Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report a genome-wide analysis for asthma using data from the UK Biobank and the Trans-National Asthma Genetic Consortium. We identify 66 previously unknown asthma loci and demonstrate that the susceptibility alleles in these regions are, either individually or as a function of cumulative genetic burden, associated with risk to a greater extent in men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including CD52, and demonstrate that asthma-associated variants are enriched in regions of open chromatin in immune cells. Lastly, we show that a murine anti-CD52 antibody mimics the immune cell-depleting effects of a clinically used human anti-CD52 antibody and reduces allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma and provide important insight into the immunological and sex-specific relevance of asthma-associated risk variants.

Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

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Background Recent studies have revealed sexually dimorphic associations between the carbamoyl‐phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease ( CAD ) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl‐phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results We sought to identify additional genetic determinants of circulating glycine levels by carrying out a meta‐analysis of genome‐wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine‐associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism ( ACADM , PHGDH , COX 18‐ ADAMTS 3 , PSPH , TRIB 1 , PTPRD , and ABO ). Glycine‐raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD . However, these effects could not be attributed directly to glycine because of associations with other CAD ‐related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity‐related traits. Conclusions These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.

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Lipid profile (total cholesterol and lipoprotein fractions) has been found to correlate with depression and cognitive impairment across the lifespan. However, the role of lipid levels in self-rated depressive state and cognitive impairment remains unclear. In this study, we examined the relationship between lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) and cognition in adults with and without self-rated depression. Four hundred and thirty-eight healthy participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Self-Rating Depression Scale (SDS), and a serum lipoprotein test. Using multivariate ANOVA, partial correlation and network analysis, a network linking lipoprotein profile, depressive state and cognition was constructed. A significant difference in serum lipid profile between the high and low depressive groups was detected. Depressive state had a strong negative correlation with cognitive performance. Of the lipid profile, only high-density lipoprotein was positively correlated with depressive symptom severity, whereas the other three indices showed negative correlation with both depressive state and cognitive performance. Our results suggest that serum lipid profile may be directly linked to self-rated depression and cognitive performance. Further studies recruiting larger clinical samples are needed to elucidate the specific effect of lipoprotein on cognitive impairment in mood disorder.

Cognitive impairment is a core feature of schizophrenia (SCH). In addition to the toxic effect of Bilirubin (BIL), it has antioxidant properties that were associated with the psychopathology and cognitive impairment of psychiatric disorders. The aim of this study was to examine the correlation of serum total BIL (TBIL) concentration with cognitive impairment in SCH patients. We recruited 34 SCH patients and 119 healthy controls (HCs) in this case-control design. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum TBIL concentration was measured using the immunoturbidimetric method. Serum TBIL concentration was significantly decreased in SCH patients compared to HCs after adjusting for age, gender, and education. Serum TBIL concentration in SCH patients was also positively correlated with the RBANS immediate memory score. Further stepwise multiple regression analysis confirmed the positive association between serum TBIL concentration and immediate memory score in SCH patients. Our findings supported that the decline in serum TBIL concentration was associated with the immediate memory impairment and psychopathology of SCH.

Insulin-like growth factor binding protein-6 (IGFBP-6) is a member of the insulin-like growth factor binding protein family, which has both Insulin-like growth factor-dependent and independent effects on cell growth. In previous studies, we have shown that recombinant IGFBP-6 could be translocated into the cell nucleus. But the effect in the nucleus of IGFBP-6 is not clear. In the present study, we use multiple methodologies including Glutathione S-transferase pull-down assay, co-immunoprecipitation, fluorescence resonance energy transfer to demonstrate that IGFBP-6 can directly interact with thyroid hormone receptor alpha 1 (TRα1) in vitro and in vivo. We also demonstrate that the DNA-binding domains and Ligand-binding domains of TRα1 and N-terminal domains and C-terminal domains of IGFBP-6 are involved in the interaction. This interaction also can block the formation of TR: retinoid X receptor heterodimers. Furthermore, immunofluorescence co-localization studies show IGFBP-6 and TRα1 could co-localize in the nucleus of the cells. Reporter gene experiment shows that IGFBP-6 negatively regulates the growth hormone promoter activity induced by ligand activated TRα1. Moreover, real-time RT-PCR demonstrates that IGFBP-6 could inhibit the osteocalcin mRNA transcription induced by Triiodothyronine (3,3',5-Triiodo-L-thyronine, T3) in osteoblastic cells. Finally, alkaline phosphatase activity was significantly decreased in osteoblastic cells when the cells were transfected with IGFBP-6 in the presence of T3. In conclusion, these studies provide evidence that overexpression of IGFBP-6 suppresses osteoblastic differentiation regulated by TR in the present of T3.