical-pathological parameters were accessed from the hospital-based laboratory service within 24 hours after the first admission. SPSS 23 and R 4.0.5 were used in analyzing the data. Moreover, Kaplan-Meier survival analysis, univariate Cox regression analysis and multivariate Cox regression analysis were performed to evaluate the prognosis of CLL patients. Comparisons of clinical characteristics between young and elderly CLL patients were made using t test and Chi-square test. p < 0.05 was defined as the borderline of statistical significance. Results The median age at diagnosis of Chinese patients, Asian American patients and patients of predominately European descent were 62, 66 and 69 years respectively (Figure 1A-C). After adjustments according to the population age distribution of China and the US, patients in the Chinese SPHCLL database presented earlier age at onset than the SEER database (Figure 1D). To further explore the clinical characteristics of young and elderly Chinese CLL patients, the general clinical data and laboratory parameters were analyzed among young and elderly CLL patients. Compared with elderly CLL patients, young CLL patients showed a higher percentage of cytogenetic aberrations detected by fluorescence in situ hybridization (p< 0.05). The proportion of patients with combined diseases was higher in elderly patients than young patients, especially coronary heart disease and hypertension (p< 0.05). The levels of prealbumin, albumin, Apolipoprotein A and Lp (a) were higher in young CLL patients, while the levels of β2-macroglobulin were lower in young CLL patients (p< 0.05). Moreover, the proportion of young CLL patients who accepted CHOP/RCHOP treatment was significantly higher. The overall survival (OS) of young CLL patients was better than elderly patients in the SPHCLL cohort and the SEER cohort (Figure 1E-F). Intriguingly, young Chinese patients experienced improved OS compared with young patients of predominately European descent (Figure 1G-H). Furthermore, univariate Cox regression analysis presented that apolipoprotein A, hemoglobin, thrombocyte and total cholesterol were positive prognostic factors among young patients, while β2-microglobulin and ADA were negative prognostic factors. In elderly CLL patients, univariate Cox regression analysis showed that albumin, apolipoprotein A, hemoglobin and superoxide dismutasewere positive prognostic factors, while β2-microglobulin, ADA and cystatin were negative prognostic factors. Multivariate Cox regression analysis showed that cystatin was an independent prognostic factor in elderly CLL patients. Conclusion In conclusion, Chinese CLL patients are characterized by earlier age at onset than patients of predominately European descent. The investigation presented a comprehensive profile of young and elderly CLL patients from China, contributing to the optimal management strategies of CLL patients in variant age groups. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Skin coloration is a culturally-specific cue for attractiveness, healthiness, and youthfulness in observers of Chinese and western European descent

Facial skin coloration signals information about an individual and plays an important role in social interactions and mate choice, due its putative association with health, attractiveness, and age. Whether skin coloration as an evolutionary significant cue is universal or specific to a particular culture is unclear and current evidence on the universality of skin color as a cue to health and attractiveness are equivocal. The current study used 80 calibrated, high-resolution, non-manipulated images of real human faces, either of Chinese or western European descent, which were rated in terms of attractiveness, healthiness, and perceived age by 44 observers, 22 western European (13 male; mean age ± SD = 24.27 ± 5.30) and 22 Chinese (7 male; mean age ± SD = 26.05 ± 3.96) observers. To elucidate the associations between skin coloration and these perceptual ratings and whether these associations are modulated by observer or image ethnicity, a linear mixed-effect model was setup with skin lightness (L*; CIELAB), redness (a*) and yellowness (b*), observer and image ethnicity as independent variables and perceived attractiveness, healthiness, and estimated age as dependent variables. We found robust positive associations between facial skin lightness (L*) and attractiveness, healthiness, and youthfulness, but only when Chinese observers judge facial images of their own ethnicity. Observers of European descent, on the other hand, associated an increase in yellowness(b*) with greater attractiveness and healthiness in Chinese facial images. We find no evidence that facial redness is positively associated with these attributes; instead, an increase in redness (a*) is associated with an increase in the estimated age of European facial images. We conclude that observers of both ethnicities make use of skin color and lightness to rate attractiveness, healthiness, and perceived age, but to a lesser degree than previously thought. Furthermore, these coloration cues are not universal and are utilized differently within the Chinese and western European ethnic groups. Our study adds to the growing body of work demonstrating the importance of skin color manipulations within an evolutionary meaningful parameter space, ideally using realistic skin models based on physical parameters.

Genetically Predicted Longer Telomere Length May Reduce Risk of Hip Osteoarthritis

Objective: This two-sample Mendelian randomization (MR) study aimed to examine the potential causal association of telomere length (TL) with the risk of osteoarthritis (OA).Method: The summary-level data for OA was derived from the United Kingdom Biobank cohort, including 50,508 individuals of European descent. Eighteen single nucleotide polymorphisms associated with TL were identified as instrumental variables from the most up-to-date TL genome-wide association study (GWAS) involving over 78,592 individuals of European descent. Based on the GWASs data, MR was performed using established statistical analysis methods including the inverse variance weighted, weighted median, MR-Egger, and MR pleiotropy residual sum and outlier.Results: Genetically determined TL was not associated with the risk of total OA (IVW odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.83, 1.21). In subgroup analyses stratified by OA site, no evidence in favor of association between genetically determined TL and knee OA was found (IVW OR = 1.18, 95% CI = 0.89, 1.58). However, using WM method, we observed a limited protective effect of longer TL on the risk of hip OA (OR = 0.60, 95% CI = 0.36–0.99), whereas the results of the IVW (p = 0.931) and MR-PRESSO (p = 0.932) showed that TL had no effect on hip OA.Conclusions: This study does not support a causal association between TL and total OA. A potential protective association between longer TL and hip OA, though possible, remains less certain.

Gene-gene Interaction of AhR with and within the Wnt Cascade Affects Susceptibility to Lung Cancer

Background Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Further, decision trees were created to investigate variant x variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g. maker rs2722278 SFRP4; OR = 1.20; 95%-CI: 1.13–1.27; p = 5.6 10− 10) and never smokers (e.g. maker rs1133683 Axin2; OR = 1.27; 95%-CI: 1.19–1.35; p = 1.0 10− 12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants Conclusions The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.