Background-The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome.Genome-wide association studies have revealed associations with human leukocyte antigen and non-human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. Methods and Results-We conducted a large-scale genetic analysis on a case-control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels (r=0.760; P<0.00001).We localized, with immunofluorescence staining, BTNL2 in CD68-positive macrophages of the coronary artery plaques. In homozygous cases, BTNL2 blocking, in T-cell stimulation assays, enhanced CD4 10,11 This may explain why the HLA-DRB1*01 association has emerged only in studies with direct HLA allele typing, but in no GWA studies.2,4 HLA-DRB1*01 may play a role in promoting coronary artery disease by affecting antigen presentation.12 Presentation of peptide fragments of oxidized low-density lipoprotein cholesterol may connect the cholesterol pathway to inflammation and immunology in atherosclerosis progression. Clinical Perspective on p 63Because of the promising results from previous GWA and candidate gene studies and the fact that the MHC contains many genes with putative immune functions, we hypothesized that analysis of other MHC genes using high-density SNPs stratified according to the HLA-DRB1*01 allele will show novel associations with acute coronary syndrome (ACS) with effective clinical implications. Materials and Methods Patient PopulationsOur entire study comprised 1 discovery population (from Finland) and 3 replication populations (I and II from Finland and III from Spain) for a total of 5376 cases and 4852 control subjects. The discovery population included 2090 ACS cases. 13 Replication population I included 742 cases either with ST-elevation myocardial infarction or non-ST-elevation myocardial infarction.14 Replication population II included 762 either ST-elevation myocardial infarction or non-STelevation myocardial infarction cases. 15 Replication population III included 1768 first myocardial infarction cases. 16,17 Control subjects for discovery and replication populations I and II were selected from The National FINRISK Study (FINRISK) 1992(FINRISK) , 1997(FINRISK) , 2002(FINRISK) , and ...

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Mutations in the autoimmune regulator gene disrupt thymic T cell development and negative selection, leading to the recessively inherited polyendocrine autoimmune disease autoimmune polyendocrine syndrome type 1 (APS-1). The patients also have a functional defect in the FOXP3 regulatory T cell population, but its origin is unclear. Here, we have used T cell receptor sequencing to analyse the clonal relationship of major CD4 T cell subsets in three patients and three healthy controls. The naive regulatory T cells showed little overlap with helper T cell subsets, supporting divergence in the thymus. The activated/memory regulatory T cell subset displayed more sharing with helper T cells, but was mainly recruited from the naive regulatory T cell population. These clonal patterns were very similar in both patients and controls. However, naive regulatory T cells isolated from the patients had a significantly longer T cell receptor complementarity-determining region 3 than any other population, suggesting failure of thymic selection. These data indicate that the peripheral differentiation of regulatory T cells in APS-1 patients is not different from that in healthy controls. Rather, the patients' naive regulatory T cells may have an intrinsic defect imprinted already in the thymus.

Introduction: Most patients with aortic stenosis (AS) are elderly and have multiple comorbidities. These conditions are often associated with poor nutrition and frailty. The purpose of this study was to assess the impact of preoperative nutritional status on symptoms and quality of life (QOL) after aortic valve replacement. Methods: We prospectively studied 220 patients with severe AS. Nutritional status was assessed using the Mini Nutritional Assessment (MNA) questionnaire. A score below 24 out of 30 indicates risk of malnutrition. Patients were evaluated preoperatively and three months after intervention. QOL was assessed using the RAND 36-item health survey. The six-minute walking test (6MWT) and the five times sit to stand test (5TSTS) were performed in 92 and 87 patients, respectively. Results: MNA score was below 24 in 28 % of the patients. Age, BMI, sex, and the proportion of patients undergoing surgery or TAVI were similar between MNA < 24 and MNA > 24 groups. There were no differences in NYHA class preoperatively, however a larger proportion of patients with MNA < 24 remained in NYHA 2 or higher after intervention (42 % vs 25 %, p = 0.03). They also remained more symptomatic, with dyspnea in 28 % vs 12 % (p = 0.01) and decreased exercise capacity in 44 % vs 16 % (p < 0.001) of the patients. Postoperative QOL was worse in patients with MNA < 24, with significant differences in seven categories (Figure). They performed worse in 6MWT at baseline (median 380 m vs 480 m, p = 0.02), but the difference was not significant after intervention (480 m vs 499 m, p = 0.4). Difference in 5TSTS was not significant at baseline (13.45 s vs 11 s, p = 0.1), but they performed worse after intervention (14.95 s vs 10.8 s, p = 0.02). Conclusions: Malnutrition is common among AS patients and is associated with worse QOL and more symptoms after intervention. Nutritional status should be assessed in AS patients before intervention for risk stratification and to find patients who might benefit from nutritional intervention.