Transcriptomic meta-analysis characterizes molecular commonalities between psoriasis and obesity.

Despite the abundance of epidemiological evidence for the high comorbid rate between psoriasis and obesity, systematic approaches to common inflammatory mechanisms have not been adequately explored. We performed a meta-analysis of publicly available RNA-sequencing datasets to unveil putative mechanisms that are postulated to exacerbate both diseases, utilizing both late-stage, disease-specific meta-analyses and consensus gene co-expression network (cWGCNA). Single-gene meta-analyses reported several common inflammatory mechanisms fostered by the perturbed expression profile of inflammatory cells. Assessment of gene overlaps between both diseases revealed significant overlaps between up- (n = 170, P value = 6.07 × 10-65) and down-regulated (n = 49, P value = 7.1 × 10-7) genes, associated with increased T cell response and activated transcription factors. Our cWGCNA approach disentangled 48 consensus modules, associated with either the differentiation of leukocytes or metabolic pathways with similar correlation signals in both diseases. Notably, all our analyses confirmed the association of the perturbed T helper (Th)17 differentiation pathway in both diseases. Our novel findings through whole transcriptomic analyses characterize the inflammatory commonalities between psoriasis and obesity implying the assessment of several expression profiles that could serve as putative comorbid disease progression biomarkers and therapeutic interventions.

Association of Lipoprotein(a) with arterial stiffness: A Mendelian randomization study.

BACKGROUND: In this study we used Mendelian randomization (MR) to investigate the potential causal association of lipoprotein (a) [Lp(a)] levels with pulse wave velocity (PWV). METHODS: Genetic variants associated with Lp(a) were retrieved from the UK Biobank GWAS (N = 290,497). A non- overlapping GWAS based on a European cohort (N = 7,000) was used to obtain genetic associations with PWV (outcome) and utilized two different measures for the same trait, brachial-ankle (baPWV) and carotid-femoral (cfPWV) PWV. We applied a two-sample MR using the inverse variance weighting method (IVW) and a series of sensitivity analyses for 170 SNPs that were selected as instrumental variables (IVs). RESULTS: Our analyses do not support a causal association between Lp(a) and PWV for neither measurement [ßiwv(baPWV) = -.0005, p = .8 and ßiwv(cfPWV) = -.006, p = .16]. The above findings were consistent across sensitivity analyses including weighted median, mode-based estimation, MR-Egger regression and MR-PRESSO. CONCLUSION: We did not find evidence indicating that Lp(a) is causally associated with PWV, the gold standard marker of arterial stiffness.

Multiple long-term conditions in people with psoriasis: a latent class and bidirectional Mendelian randomization analysis.

BACKGROUND: Coexisting long-term conditions (LTCs) in psoriasis and their potential causal associations with the disease are not well -established. OBJECTIVES: To determine distinct clusters of LTCs in people with psoriasis and the potential bidirectional causal association between these LTCs and psoriasis. METHODS: Using latent class analysis, cross-sectional data from people with psoriasis from the UK Biobank were analysed to identify distinct psoriasis-related comorbidity profiles. Linkage disequilibrium score regression (LDSR) was applied to compute the genetic correlation between psoriasis and LTCs. Two-sample bidirectional Mendelian randomization (MR) analysis assessed the potential causal direction using independent genetic variants that reached genome-wide significance (P < 5 × 10-8). RESULTS: Five comorbidity clusters were identified in a population of 10 873 people with psoriasis. LDSR revealed that psoriasis was positively genetically correlated with heart failure [genetic correlation (rg) = 0.23, P = 8.8 × 10-8], depression (rg = 0.12, P = 2.7 × 10-5), coronary artery disease (CAD; rg = 0.15, P = 2 × 10-4) and type 2 diabetes (rg = 0.19, P = 3 × 10-3). Genetic liability to CAD was associated with an increased risk of psoriasis [inverse variance weighted (IVW) odds ratio (ORIVW) 1.159, 95% confidence interval (CI) 1.055-1.274; P = 2 × 10-3]. The MR pleiotropy residual sum and outlier (MR-PRESSO; ORMR-PRESSO 1.13, 95% CI 1.042-1.228; P = 6 × 10-3) and the MR-robust adjusted profile score (RAPS) (ORMR-RAPS 1.149, 95% CI 1.062-1.242; P = 5 × 10-4) approaches corroborate the IVW findings. The weighted median (WM) generated similar and consistent effect estimates but was not statistically significant (ORWM 1.076, 95% CI 0.949-1.221; P = 0.25). Evidence for a suggestive increased risk was detected for CAD (ORIVW 1.031, 95% CI 1.003-1.059; P = 0.03) and heart failure (ORIVW 1.019, 95% CI 1.005-1.033; P = 9 × 10-3) in those with a genetic liability to psoriasis; however, MR sensitivity analyses did not reach statistical significance. CONCLUSIONS: Five distinct clusters of psoriasis comorbidities were observed with these findings to offer opportunities for an integrated approach to comorbidity prevention and treatment. Coexisting LTCs share with psoriasis common genetic and nongenetic risk factors, and aggressive lifestyle modification in these people is anticipated to have an impact beyond psoriasis risk. Genetically predicted CAD is possibly associated with an increased risk of psoriasis, altering our prior knowledge.

Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure.

BACKGROUND AND AIMS: Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function. METHODS AND RESULTS: Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [-0.044 standard deviation (SD); 95% confidence interval (CI) -0.066, -0.021] with the MR estimate strengthening (-0.087 SD; 95% CI -0.132, -0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule. CONCLUSION: Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance.

Disentangling the complexity of psoriasis in the post-genome-wide association era.

In recent years, genome-wide association studies (GWAS) have been instrumental in unraveling the genetic architecture of complex diseases, including psoriasis. The application of large-scale GWA studies in psoriasis has illustrated several associated loci that participate in the cutaneous inflammation, however explaining a fraction of the disease heritability. With the advent of high-throughput sequencing technologies and functional genomics approaches, the post-GWAS era aims to unravel the functional mechanisms underlying the inter-individual variability in psoriasis patients. In this review, we present the key advances of psoriasis GWAS in under-represented populations, rare, non-coding and structural variants and epistatic phenomena that orchestrate the interplay between different cell types. We further review the gene-gene and gene-environment interactions contributing to the disease predisposition and development of comorbidities through Mendelian randomization studies and pleiotropic effects of psoriasis-associated loci. We finally examine the holistic approaches conducted in psoriasis through system genetics and state-of-the-art transcriptomic analyses, discussing their potential implication in the expanding field of precision medicine and characterization of comorbidities.

Risk factors for preterm birth: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Preterm birth defined as delivery before 37 gestational weeks is a leading cause of neonatal and infant morbidity and mortality. The aim of this study is to summarize the evidence from meta-analyses of observational studies on risk factors associated with PTB, evaluate whether there are indications of biases in this literature, and identify which of the previously reported associations are supported by robust evidence. METHODS: We searched PubMed and Scopus until February 2021, in order to identify meta-analyses examining associations between risk factors and PTB. For each meta-analysis, we estimated the summary effect size, the 95% confidence interval, the 95% prediction interval, the between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. Evidence was graded as robust, highly suggestive, suggestive, and weak. RESULTS: Eighty-five eligible meta-analyses were identified, which included 1480 primary studies providing data on 166 associations, covering a wide range of comorbid diseases, obstetric and medical history, drugs, exposure to environmental agents, infections, and vaccines. Ninety-nine (59.3%) associations were significant at P < 0.05, while 41 (24.7%) were significant at P < 10-6. Ninety-one (54.8%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 37 (22.3%) and 12 (7.2%) associations, respectively. We evaluated all associations according to prespecified criteria. Seven risk factors provided robust evidence: amphetamine exposure, isolated single umbilical artery, maternal personality disorder, sleep-disordered breathing (SDB), prior induced termination of pregnancy with vacuum aspiration (I-TOP with VA), low gestational weight gain (GWG), and interpregnancy interval (IPI) following miscarriage < 6 months. CONCLUSIONS: The results from the synthesis of observational studies suggest that seven risk factors for PTB are supported by robust evidence. Routine screening for sleep quality and mental health is currently lacking from prenatal visits and should be introduced. This assessment can promote the development and training of prediction models using robust risk factors that could improve risk stratification and guide cost-effective preventive strategies. TRIAL REGISTRATION: PROSPERO 2021 CRD42021227296.

Protein network and pathway analysis in a pharmacogenetic study of cyclosporine treatment response in Greek patients with psoriasis.

Although cyclosporine comprises a well-established systemic therapy for psoriasis, patients show important heterogeneity in their treatment response. The aim of our study was the pharmacogenetic analysis of 200 Greek patients with psoriasis based on the cyclosporine pathway related protein-protein interaction (PPI) network, reconstructed through the PICKLE meta-database. We genotyped 27 single nucleotide polymorphisms, mapped to 22 key protein nodes of the cyclosporine pathway, via the utilization of the iPLEX®GOLD panel of the MassARRAY® System. Single-SNP analyses showed statistically significant associations between CALM1 rs12885713 (P = 0.0108) and MALT1 rs2874116 (P = 0.0006) polymorphisms with positive response to cyclosporine therapy after correction for multiple comparisons, with the haplotype analyses further enhancing the predictive value of rs12885713 as a pharmacogenetic biomarker for cyclosporine therapy (P = 0.0173). Our findings have the potential to improve our prediction of cyclosporine efficacy and safety in psoriasis patients, as well as provide the framework for the pharmacogenetics of biological therapies in complex diseases.

Interactions of platelets with obesity in relation to lung cancer risk in the UK Biobank cohort.

BACKGROUND: Platelet count (PLT) is associated positively with lung cancer risk but has a more complex association with body mass index (BMI), positive only in women (mainly never smokers) and inverse in men (mainly ever smokers), raising the question whether platelets interact with obesity in relation to lung cancer risk. Prospective associations of platelet size (an index of platelet maturity and activity) with lung cancer risk are unclear. METHODS: We examined the associations of PLT, mean platelet volume (MPV), and platelet distribution width (PDW) (each individually, per one standard deviation increase) with lung cancer risk in UK Biobank men and women using multivariable Cox proportional hazards models adjusted for BMI and covariates. We calculated Relative Excess Risk from Interaction (RERI) with obese (BMI ≥ 30 kg/m2), dichotomising platelet parameters at ≥ median (sex-specific), and multiplicative interactions with BMI (continuous scale). We examined heterogeneity according to smoking status (never, former, current smoker) and antiaggregant/anticoagulant use (no/yes). RESULTS: During a mean follow-up of 10.4 years, 1620 lung cancers were ascertained in 192,355 men and 1495 lung cancers in 218,761 women. PLT was associated positively with lung cancer risk in men (hazard ratio HR = 1.14; 95% confidence interval (CI): 1.09-1.20) and women (HR = 1.09; 95%CI: 1.03-1.15) but interacted inversely with BMI only in men (RERI = - 0.53; 95%CI: - 0.80 to - 0.26 for high-PLT-obese; HR = 0.92; 95%CI = 0.88-0.96 for PLT*BMI). Only in men, MPV was associated inversely with lung cancer risk (HR = 0.95; 95%CI: 0.90-0.99) and interacted positively with BMI (RERI = 0.27; 95%CI = 0.09-0.45 for high-MPV-obese; HR = 1.08; 95%CI = 1.04-1.13 for MPV*BMI), while PDW was associated positively (HR = 1.05; 95%CI: 1.00-1.10), with no evidence for interactions. The associations with PLT were consistent by smoking status, but MPV was associated inversely only in current smokers and PDW positively only in never/former smokers. The interactions with BMI were retained for at least eight years of follow-up and were consistent by smoking status but were attenuated in antiaggregant/anticoagulant users. CONCLUSIONS: In men, PLT was associated positively and MPV inversely with lung cancer risk and these associations appeared hindered by obesity. In women, only PLT was associated positively, with little evidence for interaction with obesity.

Investigating modifiable pathways in psoriasis: A Mendelian randomization study.

BACKGROUND: Potentially modifiable risk factors have previously been investigated only in conventional observational studies. OBJECTIVE: To assess whether genetically predicted exposures to modifiable factors are associated with the risk of psoriasis. METHODS: Two-sample Mendelian randomization (MR) analysis. RESULTS: An increased risk of psoriasis was noted for genetically predicted lifetime smoking index (odds ratio [OR]MR-IVW = 2.11; 95% confidence interval [CI], 1.28-3.51), childhood (OR MR-IVW = 1.40; 95% CI, 1.14-1.71) and adult body mass index (OR MR-IVW = 1.63; 95% CI, 1.32-2), waist (OR IVW = 1.86; 95% CI, 1.31-2.64), and hip circumference (OR MR-IVW = 1.55; 95% CI, 1.15-2.07). Protective association was also reported between genetically predicted longer sleep duration (OR MR-IVW = 0.56; 95% CI 0.37-0.84) and increased years of education (OR MR-IVW = 0.78; 95% CI, 0.62-0.98). This effect of education persisted in multivariable MR after adjusting for genetic predictors of smoking and adult body mass index (ORMVMR-IVW = 0.72; 95% CI, 0.56-0.92). LIMITATIONS: It was not possible to stratify for psoriasis severity. CONCLUSION: Smoking cessation and prevention of obesity are important strategies for decreasing the incidence of psoriasis. Similarly, targeting education inequality is expected to lead further to reductions in cases of psoriasis.

Associations of obesity and body shape with erythrocyte and reticulocyte parameters in the UK Biobank cohort.

BACKGROUND: Obesity is associated with type 2 diabetes mellitus and chronic low-grade inflammation. Although chronic inflammatory conditions and diabetes are associated with anaemia, less is known about associations of obesity and body shape, independent of each other, with erythrocyte and reticulocyte parameters. METHODS: We investigated the associations of body mass index (BMI) and the allometric body shape index (ABSI) and hip index (HI), which are uncorrelated with BMI, with erythrocyte and reticulocyte parameters (all continuous, on a standard deviation (SD) scale) in UK Biobank participants without known metabolic, endocrine, or major inflammatory conditions (glycated haemoglobin HbA1c < 48 mmol/mol, C-reactive protein CRP < 10 mg/L). We examined erythrocyte count, total reticulocyte count and percent, immature reticulocyte count and fraction (IRF), haemoglobin, haematocrit, mean corpuscular haemoglobin mass (MCH) and concentration (MCHC), mean corpuscular and reticulocyte volumes (MCV, MRV), and red cell distribution width (RDW) in multivariable linear regression models. We additionally defined body shape phenotypes with dichotomised ABSI (≥ 73 women; ≥ 80 men) and HI (≥ 64 women; ≥ 49 men), including "pear" (small-ABSI-large-HI) and "apple" (large-ABSI-small-HI), and examined these in groups according to BMI (18.5-25 normal weight; 25-30 overweight; 30-45 kg/m2 obese). RESULTS: In 105,853 women and 100,854 men, BMI and ABSI were associated positively with haemoglobin, haematocrit, and erythrocyte count, and more strongly with total reticulocyte count and percent, immature reticulocyte count and IRF. HI was associated inversely with all, but least with IRF. Associations were comparable in women and men. In groups according to obesity and body shape, erythrocyte count was ~ 0.6 SD higher for obese-"apple" compared to normal-weight-"pear" phenotype (SD = 0.31*1012/L women, SD = 0.34*1012/L men), total reticulocyte count was ~ 1.1 SD higher (SD = 21.1*109/L women, SD = 23.6*109/L men), immature reticulocyte count was ~ 1.2 SD higher (SD = 7.9*109/L women, SD = 8.8*109/L men), total reticulocyte percent was ~ 1.0 SD higher (SD = 0.48% women and men), and IFR was over 0.7 SD higher (SD = 5.7% women and men). BMI but not ABSI or HI was associated more weakly inversely with MCV, MRV, and MCH, but positively with MCHC in men and RDW in women. CONCLUSIONS: In obesity uncomplicated with diabetes, larger BMI and ABSI are associated with increased erythropoiesis and reticulocyte immaturity.

Health outcomes in primary care: a 20-year evidence map of randomized controlled trials.

OBJECTIVE: To quantify the different types of health outcomes assessed as primary outcomes in randomized controlled trials (RCTs) in the primary care (PC) setting during the last 20 years and identify whether potential gaps exist in specific types of health care and types of intervention. METHODS: We systematically searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, from January 2000 to September 2020 for published RCTs in PC. We recorded characteristics of eligible studies and mapped evidence by health outcome category (patient health outcomes, health services outcomes); and for each outcome category, by types of health care (preventive, acute, chronic, palliative), and by types of intervention (drug, behavioural, on structure, and on process). For RCTs assessing patient health outcomes as primary outcomes, we further mapped using the quality-of-care dimensions, that is, effectiveness, safety, and patient-centredness. RESULTS: Of the 518 eligible RCTs in PC, 357 (68.9%) evaluated a patient health outcome as the primary outcome, and 161 (31.1%) evaluated only health services outcomes as primary outcomes. Many focused on population with chronic illness (224 trials; 43.2%) and evaluated interventions on processes of health care (239 trials; 46.1%). Research gaps identified include preventive and palliative care, behavioural interventions, and safety and patient-centredness outcomes as primary outcomes. CONCLUSION: Our evidence map showed research gaps in certain types of health care and interventions. It also showed research gaps in assessing safety and measures to place patient at the centre of health care delivery as primary outcomes.

Prognostic factors for adverse outcomes in patients with COVID-19: a field-wide systematic review and meta-analysis.

INTRODUCTION: The individual prognostic factors for coronavirus disease 2019 (COVID-19) are unclear. For this reason, we aimed to present a state-of-the-art systematic review and meta-analysis on the prognostic factors for adverse outcomes in COVID-19 patients. METHODS: We systematically reviewed PubMed from 1 January 2020 to 26 July 2020 to identify non-overlapping studies examining the association of any prognostic factor with any adverse outcome in patients with COVID-19. Random-effects meta-analysis was performed, and between-study heterogeneity was quantified using I2 statistic. Presence of small-study effects was assessed by applying the Egger's regression test. RESULTS: We identified 428 eligible articles, which were used in a total of 263 meta-analyses examining the association of 91 unique prognostic factors with 11 outcomes. Angiotensin-converting enzyme inhibitors, obstructive sleep apnoea, pharyngalgia, history of venous thromboembolism, sex, coronary heart disease, cancer, chronic liver disease, COPD, dementia, any immunosuppressive medication, peripheral arterial disease, rheumatological disease and smoking were associated with at least one outcome and had >1000 events, p<0.005, I2<50%, 95% prediction interval excluding the null value, and absence of small-study effects in the respective meta-analysis. The risk of bias assessment using the Quality in Prognosis Studies tool indicated high risk of bias in 302 out of 428 articles for study participation, 389 articles for adjustment for other prognostic factors and 396 articles for statistical analysis and reporting. CONCLUSIONS: Our findings could be used for prognostic model building and guide patient selection for randomised clinical trials.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Treatment With Dupilumab in Patients With Atopic Dermatitis: Systematic Review and Meta-Analysis.

Atopic dermatitis (AD) is a type 2 chronic skin disorder associated with systemic and psychosocial comorbidities decreasing the quality of life for many patients. Dupilumab, a human monoclonal antibody that blocks interleukins IL-4 and IL-13, is a recently added systematic treatment option with an emerging evidence base. Here, we assessed the safety and efficacy of dupilumab in patients with AD. We conducted a systematic review and meta-analysis of placebo-controlled randomized clinical trials evaluating the safety and efficacy of dupilumab on AD-related outcomes including clinical symptoms, quality of life and adverse events (AE). Subgroup analysis was further performed in adults and children/adolescents. Fourteen trials were included: twelve in adults (n = 3,817) and two in children/adolescents (n = 618). Dupilumab decreased the Eczema Area Severity Index (EASI) score [standardized mean difference (SMD) = -0.98; 95% confidence interval (95% CI) = (-1.09, -0.88)], the percent change difference in Scoring Atopic Dermatitis (SCORAD) [mean difference (MD) = -31.56, 95% CI = (-33.75, -29.36)], and in pruritus Numeric Rating Scale (pNRS) [MD = -29.24, 95% CI = (-32.11, -26.37)]. It also achieved a reduction of at least ≥75% in the EASI score [Risk Ratio (RR) = 2.89, 95% CI = (2.47, 3.38)], the Investigator's Global Assessment (IGA) score ≤1 [RR = 3.47, 95% CI = (2.96, 4.06)] and eight additional endpoints with no signs of increased AE compared to placebo. In subgroup analysis, the results were concordant for both groups. Dupilumab improved clinical symptoms and quality of life in adults and children/adolescents with a safety profile comparable to placebo.

White Blood Cells and Blood Pressure: A Mendelian Randomization Study.

BACKGROUND: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. METHODS: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. RESULTS: A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.

Validity of observational evidence on putative risk and protective factors: appraisal of 3744 meta-analyses on 57 topics.

BACKGROUND: The validity of observational studies and their meta-analyses is contested. Here, we aimed to appraise thousands of meta-analyses of observational studies using a pre-specified set of quantitative criteria that assess the significance, amount, consistency, and bias of the evidence. We also aimed to compare results from meta-analyses of observational studies against meta-analyses of randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. METHODS: We retrieved from PubMed (last update, November 19, 2020) umbrella reviews including meta-analyses of observational studies assessing putative risk or protective factors, regardless of the nature of the exposure and health outcome. We extracted information on 7 quantitative criteria that reflect the level of statistical support, the amount of data, the consistency across different studies, and hints pointing to potential bias. These criteria were level of statistical significance (pre-categorized according to 10-6, 0.001, and 0.05 p-value thresholds), sample size, statistical significance for the largest study, 95% prediction intervals, between-study heterogeneity, and the results of tests for small study effects and for excess significance. RESULTS: 3744 associations (in 57 umbrella reviews) assessed by a median number of 7 (interquartile range 4 to 11) observational studies were eligible. Most associations were statistically significant at P < 0.05 (61.1%, 2289/3744). Only 2.6% of associations had P < 10-6, ≥1000 cases (or ≥20,000 participants for continuous factors), P < 0.05 in the largest study, 95% prediction interval excluding the null, and no large between-study heterogeneity, small study effects, or excess significance. Across the 57 topics, large heterogeneity was observed in the proportion of associations fulfilling various quantitative criteria. The quantitative criteria were mostly independent from one another. Across 62 associations assessed in both RCTs and in observational studies, 37.1% had effect estimates in opposite directions and 43.5% had effect estimates differing beyond chance in the two designs. Across 94 comparisons assessed in both MR and observational studies, such discrepancies occurred in 30.8% and 54.7%, respectively. CONCLUSIONS: Acknowledging that no gold-standard exists to judge whether an observational association is genuine, statistically significant results are common in observational studies, but they are rarely convincing or corroborated by randomized evidence.

Association of body-shape phenotypes with imaging measures of body composition in the UK Biobank cohort: relevance to colon cancer risk.

BACKGROUND: Body mass index (BMI), waist and hip circumference are strongly correlated and do not reflect body composition. A Body Shape Index (ABSI) and Hip Index (HI) define waist and hip size among individuals with the same weight and height and would thus reflect body density. We examined differences in body composition between body-shape phenotypes defined with ABSI and HI and used this information to propose explanations for associations between body-shape phenotypes and colon cancer risk. METHODS: We used data from the UK Biobank Resource for 15,520 men, 16,548 women with dual-emission X-ray absorptiometry (DXA) measurements; 3997 men, 4402 women with magnetic resonance imaging (MRI) measurements; 200,289 men, 230,326 women followed-up for colon cancer. We defined body-shape phenotypes as: large-ABSI-small-HI ("apple"), small-ABSI-large-HI ("pear"), small-ABSI-small-HI ("slim"), large-ABSI-large-HI ("wide"). We evaluated differences in body composition in linear models and associations with colon cancer risk in Cox proportional hazards models adjusted for confounders and explored heterogeneity by BMI. RESULTS: Among individuals with the same height and weight, visceral adipose tissue (VAT) was lowest for "pear" and highest for "apple", while abdominal subcutaneous adipose tissue (ASAT) was lowest for "slim" and highest for "wide" phenotype. In the gynoid region, differences between "apple" and "pear" phenotypes were accounted for mainly by fat mass in women but by lean mass in men. In men, lean mass was inversely associated with waist size, while the pattern of gynoid fat resembled ASAT in women. Lean and fat mass were higher for higher BMI, but not hand grip strength. Compared to normal weight "pear", the risk of colon cancer in men (1029 cases) was higher for "apple" phenotype for normal weight (hazard ratio HR = 1.77; 95% confidence interval: 1.16-2.69) and comparably for overweight and obese, higher for "wide" phenotype for overweight (HR = 1.60; 1.14-2.24) and comparably for obese, but higher for "slim" phenotype only for obese (HR = 1.98; 1.35-2.88). Associations with colon cancer risk in women (889 cases) were weaker. CONCLUSIONS: ABSI-by-HI body-shape phenotypes provide information for body composition. Colon cancer risk in men appears related to ASAT quantity for "slim" and "wide" but to factors determining VAT accumulation for "apple" phenotype.

Associations of Alcohol Consumption with Cardiovascular Disease-Related Proteomic Biomarkers: The Framingham Heart Study.

BACKGROUND: Alcohol consumption and cardiovascular disease (CVD) have a complex relation. OBJECTIVES: We examined the associations between alcohol consumption, fasting plasma proteins, and CVD risk. METHODS: We performed cross-sectional association analyses of alcohol consumption with 71 CVD-related plasma proteins, and also performed prospective association analyses of alcohol consumption and protein concentrations with 3 CVD risk factors (obesity, hypertension, and diabetes) in 6745 Framingham Heart Study (FHS) participants (mean age 49 y; 53% women). RESULTS: A unit increase in log10 transformed alcohol consumption (g/d) was associated with an increased risk of hypertension (HR = 1.14; 95% CI: 1.04, 1.26; P = 0.007), and decreased risks of obesity (HR = 0.80; 95% CI: 0.71, 0.91; P = 4.6 × 10-4) and diabetes (HR: 0.68; 95% CI: 0.58, 0.80; P = 5.1 × 10-6) in a median of 13-y (interquartile = 7, 14) of follow-up. We identified 43 alcohol-associated proteins in a discovery sample (n = 4348, false discovery rate <0.05) and 20 of them were significant (P <0.05/43) in an independent validation sample (n = 2397). Eighteen of the 20 proteins were inversely associated with alcohol consumption. Four of the 20 proteins demonstrated 3-way associations, as expected, with alcohol consumption and CVD risk factors. For example, a greater concentration of APOA1 was associated with higher alcohol consumption (P = 1.2 × 10-65), and it was also associated with a lower risk of diabetes (P = 8.5 × 10-6). However, several others showed unexpected 3-way associations. CONCLUSIONS: We identified 20 alcohol-associated proteins in 6745 FHS samples. These alcohol-associated proteins demonstrated complex relations with the 3 CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relation between alcohol consumption and CVD risk.

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Tocilizumab administration for the treatment of hospitalized patients with COVID-19: A systematic review and meta-analysis.

Tocilizumab has been repurposed against the 'cytokine storm' in the setting of coronavirus disease 2019 (COVID-19). Our aim was to evaluate the efficacy of tocilizumab in the management of hospitalized COVID-19 patients. We searched MEDLINE, CENTRAL and medRxiv for studies of tocilizumab in hospitalized COVID-19 patients. Primary objective was the effectiveness of tocilizumab on mortality. Secondary objectives included the need for invasive mechanical ventilation (IMV), composite endpoints of mortality or IMV and intensive care unit (ICU) admission or IMV, length of hospitalization and differences in mortality in subgroups (ICU and non-ICU patients and patients receiving or not receiving concomitant corticosteroids). We included 52 studies (nine randomized controlled trials [RCTs] and 43 observational) with a total of 27,004 patients. In both RCTs and observational studies, the use of tocilizumab was associated with a reduction in mortality; 11% in RCTs (risk ratio [RR] 0.89, 95% CI 0.82 to 0.96) and 31% in observational studies (RR 0.69, 95% CI 0.58 to 0.83). The need for IMV was reduced by 19% in RCTs (RR 0.81, 95% CI 0.71 to 0.93), while no significant reduction was observed in observational studies. Both RCTs and observational studies showed a benefit from tocilizumab on the composite endpoint of mortality or IMV. Tocilizumab improved mortality both in ICU and non-ICU patients. Reduction in mortality was evident in observational studies regardless of the use of systemic corticosteroids, while that was not the case in the RCTs. Tocilizumab was associated with lower mortality and other clinically relevant outcomes in hospitalized patients with moderate-to-critical COVID-19.