The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer: A Study in Mice and Humans.

The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer. Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (ApcMin/+). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence. Aging CB2-/- mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2-/- and ApcMin/+CB2-/- mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans. Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients.

Insights into the pleiotropic relationships between chronic back pain and inflammation-related musculoskeletal conditions: rheumatoid arthritis and osteoporotic abnormalities.

ABSTRACT: The ageing process includes the development of debilitating musculoskeletal (MSK) conditions, including chronic back pain (CBP), rheumatoid arthritis (RA), and osteoporosis (OP). The mechanisms involved in the genetic-epidemiological relationships between these MSK phenotypes are controversial and limited and thus require clarification, in particular, between CBP and the other MSK phenotypes. A cross-sectional statistical analysis was conducted using Europeans from the UK Biobank data collection, including 73,794 CBP, 4883 RA, and 7153 OP cases as well as 242,216 calcaneus bone mineral density scores. C-reactive protein (CRP) was measured for 402,165 subjects in this sample. Genetic correlations were assessed to evaluate shared genetic background between traits. Mendelian randomization was performed to assess a causal relationship between CBP and RA and OP along with other risk factors, such as CRP. Colocalization analysis was conducted to identify shared pleiotropic regions between the examined traits. Bayesian modelling was performed to determine a potential pathway that may explain the interrelationships among these traits. Mendelian randomization analyses revealed that CRP causally predicts CBP only (ß = 0.183, 95% CI = 0.077-0.290, P -value = 0.001). Horizontally pleiotropy appeared to explain the relationship between CBP and RA and OP. Through colocalization analysis, several genomic regions emerged describing common genetic influences between CBP and its proposed risk factors, including HLA-DQA1/HLA-DQB1, APOE , SOX5, and MYH7B as well as Histone 1 genes. We speculate that among other factors, CBP and its MSK comorbidities may arise from common inflammatory mechanisms. Colocalized identified genes may aid in advancing or improving the mode of treatment in patients with CBP.

Exploring potential shared genetic influences between rheumatoid arthritis and blood lipid levels.

BACKGROUND AND AIMS: The association between rheumatoid arthritis (RA) and blood lipid levels has often been described as paradoxical, despite the strong association between RA and cardiovascular disease (CVD) risk. We aimed to clarify the genetic architecture that would explain the relationship between RA and blood-lipid levels, while considering inflammation as measured by C-reactive protein (CRP). METHODS: Genome-wide association study (GWAS) summary statistics were collected from the CHARGE Consortium and Global Lipids Genetics Consortium. Blood-lipid levels includes HDL-C, LDL-C, triglycerides (TG), and total cholesterol (TC). Causality was examined by assessing Mendelian Randomization (MR) analysis. Pleiotropy, the identification of shared causal variants between traits, was assessed by conducting colocalization analyses. RESULTS: Using the MR Egger method, RA did not appear to causally predict alterations in lipid factors, rather the MR Egger intercept revealed that the genetic relationship between RA and HDL-C, LDL-C and TC may be explained by horizontal pleiotropy (p=0.003, 0.006, and 0.018, respectively). MR was suggestive of a horizontally pleiotropic relationship between CRP and lipid factors, while a causal relationship could not be ruled out. Recurring genes arising from shared causal genetic variants between RA and varying lipid factors included NAT2/PSD3, FADS2/FADS1, SH2B3, and YDJC. CONCLUSIONS: Horizontal pleiotropy appears to explain the genetic relationship between RA and blood-lipid levels. In addition, blood-lipid levels appear to suggest a horizontally pleiotropic relationship to CRP, if not mediated through RA as well. Consideration of the pleiotropic genes between RA and blood lipid levels may aid in enhancing diagnostic means to predict CVD.

Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways.

Rheumatoid arthritis (RA) and osteoporosis (OP) are two comorbid complex inflammatory conditions with evidence of shared genetic background and causal relationships. We aimed to clarify the genetic architecture underlying RA and various OP phenotypes while additionally considering an inflammatory component, C-reactive protein (CRP). Genome-wide association study summary statistics were acquired from the GEnetic Factors for OSteoporosis Consortium, Cohorts for Heart and Aging Research Consortium and UK Biobank. Mendelian randomization (MR) was used to detect the presence of causal relationships. Colocalization analysis was performed to determine shared genetic variants between CRP and OP phenotypes. Analysis of pleiotropy between traits owing to shared causal single nucleotide polymorphisms (SNPs) was performed using PL eiotropic A nalysis under CO mposite null hypothesis (PLACO). MR analysis was suggestive of horizontal pleiotropy between RA and OP traits. RA was a significant causal risk factor for CRP (ß = 0.027, 95% confidence interval = 0.016-0.038). There was no evidence of CRP→OP causal relationship, but horizontal pleiotropy was apparent. Colocalization established shared genomic regions between CRP and OP, including GCKR and SERPINA1 genes. Pleiotropy arising from shared causal SNPs revealed through the colocalization analysis was all confirmed by PLACO. These genes were found to be involved in the same molecular function 'protein binding' (GO:0005515) associated with RA, OP and CRP. We identified three major components explaining the epidemiological relationship among RA, OP and inflammation: (1) Pleiotropy explains a portion of the shared genetic relationship between RA and OP, albeit polygenically; (2) RA contributes to CRP elevation and (3) CRP, which is influenced by RA, demonstrated pleiotropy with OP.

Shared Genetic Architecture Between Rheumatoid Arthritis and Varying Osteoporotic Phenotypes.

Rheumatoid arthritis (RA) and low bone mineral density (BMD), an indicator of osteoporosis (OP), appear epidemiologically associated. Shared genetic factors may explain this association. This study aimed to investigate the presence of pleiotropy to clarify the potential genetic association between RA and OP. We examined BMDs at varying skeletal sites reported in UK Biobank as well as OP fracture acquired from the Genetic Factors for Osteoporosis (GEFOS) Consortium and the TwinsUK study. PRSice-2 was used to assess the potential shared genetic overlap between RA and OP. The presence of pleiotropy was examined using colocalization analysis. PRSice-2 revealed that RA was significantly associated with OP fracture (ß = 351.6 ± 83.9, p value = 2.76E-05), total BMD (ß = -1763.5 ± 612.8, p = 4.00E-03), spine BMD (ß = -919.8 ± 264.6, p value = 5.09E-04), and forearm BMD (ß = -66.09 ± 31.40, p value = 3.53E-02). Through colocalization analysis, the same causal genetic variants, associated with both RA and OP, were apparent in 12 genes: PLCL1, BOLL, AC011997.1, TNFAIP3, RP11-158I9.1, CDK6, CHCHD4P2, RP11-505C13.1, PHF19, TRAF1, C5, and C11orf49 with moderate posterior probabilities (>50%). Pleiotropy is involved in the association between RA and OP phenotypes. These findings contribute to the understanding of disease mechanisms and provide insight into possible therapeutic advancements and enhanced screening measures. © 2021 American Society for Bone and Mineral Research (ASBMR).

Is craniofacial morphology and body composition related by common genes: Comparative analysis of two ethnically diverse populations.

OBJECTIVES: The overarching hypothesis of the present paper is that ethnically and/or genetically diverse human populations may exhibit similarity in correlations between various aspects of human phenotypes due to the morphological integration process during the ontogenetic stages. To test this we investigated whether an association between craniofacial (CF) features and body composition (BC) variations is present in humans and the extent to which such possible associations are comparable in different populations. Furthermore, the paper examines the contribution of common genetic (additive) and shared familial environmental factors in assessing the correlation between CF and BC characteristics in humans. MATERIALS AND METHODS: Two pedigree-based samples were collected from two distinct populations, including India (Santhal) and Europe (Chuvash). Canonical correlation analysis was used to compare the association between CF and BC characteristics in the two studied samples. The contribution of genetic and familial environmental factors on the correlation between CF and BC features was analyzed through variance decomposition analysis by implementing the Mendelian Analysis package (MAN). RESULTS: Our study suggests that CF morphology is significantly (p < 0.001) associated with BC variation in both samples. CF characteristics and BC phenotypes revealed a consistent trend in both samples where condensed and broad CF morphology was significantly associated with increased fat accumulation, with slight variations between the Santhal and Chuvash samples. Despite the variations observed between the samples, the heritability estimates were impressively equivalent for traits like total facial height (55.6%Santhal vs.56.1%Chuvash ) and nasal index (42.8%Santhal vs. 43.3%Chuvash ). DISCUSSION: The genetic contribution of CF morphology appeared to be extensive and the contribution of common genetic and shared family environmental correlations between CF and BC measures were suggestively substantial. Accordingly, these correlations were consistently observed across ethnically diverse populations, despite drastic morphological differences between the samples under comparison.

The impact of PCV7/13 on the distribution of carried pneumococcal serotypes and on pilus prevalence; 14 years of repeated cross-sectional surveillance.

BACKGROUND: S. pneumoniae carriage by children is a major source of pneumococcal transmission, and the initial step prior to infection. Pilus type 1, reported in ~30% of pneumococcal strains in the pre-vaccine era, contributes to pneumococcal colonization and virulence. In this study, we report the impact of the pneumococcal conjugate vaccine (PCV), PCV7/PCV13 sequential implementation on serotype distribution, and on the prevalence of piliated strains among carried pneumococci during the pre- and post-vaccine eras. METHODS: During 2002-2016, 12 repeated cross-sectional surveillances of nasopharyngeal S. pneumoniae carriage were conducted among 8,473 children <5.5 years old visiting primary care physicians in Central Israel. Seven biannual surveillances in the pre-PCV period, 2 surveillances after PCV7 was licensed but before implementation in the National Immunization Plan, and 3 additional surveillances in the post-PCV period. S. pneumoniae serotype distribution and prevalence of piliated strains were assessed. RESULTS: Carriage of S. pneumoniae was relatively stable (45.4%). The prevalence of serotypes included in PCV13 was 65.7%, in the pre-vaccine period and the pilus was present in 26.4% of isolates. The distribution of serotypes and the pilus prevalence in the pre-PCV period was relatively stable except for a decrease in prevalence of piliated 19F, observed following the first study year. Following PCV7/PCV13 implementation, vaccine type 13 (VT13) strains were nearly eliminated to 3.3% by 2016. Piliated strains, which were primarily of VT13 serotypes, initially followed a similar trend and were nearly eliminated by 2014 (1.7%). Yet, two years later, pilus prevalence re-emerged among non-VT strains to 12.8% of all pneumococci. CONCLUSIONS: Following PCV implementation, a dramatic and rapid decrease in VT strains prevalence was observed with a concomitant increase in non-VT strains. Piliated strains were nearly eliminated, yet re-emerged 7 years following PCV7/PCV13 implementation in various non-VT strains. This suggests that the pilus confers an advantage in colonization.

Rheumatoid arthritis is associated with exacerbated body composition deterioration in Kazakh females.

OBJECTIVE: The aim of this study was to assess the magnitude of changes in nutritional body composition components as a consequence of rheumatoid arthritis (RA) and the extent to which these components are associated with RA clinical characteristics, serologic markers, and osteoporosis-related phenotypes (OP-RPs). Early pathologic signs, if detected, could assist in future preventative techniques. METHODS: The study sample was comprised of 260 women with RA and 168 first-degree female relatives without RA who returned for body composition measurements using bioelectrical impedance analysis, from a previously established epidemiologic study conducted in Kazakhstan. RESULTS: In multivariate logistic regression, body composition components, the fat mass index (odds ratio [OR], 0.848; 95% confidence interval [CI], 0.786-0.913; P < 0.001) and the phase angle (PA; OR, 0.654; 95% CI, 0.467-0.826; P = 0.001), were independently and significantly negatively associated with RA after disease development. In multilinear regression analysis, PA was consistently associated with OP-RP, specifically concerning the spongial bone mineral density (BMDSPN) and cortical index, where ageing, reduced PA and increased disease duration explained 31.5% of BMDSPN and 37.3% of cortical index variation. CONCLUSION: Data on RA in women in Kazakhstan consistently show that fat mass index and PA act as independent major covariates associated with RA affection status. These findings suggest exacerbated body composition deterioration when compared with healthy controls, potentially indicating the early appearance of sarcopenia and likely cachexic-like properties. The data also suggest that PA could serve as a potential predictor of RA prognosis, and the concomitant development of osteoporosis.

An epidemiological analysis of osteoporotic characteristics in patients affected with rheumatoid arthritis in Kazakhstan.

PURPOSE: We aimed to assess which of the major risk factors associated with rheumatoid arthritis (RA) severity are also associated with osteoporosis-related phenotypes (OP-RP) in the native population of Kazakhstan. METHODS: Four hundred six RA patients (90.6% females) with 397 controls-unaffected first-degree relatives were recruited. Biochemical factors were recorded, and OP-RP were assessed using QCT scans and ultrasound densitometry (US) of the forearm to estimate cortical indices (CI), spongial bone mineral density (BMDSPN), and US_T-scores. RESULTS: In the RA affected female population, ~ 80% suffered from osteopenia or osteoporosis. All OP-RP were negatively correlated with age and female's sex, as expected, and thus accordingly adjusted, resulting in consistent, significantly [p = 0.016 (CI), p < 0.0001 (both BMDSPN and US_T-scores)] lower OP-RP estimates in affected females. Using multiple regression analysis for OP-RP manifestations, only age and disease duration appeared consistently associated with all three studied phenotypes, while menopause status or years following the onset of menopause were also significant for BMDSPN and US_T-scores. However, when disease duration was examined, we found that it was significantly dependent on morning stiffness, ESR, total cholesterol levels, weight, and menopause status, which explains 38.6% of the disease duration. CONCLUSIONS: Approximately 80% of female RA patients suffer from osteoporosis or osteopenia in the study group, which appears from a young age. RA disease duration is the major risk factor for OP-RP deterioration, especially as assessed by BMDSPNG, and US_T-scores. As a result, all OP-RP demonstrate significantly lower levels in comparison to sex- and age-matched unaffected individuals.