Coxiella burnetii Infection Associated With Thromboangiitis Obliterans-like Phenomena With Digital Autoamputation: A Case Report and Review of Q Fever-Associated Autoimmunity.

We present a case of a patient with chronic Q fever who presented with digital necrosis, autoamputations, and positive anticentromere antibody, mimicking a scleroderma vasculopathy or thromboangiitis obliterans. Coxiella burnetii infection has long been associated with the presence of autoantibodies and autoimmune phenomena including vasculitis. Clinicians should consider Q fever testing in patients with new-onset autoimmune diseases or autoantibodies and appropriate exposure histories.

Adherence to Weight-Based Dosing Guidelines in Patients Receiving Hydroxychloroquine for Systemic Lupus Erythematosus and Rheumatoid Arthritis: Results of a Quality Improvement Initiative.

OBJECTIVE: Hydroxychloroquine (HCQ) is commonly prescribed for the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other rheumatic diseases. To limit retinal toxicity, the 2016 American Academy of Ophthalmology (AAO) guidelines recommended limiting the HCQ dose to 5 mg/kg/day or less. Our objective was to develop a quality improvement program to improve adherence to these guidelines. METHODS: We performed a retrospective analysis of 801 adult patients receiving HCQ for SLE and RA in a single academic rheumatology practice. In 2018, we calculated weight-based doses of HCQ at two time points at least 6 months apart. We surveyed provider opinions regarding the 2016 AAO guidelines and implemented a quality improvement intervention during which dosing data were shared with all prescribers (individually and in aggregate) and nurse-aided decision support was provided for HCQ refill requests. One year after the initial analysis and intervention, we again assessed weight-based doses of HCQ for the 674 patients still taking HCQ. RESULTS: At both measured time points during 2018, 22.8% of patients received doses greater than 5 mg/kg/day. For 60% of those patients, the dose of HCQ was reduced to 5 mg/kg/day or less by the study end. Between the second time point in 2018 and the postintervention time point in 2019, there was a statistically significant increase in the proportion of patients receiving of dose of 5 mg/kg/day or less (from 74% to 87%; P < 0.0001). CONCLUSION: We observed a significant increase in adherence with current AAO guidelines for weight-based HCQ dosing after providing feedback to providers regarding their prescribing data and reviewing weight-based dosing prior to refilling prescriptions.

TREM2 is associated with increased risk for Alzheimer's disease in African Americans.

BACKGROUND: TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer's disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case-control analyses in a total of 906 LOAD cases vs. 2,487 controls. RESULTS: We identified significant LOAD risk association with p.L211P (p=0.01, OR=1.27, 95%CI=1.05-1.54) and suggestive association with p.W191X (p=0.08, OR=1.35, 95%CI=0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk. CONCLUSIONS: Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action.

Coding variants in TREM2 increase risk for Alzheimer's disease.

The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer''s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [P = 9.17 × 10(-4), odds ratio (OR) = 2.63 (1.44-4.81)] and p.R62H [P = 2.36 × 10(-4), OR = 2.36 (1.47-3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [PSKAT-O = 5.37 × 10(-7); OR = 2.55 (1.80-3.67)]. The association of TREM2 variants with AD is still highly significant after excluding p.R47H [PSKAT-O = 7.72 × 10(-5); OR = 2.47 (1.62-3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P = 4.65 × 10(-2)) and p.R62H (P = 6.87 × 10(-3)) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-ß precursor protein (APP) and extracellular Aß42 and Aß40 (the 42- and 40-residue isoforms of the amyloid-ß peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aß42 and Aß40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Novel progranulin variants do not disrupt progranulin secretion and cleavage.

A subset of frontotemporal dementia cases are neuropathologically defined by tau-negative, TAR DNA-binding protein-43, and ubiquitin-positive inclusions in the brain and are associated with mutations in the progranulin gene (GRN). Deep sequencing of families exhibiting late-onset dementia revealed several novel variants in GRN. Because of the small size of these families and limited availability of samples, it was not possible to determine whether the variants segregated with the disease. Furthermore, none of these families had autopsy confirmation of diagnosis. We sought to determine if these novel GRN variants alter progranulin (PGRN) protein stability, PGRN secretion, and PGRN cleavage in cultured cells. All the novel GRN variants behave like PGRN wild-type protein, suggesting that these variants represent rare polymorphisms. However, it remains possible that these variants affect other aspects of PGRN function or represent risk factors for dementia when combined with other modifying genes.

GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aß42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻8 and p = 3.22 × 10⁻9 for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻4, 0.039, 4.86 × 10⁻5, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.