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Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?

ABSTRACT: Multiple genome-wide association studies have shown that the single-nucleotide polymorphism (SNP) rs2281808 TT variant, present within the signal regulatory protein gamma (SIRPG) gene, is associated with autoimmune diseases, such as type 1 diabetes. SIRP? is the only SIRP expressed on T cells. The role of SIRP? in human T-cells or the effect of the TT variant are poorly understood. In this short report, we demonstrate the rather unusual finding that this intronic SNP is associated with a reduction of SIRP? expression on T cells, both in healthy subjects as well as patients with type 1 diabetes. Using this information, we propose that a simple flow cytometric detection of SIRP? could be a potential diagnostic testing approach for the presence of SNP in the appropriate clinical context.

SUBMITTER: Sinha S

PROVIDER: S-EPMC6361684 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?

Sinha Sushmita S Renavikar Pranav S PS Crawford Michael P MP Rodgers Jake W JW Tsalikian Eva E Tansey Michael M Karandikar Nitin J NJ

Clinical immunology (Orlando, Fla.) 20181221

Multiple genome-wide association studies have shown that the single-nucleotide polymorphism (SNP) rs2281808 TT variant, present within the signal regulatory protein gamma (SIRPG) gene, is associated with autoimmune diseases, such as type 1 diabetes. SIRPγ is the only SIRP expressed on T cells. The role of SIRPγ in human T-cells or the effect of the TT variant are poorly understood. In this short report, we demonstrate the rather unusual finding that this intronic SNP is associated with a reducti ...[more]

PMID: 30579937

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Project description:BackgroundKetone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored.Methods51 PAH patients were dichotomized into preserved or impaired RV function based on a cardiac index of 2.2 L/min/m2. Impaired RV function patients were further segmented into intermediate or severe RV dysfunction based on a right atrial pressure of 8 mm Hg. Serum ketone bodies acetoacetate (AcAc) and beta-hydroxybutyrate (βOHB) were quantified using ultra performance liquid chromatography and mass spectrometry. In rodent studies, male Sprague Dawley rats were assigned to three groups: control (saline injection), monocrotaline (MCT) standard chow diet (MCT-Standard), and MCT ketogenic diet (MCT-Keto). Immunoblots and confocal microscopy probed macrophage NLRP3 activation in RV extracts and sections. RV fibrosis was determined by Picrosirus Red. Echocardiography evaluated RV function. Pulmonary arteriole remodeling was assessed from histological specimens.ResultsHuman RVF patients lacked a compensatory ketosis as serum AcAc and βOHB levels were not associated with hemodynamic, echocardiographic, or biochemical measures of RV dysfunction. In rodent studies, AcAc and βOHB levels were also not elevated in MCT-mediated RVF, but the ketogenic diet significantly increased AcAc and βOHB levels. MCT-Keto exhibited suppressed NLRP3 activation with a reduction in NLRP3, ASC (apoptosis-associated speck-like protein), pro-caspase-1, and interleukin-1 beta on immunoblots. Moreover, the number of ASC-positive macrophage in RV sections was reduced, RV fibrosis was blunted, and RV function was augmented in MCT-Keto rats.ConclusionThe ketogenic response is blunted in pulmonary arterial hypertension (PAH) patients with RVF. In the MCT rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.

Dataset Information

Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?

Publications

Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?

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