Background The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. Objective To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls. Design Case control. Setting Academic medical centres. Participants 129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels. Outcome Measures Chi-square comparison of autoimmune prevalence and follow up logistic regression. Results There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC. Conclusions svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.

Objectives-Few studies have examined thrombosis in systemic lupus erythematosus (SLE), none have included Asian-Americans, and most have had small sample sizes. We analysed risk factors for thrombosis in a large, multiethnic SLE cohort.Methods-We studied 1930 SLE subjects, including Caucasians, African-Americans, AsianAmericans and Hispanics. Data were derived from questionnaires and medical records. Documented history of thrombosis was the primary outcome. Explanatory variables included age at SLE diagnosis, gender, ethnicity, disease duration, smoking, antiphospholipid antibody (aPL) status, nephritis and specific medications.

A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value ¼ 0.0056 and P-value ¼ 0.0044, respectively) and a region with P-valueo0.01 on 16p13-q12.2. The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.

Objective Scleroderma is a genetically complex autoimmune disease with substantial phenotypic heterogeneity. Previous genome-wide association studies have identified common genetic variants associated with disease risk, but these studies are not designed to capture rare or potential causal variants. Our goal was to identify rare, as well as common genetic variants in patients with diffuse cutaneous systemic sclerosis (dcSSc) through whole exome sequencing (WES) in order to identify potential causal variants. Methods We generated WES data for 32 dcSSc patients with or without interstitial lung disease (ILD) and 17 healthy “in-house” controls. Variants were annotated and filtered by quality, minor allele frequency, and deleteriousness on gene function. We applied a gene burden test to identify novel dcSSc and dcSSc-associated ILD candidate genes that were enriched with deleterious variants in cases compared to in-house controls as well as controls from the 1000 Genomes Project (n=130). Results We identified 70 genes that were enriched with deleterious variants in dcSSc patients. Two of them (BANK1 and TERT) are in pathways previously implicated in SSc or ILD pathogenesis or known susceptibility loci. Newly-identified genes are significantly enriched in the extracellular matrix-related pathway (COL4A3, COL4A4, COL5A2, COL13A1, and COL22A1), which is relevant to the fibrotic features of dcSSc, and the DNA repair pathway (XRCC4). Conclusion This study demonstrates the value of WES for the identification of novel gene variants and pathways that may contribute to scleroderma risk and/or severity. The candidate genes we discovered are potential targets for in-depth functional studies.