Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait.

BACKGROUND: Sickle cell trait affects approximately 8% of Black individuals in the United States, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests that sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including kidney failure. The mechanisms underlying these associations remain poorly understood. We used proteomic profiling to gain insight into the pathobiology of sickle cell trait. METHODS: We measured proteomics ( N =1285 proteins assayed by Olink Explore) using baseline plasma samples from 592 Black participants with sickle cell trait and 1:1 age-matched Black participants without sickle cell trait from the prospective Women's Health Initiative cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait. RESULTS: In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in Black participants from two independent cohorts (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are known biomarkers of kidney function or injury ( e.g. , hepatitis A virus cellular receptor 1 [HAVCR1]/kidney injury molecule-1 [KIM-1], uromodulin [UMOD], ephrins), related to red cell physiology or hemolysis (erythropoietin [EPO], heme oxygenase 1 [HMOX1], and α -hemoglobin stabilizing protein) and/or inflammation (fractalkine, C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 [MCP-1], and urokinase plasminogen activator surface receptor [PLAUR]). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during Women's Health Initiative follow-up (odds ratio, 1.32; 95% confidence interval, 1.10 to 1.58). CONCLUSIONS: We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.

Effects of Yijinjing combined with resistance training on body fat distribution and hepatic lipids in middle-aged and older people with prediabetes mellitus: A randomized controlled trial.

PURPOSE: This randomized controlled trial aimed to study the effects of Yijinjing plus Elastic Band Resistance exercise on intrahepatic lipid (IHL), body fat distribution, glucolipid metabolism and biomarkers of inflammation in middle-aged and older people with pre-diabetes mellitus (PDM). PARTICIPANTS AGESND METHODS: 34 PDM participants (mean age, 62.62 ± 4.71 years; body mass index [BMI], 25.98 ± 2.44 kg/m2) were randomly assigned to the exercise group (n = 17) or control group (n = 17). The exercise group performed moderate-intensity Yijinjing and Elastic Band Resistance training 5 times per week for 6 months. The control group maintained their previous lifestyle. We measured body composition (body weight and body fat distribution), IHL, plasma glucose, lipid and the homeostatic model assessment of insulin resistance (HOMA-IR), inflammatory cytokines at baseline and 6 months. RESULTS: Compared with baseline, exercise significantly reduced IHL (reduction of 1.91 % ± 2.61 % vs an increase of 0.38 % ± 1.85 % for controls; P = 0.007), BMI (reduction of 1.38 ± 0.88 kg/m2 vs an increase of 0.24 ± 1.02 kg/m2 for controls; P = 0.001), upper limb fat mass, thigh fat mass and whole body fat mass. Fasting glucose, HOMA-IR, plasma total cholesterol (TC), and triglyceride (TG) were decreased in the exercise group (P < 0.05). There were no effects of exercise on liver enzyme levels and inflammatory cytokines. The decrease in IHL was positively correlated with the decreases in BMI, body fat mass and HOMA-IR. CONCLUSION: Six months of Yijinjing and resistance exercise significantly reduced hepatic lipids and body fat mass in middle-aged and older people with PDM. These effects were accompanied by weight loss, improved glycolipid metabolism and insulin resistance.

Effect of Yi Jin Jing exercise plus Elastic Band Resistance exercise on overall bone mineral density in postmenopausal women.

OBJECTIVES: This work aimed to study the effects of Yi Jin Jing plus Elastic Band Resistance exercise on bone mineral density at all parts of the body and bone metabolism index levels in postmenopausal women. DESIGN: Randomized controlled trial. METHODS: Forty postmenopausal women were randomly assigned equally to the exercise or to the control group. The control group maintained their lifestyle behaviors unaltered, whereas the exercise group received  Yi Jin Jing plus Elastic Band Resistance exercise. The primary outcome was overall bone mineral density at each part, and the secondary one was bone metabolism indicator levels and bone mineral density on both sides. RESULTS: The results after six months showed increased bone mineral density at all parts of the body in the exercise group (spine, P = 0.002; thighs, lumbar, and whole body, P < 0.05) and decreased bone mineral density in the control group (trunk, pelvis, and spine, P < 0.01). In particular, the decrease and increase were greater on the non-preferred (left) side than on the right side. As for bone metabolism indexes, ß-Crosslaps levels reduced (P = 0.016) and a significant increase in 1,25-(OH)2-D3 (P < 0.001) can be observed in the exercise group. CONCLUSIONS: The results suggested that Yi Jin Jing plus Elastic Band Resistance exercise could delay the overall decrease of bone mineral density in postmenopausal women, especially on the non-preferred side. It also increased bone formation metabolite levels and inhibited bone resorption metabolite levels.

Effect of Yijinjing combined with elastic band exercise on muscle mass and function in middle-aged and elderly patients with prediabetes: A randomized controlled trial.

Introduction: This study investigated the effect of Yijinjing combined with elastic band exercise on muscle mass and muscle function in patients with prediabetes. Methods: This study was a randomized controlled trial designed in parallel (Chinese Clinical Trial Registry: ChiCTR2000039049). Participants with prediabetes (n = 47) were randomly divided into control (n = 21, 63.5 ± 4.7 years,16 females) and exercise (n = 26, 62.0 ± 5.0 years, 20 females) groups. The former maintained their original lifestyle, and the latter received Yijinjing combined with elastic band exercise five times a week for 6 months. All the outcome measures were assessed immediately at baseline, after 3- and 6-month intervention. Results: After 6-month of the exercise, the body weight, body mass index, leg fat mass, gynoid fat mass, and total body fat mass in exercise group were significantly decreased compared with those at baseline (p < 0.05). Compared with those at baseline, total lean mass decreased at 3 and 6 months in both groups. The total muscle mass loss in the exercise group was always less than that in control group at all time periods, but the difference was not statistically significant. Handgrip strength, gait speed, reaction time, leg power, eye-closed and single-legged standing, and sit-and-reach were significantly improved for the exercise group at 3 and 6 months (p < 0.05). Gait speed and reaction time between both groups at 3 and 6 months were significant different (p < 0.05), and leg power at 6 months (p < 0.05). Compared with baseline, the reaction time of control group at six months was significantly improved (p < 0.05), and no other significant changes were observed. Compared with those at baseline, fasting plasma glucose, 2-h post-meal plasma glucose, fasting insulin, total cholesterol, and insulin resistance index in exercise group gradually decreased, and growth hormone was gradually increased with significance at 6 months (p < 0.05). 25-hydroxyvitamin D gradually and significantly increased in both groups at 3 and 6 months (p < 0.05). But two groups' testosterone levels weren't significant change. Conclusion: Yijinjing combined with elastic band exercise can substantially reduce the body weight and body fat content of middle-aged and elderly patients with Prediabetes, improve muscle function and growth hormone secretion, and delay muscle mass reduction and diabetes development. Clinical trial registration: [http://www.chictr.org.cn/showproj.aspx?proj=62753], identifier [ChiCTR2000039049].

Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.

Development of TAK-875 was discontinued when a small number of serious drug-induced liver injury (DILI) cases were observed in Phase 3 clinical trials. Subsequent studies have identified hepatocellular oxidative stress, mitochondrial dysfunction, altered bile acid homeostasis, and immune response as mechanisms of TAK-875 DILI and the contribution of genetic risk factors in oxidative response and mitochondrial pathways to the toxicity susceptibility observed in patients. We tested the hypothesis that a novel preclinical approach based on gene pathway analysis in the livers of Collaborative Cross mice could be used to identify human-relevant mechanisms of toxicity and genetic risk factors at the level of the hepatocyte as reported in a human genome-wide association study. Eight (8) male mice (4 matched pairs) from each of 45 Collaborative Cross lines were treated with a single oral (gavage) dose of either vehicle or 600 mg/kg TAK-875. As expected, liver injury was not detected histologically and few changes in plasma biomarkers of hepatotoxicity were observed. However, gene expression profiling in the liver identified hundreds of transcripts responsive to TAK-875 treatment across all strains reflecting alterations in immune response and bile acid homeostasis and the interaction of treatment and strain reflecting oxidative stress and mitochondrial dysfunction. Fold-change expression values were then used to develop pathway-based phenotypes for genetic mapping which identified candidate risk factor genes for TAK-875 toxicity susceptibility at the level of the hepatocyte. Taken together, these findings support our hypothesis that a gene pathway-based approach using Collaborative Cross mice could inform sensitive strains, human-relevant mechanisms of toxicity, and genetic risk factors for TAK-875 DILI. This novel preclinical approach may be helpful in understanding, predicting, and ultimately preventing clinical DILI for other drugs.

Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach.

Idelalisib is a phosphatidylinositol 3-kinase inhibitor highly selective for the delta isoform that has shown good efficacy in treating chronic lymphocytic leukemia and follicular lymphoma. In clinical trials, however, idelalisib was associated with rare, but potentially serious liver and lung toxicities. In this study, we used the Collaborative Cross (CC) mouse population to identify genetic factors associated with the drug response that may inform risk management strategies for idelalisib in humans. Eight male mice (4 matched pairs) from 50 CC lines were treated once daily for 14 days by oral gavage with either vehicle or idelalisib at a dose selected to achieve clinically relevant peak plasma concentrations (150 mg/kg/day). The drug was well tolerated across all CC lines, and there were no observations of overt liver injury. Differences across CC lines were seen in drug concentration in plasma samples collected at the approximate Tmax on study Days 1, 7, and 14. There were also small but statistically significant treatment-induced alterations in plasma total bile acids and microRNA-122, and these may indicate early hepatocellular stress required for immune-mediated hepatotoxicity in humans. Idelalisib treatment further induced significant elevations in the total cell count of terminal bronchoalveolar lavage fluid, which may be analogous to pneumonitis observed in the clinic. Genetic mapping identified loci associated with interim plasma idelalisib concentration and the other 3 treatment-related endpoints. Thirteen priority candidate quantitative trait genes identified in CC mice may now guide interrogation of risk factors for adverse drug responses associated with idelalisib in humans.

Inbred Strain Variant Database (ISVdb): A Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders.

The Collaborative Cross (CC) is a panel of recently established multiparental recombinant inbred mouse strains. For the CC, as for any multiparental population (MPP), effective experimental design and analysis benefit from detailed knowledge of the genetic differences between strains. Such differences can be directly determined by sequencing, but until now whole-genome sequencing was not publicly available for individual CC strains. An alternative and complementary approach is to infer genetic differences by combining two pieces of information: probabilistic estimates of the CC haplotype mosaic from a custom genotyping array, and probabilistic variant calls from sequencing of the CC founders. The computation for this inference, especially when performed genome-wide, can be intricate and time-consuming, requiring the researcher to generate nontrivial and potentially error-prone scripts. To provide standardized, easy-to-access CC sequence information, we have developed the Inbred Strain Variant Database (ISVdb). The ISVdb provides, for all the exonic variants from the Sanger Institute mouse sequencing dataset, direct sequence information for CC founders and, critically, the imputed sequence information for CC strains. Notably, the ISVdb also: (1) provides predicted variant consequence metadata; (2) allows rapid simulation of F1 populations; and (3) preserves imputation uncertainty, which will allow imputed data to be refined in the future as additional sequencing and genotyping data are collected. The ISVdb information is housed in an SQL database and is easily accessible through a custom online interface (http://isvdb.unc.edu), reducing the analytic burden on any researcher using the CC.

Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis.

OBJECTIVE: Interleukin 23 (IL-23) stimulates the differentiation of T helper 17 (Th17) cells, which are involved in the pathogenesis of ankylosing spondylitis (AS). Binding of IL-23 to the IL-23 receptor complex activates Janus kinases 2 and tyrosine kinase 2, which phosphorylate IL-23R and subsequently promote the transcription of the IL-17 gene. IL-12B encodes a p40 subunit common to IL-12 and IL-23. We evaluated the effects of IL-12B and IL-23R genotype on the occurrence and clinical features of AS. METHODS: A total of 362 patients with AS and 362 healthy controls were enrolled in the study. Genotypes of IL-12B A1188C (rs3212227) and IL-23R C2370A (rs10889677) were identified by polymerase chain reaction/restriction fragment-length polymorphism. Disease activity and functional status were assessed by Bath AS indices. RESULTS: Subjects carrying IL-12B CC [matched relative risk (RR(m)) 1.93, 95% CI 1.23-3.03] and IL-12B AC (RR(m) 1.73, 95% CI 1.21-2.46) genotypes had a significantly greater risk of developing AS than subjects with the IL-12B AA genotype. Subjects carrying both IL-12B CC and IL-23R AA genotypes also had a significantly higher risk (RR(m) 2.98, 95% CI 1.51-5.89) of developing AS compared to those with IL-12B AA and IL-23R CC/CA genotypes, and this interaction between IL-12B and IL-23R was significant. Patients with AS who had IL-12B CC and IL-12B AC genotypes had an obviously increased Bath Ankylosing Spondylitis Disease Activity Index score compared to those who carried the IL-12B AA genotype (4.3 vs 3.7). CONCLUSION: The IL-12B A1188C genotype was associated with the development and disease severity of AS.