Intraocular pressure (IOP) is an important clinical parameter in the evaluation of ocular health. Elevated IOP is a major risk factor for primary open-angle glaucoma (POAG). The goal of this study ...was to identify rare and less common variants that influence IOP.
We performed an exome array analysis in a subset of 1660 individuals from a population-based cohort, the Beaver Dam Eye Study. Associations with IOP were tested on 45,849 single nucleotide variants and 12,390 autosomal genes across the genome.
Intraocular pressure was suggestively associated with novel variants located in FAR2 at 12p11.22 (rs4931170, P = 1.2 × 10(-5)), in GGA3 at 17q25.1 (rs52809447, P = 6.7 × 10(-5)), and in PKDREJ at 22q13.31 (rs7291444, P = 7.4 × 10(-5)). Gene-based analysis found suggestive associations between IOP and the genes HAP1, MTBP, FREM3, and PHF12. We successfully replicated the associations with GAS7 (P = 7.4 × 10(-3)) for IOP, and also identified a previously reported POAG locus in the CAV1/CAV2 region to be associated with IOP (P = 3.3 × 10(-3)). This association was confirmed in a meta-analysis with three published genome-wide association studies (Pcombined = 4.0 × 10(-11)).
Our results suggest that novel genetic variants and genes with multiple, less common variants may play a role in the control of IOP. The implication of the caveolin genes, CAV1/CAV2, as a common genetic factor influencing both IOP variations and POAG may provide new insights of the underlying mechanism leading to glaucoma and glaucomatous visual field loss.
Summary
Whole blood cytokine release assays (CRA) assessing cellular immunity to gluten could simplify the diagnosis and monitoring of coeliac disease (CD). We aimed to determine the effectiveness of ...electrochemiluminescence CRA to detect responses to immunodominant gliadin peptides. HLA‐DQ2·5+ CD adults (cohort 1, n = 6; cohort 2, n = 12) and unaffected controls (cohort 3, n = 9) were enrolled. Cohort 1 had 3‐day gluten challenge (GC). Blood was collected at baseline, and for cohort 1 also at 3 h, 6 h and 6 days after commencing 3‐day GC. Gliadin peptide‐stimulated proliferation, interferon (IFN)‐γ enzyme‐linked immunospot (ELISPOT) and 14‐ and 3‐plex electrochemiluminescence CRA were performed. Poisson distribution analysis was used to estimate responding cell frequencies. In cohort 1, interleukin (IL)‐2 dominated the gliadin peptide‐stimulated cytokine release profile in whole blood. GC caused systemic IL‐2 release acutely and increased gliadin peptide‐stimulated IFN‐γ ELISPOT and whole blood CRA responses. Whole blood CRA after GC was dominated by IL‐2, but also included IFN‐γ, C‐X‐C motif chemokine ligand 10/IFN‐γ‐induced protein 10 (CXCL10/IP‐10), CXCL9/monokine induced by IFN‐γ (MIG), IL‐10, chemokine (C‐C motif) ligand 3/macrophage inflammatory protein 1‐alpha (CCL3/MIP‐1α), TNF‐α and IL‐8/CXCL8. In cohorts 2 and 3, gliadin peptide‐stimulated whole blood IL‐2 release was 100% specific and 92% sensitive for CD patients on a gluten‐free diet; the estimated frequency of cells in CD blood secreting IL‐2 to α‐gliadin peptide was 0·5 to 11 per ml. Whole blood IL‐2 release successfully mapped human leucocyte antigen (HLA)‐DQ2·5‐restricted epitopes in an α‐gliadin peptide library using CD blood before and after GC. Whole blood IL‐2 release assay using electrochemiluminescence is a sensitive test for rare gliadin‐specific T cells in CD, and could aid in monitoring and diagnosis. Larger studies and validation with tetramer‐based assays are warranted.
Detection of rare circulating gluten‐specific T cells may simplify the diagnosis of coeliac disease but current approaches using tetramers are technically demanding. Here we show that a highly sensitive cytokine release assay assessing gliadin peptide‐stimulated interleukin‐2 release in whole blood was 100% specific and 92% sensitive for patients with coeliac disease adhering to a gluten free diet. Whole blood interleukin‐2 release assay using electrochemiluminescence is a sensitive test for rare gluten‐specific T cells in coeliac disease, and could aid in disease monitoring and diagnosis.
Summary
Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early ...elevations in serum interleukin (IL)‐2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten‐mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free‐diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour; 187 cytokines were assessed. Confirmatory analyses were performed by high‐sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL‐2, chemokine (C‐C motif) ligand 20 (CCL20), IL‐6, chemokine (C‐X‐C motif) ligand (CXCL)9, CXCL8, interferon (IFN)‐γ, IL‐10, IL‐22, IL‐17A, tumour necrosis factor (TNF)‐α, CCL2 and amphiregulin. IL‐2 and IL‐17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL‐2 increased most (median 57‐fold), then CCL20 (median 10‐fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL‐2, IL‐17A, IL‐22 and IFN‐γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis.
Patients with coeliac disease develop acute digestive symptoms after consuming gluten. Coeliac disease and control volunteers consumed gluten, and serial serum cytokine assessments over 6 h defined a consistent cytokine profile that was temporally and quantitatively correlated with timing and severity of symptoms. Cytokine elevation after gluten in patients with coeliac disease were consistent with rapid activation of T cells and has the potential to guide therapeutics development and aid in diagnosis and immune monitoring.
Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ...ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 1.0 × 10
and 6.7 × 10
This now allows prioritization of the gene of interest for subsequent functional studies.
Colesevelam improves glycemic control in patients with type 2 diabetes when added to existing metformin-, sulfonylurea-, or insulin-based regimens. We evaluated colesevelam's effects in subjects on ...stable pioglitazone-based therapy. This 24-week multicenter, double-blind, randomized, placebo-controlled study enrolled adults with type 2 diabetes who had suboptimal glycemic control HbA1c ≥ 58 mmol/mol (7.5%) and ≤ 80 mmol/mol (9.5%) on pioglitazone (30 or 45 mg) with or without 1-2 other oral antidiabetes medications. Subjects were randomized to colesevelam 3.8 g/day (n = 280) or placebo (n = 282) added to existing pioglitazone-based therapy. Primary efficacy variable was mean change in HbA1c from baseline to Week 24. Secondary variables included safety and tolerability, fasting plasma glucose changes, glycemic responses, and lipid profile. Tertiary variables included lipid particle profile changes by nuclear magnetic resonance. Colesevelam decreased HbA1c least-squares mean treatment difference, - 3.5 mmol/mol (- 0.32%); p < 0.001 and fasting plasma glucose (- 14.7 mg/dl; p<0.001) vs. placebo at Week 24. More subjects receiving colesevelam vs. placebo achieved HbA1c reduction ≥ 7.7 mmol/mol (0.7%) (40% vs. 25%; p<0.001) or HbA1c < 53 mmol/mol (7.0%) (21% vs. 13%; p = 0.012). Colesevelam also decreased total cholesterol (mean treatment difference, - 6.5%), LDL-cholesterol (- 16.4%), non-HDL-cholesterol (- 9.8%), apolipoprotein B (- 8.8%), and total LDL particle concentration, and increased apolipoprotein A1 (+3.4%) and triglycerides (median treatment difference, + 11.3%) vs. placebo (all p < 0.001). There were no serious drug-related adverse events, and the majority of adverse events were mild or moderate. In subjects with type 2 diabetes inadequately controlled with pioglitazone-based therapy, add-on colesevelam therapy improved glycemic control and lipid parameters and was well tolerated. ClinicalTrials.gov identifier: NCT00789750.
Ocular refraction is measured in spherical equivalent as the power of the external lens required to focus images on the retina. Myopia (nearsightedness) and hyperopia (farsightedness) are the most ...common refractive errors, and the leading causes of visual impairment and blindness in the world. The goal of this study is to identify rare and low-frequency variants that influence spherical equivalent.
We conducted variant-level and gene-level quantitative trait association analyses for mean spherical equivalent, using data from 1,560 individuals in the Beaver Dam Eye Study. Genotyping was conducted using the Illumina exome array. We analyzed 34,976 single nucleotide variants and 11,571 autosomal genes across the genome, using single-variant tests as well as gene-based tests.
Spherical equivalent was significantly associated with five genes in gene-based analysis: PTCHD2 at 1p36.22 (p = 3.6 × 10(-7)), CRISP3 at 6p12.3 (p = 4.3 × 10(-6)), NAP1L4 at 11p15.5 (p = 3.6 × 10(-6)), FSCB at 14q21.2 (p = 1.5 × 10(-7)), and AP3B2 at 15q25.2 (p = 1.6 × 10(-7)). The variant-based tests identified evidence suggestive of association with two novel variants in linkage disequilibrium (pairwise r(2) = 0.80) in the TCTE1 gene region at 6p21.1 (rs2297336, minor allele frequency (MAF) = 14.1%, β = -0.62 p = 3.7 × 10(-6); rs324146, MAF = 16.9%, β = -0.55, p = 1.4 × 10(-5)). In addition to these novel findings, we successfully replicated a previously reported association with rs634990 near GJD2 at 15q14 (MAF = 47%, β = -0.29, p=1.8 × 10(-3)). We also found evidence of association with spherical equivalent on 2q37.1 in PRSS56 at rs1550094 (MAF = 31%, β = -0.33, p = 1.7 × 10(-3)), a region previously associated with myopia.
We identified several novel candidate genes that may play a role in the control of spherical equivalent. However, further studies are needed to replicate these findings. In addition, our results contribute to the increasing evidence that variation in the GJD2 and PRSS56 genes influence the development of refractive errors. Identifying that variation in these genes is associated with spherical equivalent may provide further insight into the etiology of myopia and consequent vision loss.
Central regulation of ejaculation Coolen, Lique M.; Allard, Julien; Truitt, William A. ...
Physiology & behavior,
11/2004, Volume:
83, Issue:
2
Journal Article
Peer reviewed
Ejaculation is a reflex mediated by a spinal control center, referred to as a spinal ejaculation generator. This spinal ejaculation generator coordinates sympathetic, parasympathetic and motor ...outflow to induce the two phases of ejaculation, i.e., emission and expulsion. In addition, the spinal ejaculation generator integrates this outflow with inputs that are related to the summation of sexual activity prior to ejaculation that are required to trigger ejaculation. Recently, a group of spinothalamic neurons in the lumbar spinal cord (LSt cells) were demonstrated to comprise an integral part of the spinal ejaculation generator. Specifically, lesions of LSt cells completely ablate ejaculatory function. Moreover, LSt cells are activated following ejaculation, but not following other components of sexual behavior. Furthermore, based on their relationship with autonomic nuclei, motoneurons and genital sensory inputs, LSt cells are also in the ideal anatomical position to integrate sensory inputs and autonomic and motor outflow. Additionally, the spinal ejaculation generator is under inhibitory and excitatory influence of supraspinal sites, including the nucleus paragigantocellularis (nPGi), the paraventricular nucleus of the hypothalamus (PVN) and the medial preoptic area (MPOA). Finally, sensory information related to ejaculation is processed in the spinal cord and brain, possibly contributing to the rewarding properties of ejaculation. One candidate pathway for relay of ejaculation-related cues consists of LSt cells and their projections to the parvocellular subparafascicular thalamic nucleus. Moreover, neural activation specifically related to ejaculation is observed in the brain and may reflect of processing of ejaculation-related sensory cues.
Purpose: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the ...optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data.
Methods: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status.
Results: No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10
-6
; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10
-5
). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10
-6
) and among never smokers (N = 790, p = 2.67 × 10
-6
).
Conclusions: This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.
Aims
To evaluate the efficacy and safety of rivoglitazone, a peroxisome proliferator‐activated receptor γ agonist in the thiazolidinedione class, in subjects with suboptimally controlled type 2 ...diabetes mellitus (T2DM).
Methods
Subjects aged ≥18 years with T2DM and haemoglobin A1c (HbA1c) >7.0% and ≤8.5%, who were treatment naïve or receiving a non‐thiazolidinedione antidiabetes monotherapy, entered a 2‐week washout and single‐blind placebo run‐in period and were then randomized 2 : 4 : 11 : 11 to double‐blind treatment with placebo, rivoglitazone 1.0 mg/day, rivoglitazone 1.5 mg/day, or pioglitazone 45 mg/day, for 26 weeks.
Results
A total of 1912 subjects received placebo (n = 137), rivoglitazone 1.0 mg (n = 274), rivoglitazone 1.5 mg (n = 750) or pioglitazone (n = 751). Rivoglitazone 1.5 mg was statistically superior (p = 0.0339) and rivoglitazone 1.0 mg was non‐inferior (p = 0.0339) to pioglitazone in reducing HbA1c from baseline (changes of −0.7%, −0.4% and −0.6%, respectively). Rivoglitazone also significantly reduced fasting plasma glucose from baseline (p < 0.0001). Rivoglitazone significantly improved estimates of insulin sensitivity, high‐density lipoprotein cholesterol levels, and other metabolic and inflammatory biomarkers. Rivoglitazone was generally well tolerated at both doses, with treatment‐emergent adverse event (TEAE) rates similar to pioglitazone. The most common drug‐related TEAEs were peripheral oedema (active, 5.2–6.2%; placebo 0.7%), increased weight (active, 1.6–3.1%; placebo, 0%) and pitting oedema (active, 1.3–2.2%; placebo, 0%).
Conclusions
In subjects with suboptimally controlled T2DM, rivoglitazone 1.5 mg was associated with statistically superior glycaemic control to pioglitazone 45 mg, while rivoglitazone 1.0 mg was non‐inferior; the safety profiles of the two drugs appeared similar.
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