Significance: TNF signals via 2 receptors, TNFR1 and TNFR2. Anti-TNF biologics, which block signaling via both receptors, are now being used to treat millions of patients worldwide for immune-mediated inflammatory diseases. This study demonstrates that TNFR2 plays a major role in limiting the severity and duration of arthritis in animal models and that TNFR2 is important for maintaining the functional activity and phenotypic stability of Treg cells, which are major cellular mediators of immune homeostasis. Treg cells express the functionally important transcription factor FoxP3, and we show that TNFR2 is required for preventing DNA methylation at the Foxp3 promoter thereby maintaining its transcriptional activity. This suggests that specific blockade of TNFR1 would be advantageous.

Strong familial aggregation of schizophrenia has been reported but there is uncertainty concerning the degree of genetic contribution to the phenotypic variance of the disease. This study aimed to examine the familial aggregation and heritability of schizophrenia, and the relative risks (RRs) of other psychiatric diseases, in relatives of people with schizophrenia using the Taiwan National Health Insurance Database. The study population included individuals with affected first-degree or second-degree relatives identified from all beneficiaries (n = 23 422 955) registered in 2013. Diagnoses of schizophrenia made by psychiatrists were ascertained between January 1, 1996 and December 31, 2013. Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR (95% CI) of 37.86 (30.55–46.92), 6.30 (6.09–6.53), 2.44 (1.91–3.12), and 1.88 (1.64–2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79–6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00–16.53) for schizophrenia. The accountability for the phenotypic variance of schizophrenia was 47.3% for genetic factors, 15.5% for shared environmental factors, and 37.2% for non-shared environmental factors. The RR (95% CI) in individuals with a first-degree relative with schizophrenia was 3.49 (3.34–3.64) for mood disorders and 3.91 (3.35–4.57) for delusional disorders. A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia.

Cells respond to diverse types of mechanical stimuli using a wide range of plasma membrane-associated mechanosensitive receptors to convert extracellular mechanical cues into intracellular signaling. G protein-coupled receptors (GPCRs) represent the largest cell surface protein superfamily that function as versatile sensors for a broad spectrum of bio/chemical messages. In recent years, accumulating evidence has shown that GPCRs can also engage in mechano-transduction. According to the GRAFS classification system of GPCRs, adhesion GPCRs (aGPCRs) constitute the second largest GPCR subfamily with a unique modular protein architecture and post-translational modification that are well adapted for mechanosensory functions. Here, we present a critical review of current evidence on mechanosensitive aGPCRs.

Objectives: Systemic sclerosis (SSc) has been associated with high cancer risk. We compared the cancer risk among SSc patients with that among the general Taiwanese population. Methods: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) was used to identify patients diagnosed with SSc and cancer in Taiwan during 1996–2008. The standardized incidence ratio (SIR) for cancer was calculated, and mortality was ascertained using the data from the National Death Registry. Results: Data analysis revealed that 2053 (472 men, 1581 women) Taiwanese individuals were diagnosed with SSc during the study period and 83 (30 men, 53 women) had cancer. The incidence of cancer was 6.9/1000 person-years. The most common cancer sites in male SSc patients were the lung (n = 10), oral cavity and pharynx (n = 8), and gastrointestinal tract (n = 4), and those in female patients were the breast (n = 11), lungs (n = 11), and blood (n = 6). Compared to the Taiwanese population of 1996, the all-cancer SIR for SSc was 1.63 [95% confidence interval (CI) 1.31–2.01]. Cancer risk was elevated for cancers of the lung (SIR 4.20), oral cavity and pharynx (SIR 3.67), and blood (SIR 3.50). A cancer diagnosis in SSc patients was associated with a hazard ratio (HR) of 2.15 (95% CI 1.30–3.53). Among cancer patients, a diagnosis of SSc was not associated with increased mortality. Conclusions: SSc patients are at high risk of developing cancer, especially of the lung, oral cavity and pharynx, and blood.

Objectives: There have been few nationwide population studies of systemic sclerosis (SSc). We describe the epidemiological features of SSc in Taiwan. Methods: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) and the National Death Registry of Taiwan were used to calculate estimates of the incidence, prevalence, and mortality of SSc. Results: A total of 1479 persons (325 males, 1154 females) with incident SSc were enrolled in the study. The annual incidence of SSc in Taiwan was found to be 10.9 cases (4.7 males, 17.4 females) per million population. During 2002–2007, the mean prevalence was 56.3 cases per million population. There were 204 deaths (70 males, 134 females) during the study period; 1-, 2-, and 5-year survival rates were 94.9, 92.0, and 83.2%, respectively. SSc patients had a standardized mortality ratio (SMR) of 3.24 [95% confidence interval (CI) 2.82–3.71] for all-cause mortality, as compared with the national population in 2002. There was excess mortality from neoplasms (SMR 1.50, 95% CI 1.03–2.11), cardiovascular diseases (2.23, 1.52–3.16), kidney disease (4.67, 2.66–7.64), gastrointestinal diseases (2.50, 1.27–4.46), and pulmonary diseases (3.20, 1.89–5.09). In addition to male sex and older age, cancer and end-stage renal disease (ESRD) diagnosis were risk factors for death, with hazard ratios (HRs) of 2.71 (95% CI 1.27–5.76) and 2.59 (1.14–5.90), respectively. Conclusion: SSc patients had a threefold greater risk of all-cause mortality than the general population of Taiwan. Male sex, older age, diagnosis of cancer, and ESRD were risk factors for death.

Objectives: To investigate the association between gout and non-alcoholic fatty liver disease (NAFLD). Methods: The study subjects were participants in a health-screening programme at Chang Gung Memorial Hospital from 2000 to 2006. Subjects were classified into eight groups based on serum urate (SU) level and gout status (≤ 4.9, 5.0–6.9, 7.0–8.9, and ≥ 9.0 mg/dL, without and with gout). The association between gout and NAFLD was assessed by multiple logistic regression. Results: Among a total of 54 325 subjects, 1930 (3.6%) had gout and 6169 (11.3%) had NAFLD. The prevalence of NAFLD was significantly higher in subjects with gout (23.1%, n = 445) than in those without gout (10.9%, n = 5724, p < 0.001). Among subjects with NAFLD, the severity of NAFLD was higher in gout patients. Gout was associated with an increased risk for NAFLD [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.25–1.60, p < 0.001], after adjustment for age, sex, presence of metabolic syndrome, and low estimated glomerular filtration rate (eGFR). With SU ≤ 4.9 mg/dL in the absence of gout as reference, the ORs (95% CI) for NAFLD, after adjustment for age, sex, presence of metabolic syndrome, and low eGFR, were, respectively, 2.16 (1.94–2.41), 3.98 (3.55–4.46), and 5.99 (5.19–6.90) for SU levels 2–4 in those without gout and 2.61 (1.39–4.91), 2.87 (2.04–4.04), 4.53 (3.70–5.56), and 6.31 (5.12–7.77) for SU levels 1–4 in those with gout. Conclusions: There was an independent association between gout and the risk for NAFLD. In addition, there was a dose–response relationship between SU and NAFLD in subjects with and without gout.