Resistance to TGFβ suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22

Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8⁺ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22‾/‾ T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor-restricted T cells with mutations identified as risk factors for autoimmunity

Pathway Analysis of Metabolic Syndrome Using a Genome-Wide Association Study of Korea Associated Resource (KARE) Cohorts

Metabolic syndrome (MetS) is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs), important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs), explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE) was used for analysis, which include 8,842 individuals (age, 52.2 ± 8.9 years; body mass index, 24.6 ± 3.2 kg/m2). A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene-Set Enrichment of Variant Associations (MAGENTA) to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 × 10-6), and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 × 10-7, Bonferroni-adjusted p < 0.05). Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet-derived growth factor (PDGF), the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR) signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS

Long Menstrual Cycle Is Associated with Type 2 Diabetes Mellitus in Korean Women

BackgroundLong menstrual cycle is a risk factor for developing type 2 diabetes and cardiovascular disease in women. We aimed to evaluate the association between existing type 2 diabetes and oligomenorrhea before diagnosis of diabetes, and to observe the differences in this association among obese and non-obese Korean women.MethodsPatients with type 2 diabetes (n=118) and without any clinical evidence of abnormal glucose regulation (n=258) who attended the outpatient clinic of a university hospital and were over age 30. Patients self-reporting a menstrual cycle over 40 days during their 20s were defined as oligomenorrhea before diagnosis of diabetes. Obesity was defined as having a body mass index (BMI) over 25 kg/m2.ResultsThe frequency of oligomenorrhea before diagnosis of diabetes was almost two-fold higher in women with type 2 diabetes than in the control group (16.1% vs. 8.5%, P=0.03). Oligomenorrhea was associated with type 2 diabetes after adjusting for age, BMI, systolic blood pressure, triglycerides, and high density lipoprotein cholesterol (odds ratio, 3.89; 95% confidence interval, 1.37 to 11.04). Among women with oligomenorrhea before diagnosis of diabetes, the frequency of type 2 diabetes was significantly higher in obese subjects than in their non-obese counterparts (90.9% vs. 30.0%, P=0.03).ConclusionHaving a long menstrual cycle could be a risk factor for the development of type 2 diabetes, especially in obese women

Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is affected by both environmental and genetic factors. Although the genetic component of PCOS is evident, studies aiming to identify susceptibility genes have shown controversial results. This study conducted a pathway-based analysis using a dataset obtained through a genome-wide association study (GWAS) to elucidate the biological pathways that contribute to PCOS susceptibility and the associated genes.We used GWAS data on 636,797 autosomal single nucleotide polymorphisms (SNPs) from 1,221 individuals (432 PCOS patients and 789 controls) for analysis. A pathway analysis was conducted using meta-analysis gene-set enrichment of variant associations (MAGENTA). Top-ranking pathways or gene sets associated with PCOS were identified, and significant genes within the pathways were analyzed.The pathway analysis of the GWAS dataset identified significant pathways related to oocyte meiosis and the regulation of insulin secretion by acetylcholine and free fatty acids (all nominal gene-set enrichment analysis (GSEA) P-values < 0.05). In addition, INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3 and PLCZ1 were significant genes observed within the biological pathways (all gene P-values < 0.05).By applying MAGENTA pathway analysis to PCOS GWAS data, we identified significant pathways and candidate genes involved in PCOS. Our findings may provide new leads for understanding the mechanisms underlying the development of PCOS

Personality Traits and Body Mass Index in a Korean Population

<div><p>Background</p><p>Overweight and obesity is a serious problem worldwide related to cardiovascular and other diseases. Personality traits are associated with the abnormal body mass indices (BMIs) indicative of overweight and obesity. However, the links between personality traits and BMI have been little studied in Korea.</p><p>Methods</p><p>We evaluated the association between personality traits and BMI in men and women using the rural Ansung and urban Ansan cohort from the Korean Genome Epidemiology Study, and the Kangbuk Samsung Hospital Cohort Study datasets. A shorter version of the original Revised Neuroticism-Extroversion-Openness Personality Inventory (NEO-PI-R) was used to measure the five-factor model of personality (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness).</p><p>Results</p><p>Data from a total of 1,495 men (mean age 60.0±9.8 years; mean BMI 24.3±3.0 kg/m²) and 2,547 women (mean age 47.0±15.5 years; mean BMI 22.8±3.4 kg/m²) were included in the analysis. Compared with the normal weight groups, overweight and obese men scored higher on openness to experience and lower on conscientiousness. Overweight and obese women scored lower on neuroticism and openness to experience and higher on agreeableness. Extraversion was positively associated with BMI in men (β = 0.032, <i>P</i><0.05). BMI and waist circumference were significantly increased in individuals who were less dutiful. In women, neuroticism was inversely associated with BMI (β = −0.026, <i>P</i><0.05). Openness to experience was negatively, and agreeableness was positively, associated with BMI (openness to experience: β = −0.072, agreeableness β = 0.068) and waist circumference (openness to experience: β = −0.202, agreeableness: β = 0.227) (<i>P</i><0.05).</p><p>Conclusion</p><p>Personality traits were associated with underweight, overweight, and obesity in men and women. Increased understanding of the underlying factors contributing to this association will aid in the prevention and treatment of abnormal BMI.</p></div

Clinical characteristic of subjects.

<p>Data are presented as mean ± standard deviation.</p><p>BMI, body mass index.</p

Regression analyses of personality traits, body mass index (BMI) and waist circumference, men and women.

<p>*<i>P</i><0.05 after controlling for age, age squared and education.</p

Association between Blood Lipid Levels and Personality Traits in Young Korean Women

<div><p>Abnormal lipid levels are important etiological factors associated with the development of atherosclerosis and with increased cardiovascular morbidity and mortality. Lipid levels are also influenced by lifestyle and behavioral factors, which suggests that personality traits might be related to abnormal lipid profiles. Studies on personality traits and lipid levels are relatively scarce in Korea. Therefore, the objective of this study was to examine the association between lipid levels and personality traits in young Korean women. A total of 1,701 young Korean women [mean age  = 24.9±4.6 years (range 17–39)] who volunteered for personality trait evaluation were recruited for this study. Lipid levels, including total cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride, were measured in all subjects after an overnight fast, and a low density lipoprotein (LDL) cholesterol level was calculated. The study population was divided into abnormal and normal lipid level groups according to the clinical criteria. Personality traits were measured using the Revised NEO Personality Inventory for the Five-Factor Model of personality. High neuroticism was associated with low HDL cholesterol levels. Low extraversion and openness were associated with high levels of triglyceride. At the facet level, the association between personality and lipid levels were generally consistent. Angry hostility, self-consciousness, vulnerability to stress, activity, and straightforwardness were associated with HDL cholesterol levels. Activity, positive emotion, aesthetics, actions, and deliberation were associated with triglyceride. When applying clinical criteria, conscientiousness was less likely to have abnormal total cholesterol levels. Our results showed that the women with the low HDL cholesterol levels are like to be more neurotic and the hyperglycemic women are prone to lower extraversion and openness in Korea. Understanding the associations between blood lipid levels and personality traits may have a beneficial effect for the managing of dyslipidemia.</p></div