Evaluating the Perception Among Rheumatologists of Maintenance of Board Certification in the US

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148252/1/acr23823.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148252/2/acr23823-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148252/3/acr23823_am.pd

EZH2 Modulates the DNA Methylome and Controls T Cell Adhesion Through Junctional Adhesion Molecule A in Lupus Patients

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141024/1/art40338_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141024/2/art40338.pd

Ethnicity-specific epigenetic variation in naïve CD4+ T cells and the susceptibility to autoimmunity

Abstract Background Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. T cells play an important role in several autoimmune conditions, including lupus, which is more common and more severe in people of African descent. To investigate inherent epigenetic differences in T cells between ethnicities, we characterized genome-wide DNA methylation patterns in naïve CD4+ T cells in healthy African-Americans and European-Americans, and then confirmed our findings in lupus patients. Results Impressive ethnicity-specific clustering of DNA methylation profiling in naïve CD4+ T cells was revealed. Hypomethylated loci in healthy African-Americans were significantly enriched in pro-apoptotic and pro-inflammatory genes. We also found hypomethylated genes in African-Americans to be disproportionately related to autoimmune diseases including lupus. We then confirmed that these genes, such as IL32, CD226, CDKN1A, and PTPRN2 were similarly hypomethylated in lupus patients of African-American compared to European-American descent. Using patch DNA methylation and luciferase reporter constructs, we showed that methylation of the IL32 promoter region reduces gene expression in vitro. Importantly, bisulfite DNA sequencing demonstrated that cis-acting genetic variants within and directly disrupting CpG sites account for some ethnicity-specific variability in DNA methylation. Conclusion Ethnicity-specific inherited epigenetic susceptibility loci in CD4+ T cells provide clues to explain differences in the susceptibility to autoimmunity and possibly other T cell-related diseases between populations.http://deepblue.lib.umich.edu/bitstream/2027.42/116042/1/13072_2015_Article_37.pd

Corrigendum: Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Corrigendu

Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behcet's Disease

Objective. Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population.Methods. A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray- 24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed.Results. We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1(rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10−9) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10−8). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide- stimulated monocytes. In addition, our results replicated the association (P 30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10−5), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated.Conclusion. We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored

Analysis of the common genetic component of large-vessel vasculitides through a meta- Immunochip strategy

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P?=?7.54E-07; ORGCA?=?1.19, ORTAK?=?1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA?=?5.52E-04, ORGCA?=?1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

A Longitudinal and Transancestral Analysis of DNA Methylation Patterns in Systemic Lupus Erythematosus

Objective: Systemic lupus erythematosus (SLE or lupus) is a complex heterogeneous autoimmune disease that can affect multiple organ systems. Lupus predominantly affects women, with African-American women carrying higher disease burden and poorer outcomes than European-American women. Disruption in the epigenetic landscape of immune cells, including DNA methylation, is a recognized feature of lupus. Global hypomethylation is consistently detected across lymphoid and myeloid immune cells from lupus patients, with the most extensive hypomethylation occurring in type I interferon response genes. Genetic background plays a role in shaping the epigenome of immune cells and in the risk of developing lupus. The aim of this dissertation was to measure the influence of genetics on DNA methylation differences between African-American and European-American lupus patients and those between lupus patients and healthy controls. Further, we sought to measure the variation in DNA methylation longitudinally over time and with disease activity in lupus. Results: We first analyzed granulocyte DNA methylation over time in a longitudinal cohort of African-American and European-American lupus patients followed for up to four years. Ethnicity-associated differential methylation in lupus granulocytes included genes associated with the type I interferon response and NFκB pathways. Approximately 16% of differentially methylated sites between ethnicities were associated with a nearby (≤ 1kb) genetic variant known as methylation quantitative trait loci (meQTL). An meQTL involving the promoter region of TREML4, a regulator of TLR7 response in myeloid cells, was among the strongest meQTL detected. Genotype-specific mRNA expression of TREML4 negatively correlated with promoter methylation in this locus. Methylation levels in two CpG sites were associated with changes in disease activity in African-American, but not European-American patients. Hypomethylation in GALNT18 was associated with the development of lupus nephritis during follow up. The lupus-associated epigenotype in granulocytes was not explained by genetics in lupus patients. To further examine the role of genetics in lupus-associated epigenetic changes, we studied DNA methylation in naïve CD4+ T cells from lupus patients and controls. CpG-associated genes in meQTL of lupus patients showed overlap with lupus risk genes. Some meQTL were shared between lupus granulocytes and naïve CD4+ T cells, including HLA-DQB1 and IRF7. However, confirming the results in lupus granulocytes, less than 1% of differentially methylated sites in lupus T cells were associated with meQTL. We then used a trend deviation analysis to compare disease-associated DNA methylation differences between lupus patients and controls in naïve CD4+ T cells, with methylation correlation patterns in over 16,000 tissue samples. The promoter of the miR-17-92 cluster, which regulates T cell proliferation and differentiation, was hypomethylated in lupus. Expression of two member microRNAs in this cluster were positively correlated with lupus disease activity. Conclusions: We have identified significant differences in the DNA methylome between African-American and European-American lupus patients, which are in part associated with nearby genetic variants. We have determined that granulocyte DNA methylation is predominantly stable over time and across disease activity levels in both African-American and European-American lupus patients. Furthermore, using DNA methylation profiles in granulocytes and naïve CD4+ T cells, we have determined that the DNA methylation signature of lupus, which is defined by robust hypomethylation of type I interferon genes, has little association with nearby genetic variants. These findings suggest that non-genetic factors play a predominant role in the DNA methylation signature of lupus.PHDImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/172518/1/pscoit_1.pd