CARD9 deficiency with allergic bronchopulmonary aspergillosis (ABPA)-like presentation: a case report.

PURPOSE: We present a patient with CARD9 deficiency and allergic bronchopulmonary aspergillosis (ABPA)-like presentation. METHODS: Following medical history taking and routine laboratory investigations, an inborn error of immunity was suspected, and the responsible variant was identified using Whole Exome Sequencing and confirmed by Sanger sequencing. RESULTS: A 14-year-old Iranian female presented with a history of chest pain, productive cough, dyspnea, malaise, and recurrent fever. Imaging by computed tomography (CT scan), chest X-ray (CXR), bronchoscopy, transbronchial lung biopsy (TBLB), and histopathology findings led to a diagnosis of ABPA-like presentation. The genetic study showed an autosomal recessive homozygous mutation in the CARD9 gene. Clinical remission was achieved following the administration of voriconazole, which was continued as prophylaxis. CONCLUSIONS: This is the first-time report of a patient with inherited CARD9 deficiency and ABPA-like presentation due to Aspergillus Terrus. This study paves the way to elucidate immunological mechanisms underlying CARD9 deficiency and aspergillosis.

Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler.

A primary obstacle in translating genetic associations with disease into therapeutic strategies is elucidating the cellular programs affected by genetic risk variants and effector genes. Here, we introduce LipocyteProfiler, a cardiometabolic-disease-oriented high-content image-based profiling tool that enables evaluation of thousands of morphological and cellular profiles that can be systematically linked to genes and genetic variants relevant to cardiometabolic disease. We show that LipocyteProfiler allows surveillance of diverse cellular programs by generating rich context- and process-specific cellular profiles across hepatocyte and adipocyte cell-state transitions. We use LipocyteProfiler to identify known and novel cellular mechanisms altered by polygenic risk of metabolic disease, including insulin resistance, fat distribution, and the polygenic contribution to lipodystrophy. LipocyteProfiler paves the way for large-scale forward and reverse deep phenotypic profiling in lipocytes and provides a framework for the unbiased identification of causal relationships between genetic variants and cellular programs relevant to human disease.

A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.

Recent large-scale genomic association studies found evidence for a genetic link between increased risk of type 2 diabetes and decreased risk for adiposity-related traits, reminiscent of metabolically obese normal weight (MONW) association signatures. However, the target genes and cellular mechanisms driving such MONW associations remain to be identified. Here, we systematically identify the cellular programmes of one of the top-scoring MONW risk loci, the 2q24.3 risk locus, in subcutaneous adipocytes. We identify a causal genetic variant, rs6712203, an intronic single-nucleotide polymorphism in the COBLL1 gene, which changes the conserved transcription factor motif of POU domain, class 2, transcription factor 2, and leads to differential COBLL1 gene expression by altering the enhancer activity at the locus in subcutaneous adipocytes. We then establish the cellular programme under the genetic control of the 2q24.3 MONW risk locus and the effector gene COBLL1, which is characterized by impaired actin cytoskeleton remodelling in differentiating subcutaneous adipocytes and subsequent failure of these cells to accumulate lipids and develop into metabolically active and insulin-sensitive adipocytes. Finally, we show that perturbations of the effector gene Cobll1 in a mouse model result in organismal phenotypes matching the MONW association signature, including decreased subcutaneous body fat mass and body weight along with impaired glucose tolerance. Taken together, our results provide a mechanistic link between the genetic risk for insulin resistance and low adiposity, providing a potential therapeutic hypothesis and a framework for future identification of causal relationships between genome associations and cellular programmes in other disorders.

Genetics of sexually dimorphic adipose distribution in humans.

Obesity-associated morbidity is exacerbated by abdominal obesity, which can be measured as the waist-to-hip ratio adjusted for the body mass index (WHRadjBMI). Here we identify genes associated with obesity and WHRadjBMI and characterize allele-sensitive enhancers that are predicted to regulate WHRadjBMI genes in women. We found that several waist-to-hip ratio-associated variants map within primate-specific Alu retrotransposons harboring a DNA motif associated with adipocyte differentiation. This suggests that a genetic component of adipose distribution in humans may involve co-option of retrotransposons as adipose enhancers. We evaluated the role of the strongest female WHRadjBMI-associated gene, SNX10, in adipose biology. We determined that it is required for human adipocyte differentiation and function and participates in diet-induced adipose expansion in female mice, but not males. Our data identify genes and regulatory mechanisms that underlie female-specific adipose distribution and mediate metabolic dysfunction in women.

Transcriptome and fatty-acid signatures of adipocyte hypertrophy and its non-invasive MR-based characterization in human adipose tissue.

BACKGROUND: The adipocyte-hypertrophy associated remodeling of fat cell function is considered causal for the development of metabolic disorders. A better understanding of transcriptome and fatty acid (FA) related alterations with adipocyte hypertrophy combined with less-invasive strategies for the detection of the latter can help to increase the prognostic and diagnostic value of adipocyte size and FA composition as markers for metabolic disease. METHODS: To clarify adipocyte-hypertrophy associated transcriptomic alterations, fat cell size was related to RNA-Seq data from white adipose tissue and size-separated adipocytes. The relationship between adipocyte size and adipose tissue FA composition as measured by GC-MS was investigated. MR spectroscopy (MRS) methods for clinical scanning were developed to characterize adipocyte size and FA composition in a fast and non-invasive manner. FINDINGS: With enlarged adipocyte size, substantial transcriptomic alterations of genes involved in mitochondrial function and FA metabolism were observed. Investigations of these two mechanisms revealed a reciprocal relationship between adipocyte size and estimated thermogenic adipocyte content as well as depot-specific correlations of adipocyte size and FA composition. MRS on a clinical scanner was suitable for the in-parallel assessment of adipose morphology and FA composition. INTERPRETATION: The current study provides a comprehensive overview of the adipocyte-hypertrophy associated transcriptomic and FA landscape in both subcutaneous and visceral adipose tissue. MRS represents a promising technique to translate the observed mechanistic, structural and functional changes in WAT with adipocyte hypertrophy into a clinical context for an improved phenotyping of WAT in the context of metabolic diseases. FUNDING: Competence network for obesity (FKZ 42201GI1128), ERC (No 677661, ProFatMRI; No 875488, FatVirtualBiopsy), Else Kröner-Fresenius-Foundation.

A single-cell atlas of human and mouse white adipose tissue.

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo.

Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates Irx3 and Irx5 gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.

A MicroRNA Linking Human Positive Selection and Metabolic Disorders.

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.

Adherence to infliximab therapy in inflammatory bowel disease patients in a real-life setting.

OBJECTIVE: To assess adherence to infliximab (IFX) therapy in inflammatory bowel disease patients, to investigate reasons for non-adherence and to identify predictors for non-adherence. METHODS: This observational study was conducted in two French referral university hospitals between 1 September and 31 October, 2011. Patients were systematically asked if they had already delayed or missed an IFX perfusion since the beginning of the treatment and about the reasons for their non-adherence. RESULTS: Of the 162 included patients (121 Crohn's disease [CD], 41 ulcerative colitis), 87 (53.7%) reported a delay of at least one IFX injection and 14 (8.6%) missed at least one IFX perfusion since the beginning of the treatment. The overall non-adherence rate was 54.3%. Pooling all misses, the main reasons for non-adherence were pregnancy (33.3%), intentional non-adherence (20%) and forgetfulness (13.3%). Pooling all delays, the main reasons for non-adherence were professional constraints (46.9%), infections (17.3%) and travels (14.3%). Perineal disease was associated with IFX delays (P = 0.0007, odds ratio 4.0), whereas active CD/UC was associated with IFX misses (P = 0.0258, OR = 5.4). CONCLUSIONS: The overall non-adherence rate for IFX use was 54.3%. Professional constraints and intentional non-adherence were the leading causes of non-adherence. Perineal disease and active CD were negatively related to adherence.