Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis

Introduction: The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA). Methods: We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined. Results: 2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P < 0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P < 0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013). Conclusion: TGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA

The genetic contribution to severe post-traumatic osteoarthritis

Objective: to compare the combined role of genetic variants loci associated with risk of knee or hip osteoarthritis (OA) in post-traumatic (PT) and non-traumatic (NT) cases of clinically severe OA leading to total joint replacement. Methods: A total of 1590 controls, 2168 total knee replacement (TKR) cases (33.2% PT) and 1567 total hip replacement (THR) cases (8.7% PT) from 2 UK cohorts were genotyped for 12 variants previously reported to be reproducibly associated with risk of knee or hip OA. A genetic risk score was generated and the association with PT and NT TKR and THR was assessed adjusting for covariates. Results: For THR, each additional genetic risk variant conferred lower risk among PT cases (OR=1.07, 95% CI 0.96 to 1.19; p=0.24) than NT cases (OR 1.11, 95% CI 1.06 to 1.17; p=1.55×10−5). In contrast, for TKR, each risk variant conferred slightly higher risk among PT cases (OR 1.12, 95% CI 1.07 to 1.19; p=1.82×10−5) than among NT cases (OR 1.08, 95% CI 1.03 to 1.1; p=0.00063). Conclusions: Based on the variants reported to date PT TKR cases have at least as high a genetic contribution as NT cases

Intestinal-derived ILCs migrating in lymph increase IFNγ production in response to Salmonella Typhimurium infection

Innate lymphoid cells (ILCs) are enriched in mucosae and have been described as tissue-resident. Interestingly, ILCs are also present within lymph nodes (LNs), in the interfollicular regions, the destination for lymph-migratory cells. We have previously shown that LN ILCs are supplemented by peripheral tissue-derived ILCs. Using thoracic duct cannulations, we here enumerate the intestinal lymph ILCs that traffic from the intestine to the mesenteric LNs (MLNs). We provide, for the first time, a detailed characterisation of these lymph-migratory ILCs. We show that all ILC subsets migrate in lymph, and while global transcriptional analysis reveals a shared signature with tissue-resident ILCs, lymph ILCs express migration-associated genes including S1PRs, SELL (CD62L) and CCR7. Interestingly, we discovered that while Salmonella Typhimurium infections do not increase the numbers of migrating ILCs, infection changes their composition and cytokine profile. Infection increases the proportions of RORyt+ T-bet+ ILCs, levels of IFNγ, and IFNγ/GM-CSF co-expression. Infection-induced changes in migratory ILCs are reflected in colon-draining MLN ILCs, where RORyt+ T-bet+ ILCs accumulate and display corresponding increased cytokine expression. Thus, we reveal that ILCs respond rapidly to intestinal infection and can migrate to the MLN where they produce cytokines

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs49654

Urocortin-1 within the Centrally-Projecting Edinger-Westphal Nucleus Is Critical for Ethanol Preference

Converging lines of evidence point to the involvement of neurons of the centrally projecting Edinger-Westphal nucleus (EWcp) containing the neuropeptide Urocortin-1 (Ucn1) in excessive ethanol (EtOH) intake and EtOH sensitivity. Here, we expanded these previous findings by using a continuous-access, two-bottle choice drinking paradigm (3%, 6%, and 10% EtOH vs. tap water) to compare EtOH intake and EtOH preference in Ucn1 genetic knockout (KO) and wild-type (WT) mice. Based on previous studies demonstrating that electrolytic lesion of the EWcp attenuated EtOH intake and preference in high-drinking C57BL/6J mice, we also set out to determine whether EWcp lesion would differentially alter EtOH consumption in Ucn1 KO and WT mice. Finally, we implemented well-established place conditioning procedures in KO and WT mice to determine whether Ucn1 and the corticotropin-releasing factor type-2 receptor (CRF-R2) were involved in the rewarding and aversive effects of EtOH (2 g/kg, i.p.). Results from these studies revealed that (1) genetic deletion of Ucn1 dampened EtOH preference only in mice with an intact EWcp, but not in mice that received lesion of the EWcp, (2) lesion of the EWcp dampened EtOH intake in Ucn1 KO and WT mice, but dampened EtOH preference only in WT mice expressing Ucn1, and (3) genetic deletion of Ucn1 or CRF-R2 abolished the conditioned rewarding effects of EtOH, but deletion of Ucn1 had no effect on the conditioned aversive effects of EtOH. The current findings provide strong support for the hypothesis that EWcp-Ucn1 neurons play an important role in EtOH intake, preference, and reward

Beer and wine consumption and risk of knee or hip osteoarthritis : a case control study

Introduction: The aim of this study was to investigate the association between alcoholic and non-alcoholic beverages and knee or hip osteoarthritis (OA). Methods: We conducted a case–control study of Caucasian men and women aged 45 to 86 years of age from Nottingham, UK. Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee or hip OA. Exposure information was sought using interview-based questionnaires and a semi-quantitative food frequency questionnaire to assess beverage consumption at ages 21 to 50 years. Odds ratios (ORs), adjusted ORs (aORs), 95% confidence intervals (CI) and P values were estimated using logistic regression models. Results: A total of 1,001 knee OA, 993 hip OA and 933 control participants were included in the study. Increasing beer consumption was associated with an increasing risk of OA (P for trend ≤0.001). Compared to those who did not consume beer, aORs for people who consumed 20 or more servings of beer were 1.93 (95% CI 1.26 to 2.94) and 2.15 (95% CI 1.45 to 3.19) for knee OA and hip OA, respectively. In contrast, increasing levels of wine consumption were associated with decreased likelihood of knee OA (P for trend <0.001). Compared to those who did not consume wine, aOR for knee OA among those who consumed 4 to 6 glasses of wine per week and ≥7 glasses of wine per week was 0.55 (95% CI 0.34 to 0.87) and 0.48 (95% CI 0.29 to 0.80), respectively. No association was identified between non-alcoholic beverages and knee or hip OA. Conclusions: Beer consumption appears to be a risk factor for knee and hip OA whereas consumption of wine has a negative association with knee OA. The mechanism behind these findings is speculative but warrants further study