Abnormal composition and function of high-density lipoproteins in atopic dermatitis patients.
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ABSTRACT:
SUBMITTER: Trieb M
PROVIDER: S-EPMC6491993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
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Project description:BackgroundStructural abnormalities in the brain of patients with atopic dermatitis (AD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of AD on brain structure.MethodsThis study utilized summary statistics from genome-wide association studies (GWASs) to investigate a collection of cerebral structural measures, encompassing cortical thickness (CT), cortical surface area (CA), and subcortical volumes in T1 images. A comprehensive GWAS meta-analysis identified a total of 20 independent single nucleotide polymorphisms linked to AD, surpassing the genome-wide significance threshold (p < 5 × 10⁻⁸). MR estimates were aggregated through the application of the inverse variance weighted method. Additional complementary analyses (i.e., MR-Egger and weighted median approaches) were conducted to further assess the robustness of the obtained results. Sensitivity analysis and multivariate MR (MVMR) while adjusting for brain structural changes risk factors (i.e., depression and anxiety) were performed to assess the reliability and stability of observed causality.ResultsGenetically determined AD exhibited a causal link with reduced caudate volumes (IVW-MR: β = -0.186, p = 0.001, p-corrected = 0.009). Furthermore, we identified potential causal associations between AD and reduced CT in the cingulate region (posterior cingulate, IVW-MR: β = -0.065, p = 0.018, p-corrected = 0.551; isthmus cingulate, IVW-MR: β = -0.086, p = 0.003, p-corrected = 0.188), as well as abnormal cortical surface area (CA) in the supramarginal (IVW-MR: β = -0.047, p = 0.044, p-corrected = 0.714) and isthmus cingulate (IVW-MR: β = 0.053, p = 0.018, p-corrected = 0.714). Additional supplementary analyses yielded consistent outcomes. There was no evidence of horizontal pleiotropy. MVMR analysis showed that the causal effects of AD on abnormal brain structure remained significant while adjusting for depression and anxiety.ConclusionThis MR study provided suggestive evidence that decreased caudate nucleus, posterior cingulate cortex, isthmus cingulate cortex and supramarginal gyrus are suggestively associated with higher AD risk. Future investigation into the brain regions is recommended, which helps to clarify the underlying mechanisms and point to new therapies against AD.
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2014-02-27 | GSE53314 | GEO
Project description:ObjectiveDamage to the vascular endothelium is strongly implicated in the pathogenesis of idiopathic inflammatory myopathies (IIM). Normally, high-density lipoprotein (HDL) protects the vascular endothelium from damage from oxidized phospholipids, which accumulate under conditions of oxidative stress. The current work evaluated the antioxidant function of HDL in IIM patients.MethodsHDL's antioxidant function was measured in IIM patients using a cell-free assay, which assesses the ability of isolated patient HDL to inhibit oxidation of low-density lipoproteins and is reported as the HDL inflammatory index (HII). Cholesterol profiles were measured for all patients, and subgroup analysis included assessment of oxidized fatty acids in HDL and plasma MPO activity. A subgroup of IIM patients was compared with healthy controls.ResultsThe antioxidant function of HDL was significantly worse in patients with IIM (n = 95) compared with healthy controls (n = 41) [mean (S.d.) HII 1.12 (0.61) vs 0.82 (0.13), P < 0.0001]. Higher HII associated with higher plasma MPO activity [mean (S.d.) 13.2 (9.1) vs 9.1 (4.6), P = 0.0006] and higher oxidized fatty acids in HDL. Higher 5-hydroxyeicosatetraenoic acid in HDL correlated with worse diffusion capacity in patients with interstitial lung disease (r = -0.58, P = 0.02), and HDL's antioxidant function was most impaired in patients with autoantibodies against melanoma differentiation-associated protein 5 (MDA5) or anti-synthetase antibodies. In multivariate analysis including 182 IIM patients, higher HII was associated with higher disease activity and DM diagnosis.ConclusionThe antioxidant function of HDL is abnormal in IIM patients and may warrant further investigation for its role in propagating microvascular inflammation and damage in this patient population.
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