A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease

Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome

Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For this reason, we tested the hypothesis that natural autoantibodies (aAb) to the follicle-stimulating hormone receptor (FSHR) or luteinizing hormone receptor (LHR) are prevalent in PCOS. To this end, new luminometric assays for quantifying aAb to the FSHR (FSHR-aAb) or LHR (LHR-aAb) were developed using full-length recombinant human receptors as fusion proteins with luciferase as reporter. Prevalence of FSHR-aAb and LHR-aAb was determined in serum samples from healthy controls and PCOS patients. Steroid hormone profiles were compared between patients with and without FSHR-aAb or LHR-aAb. Signal linearity and detection ranges were characterized and both methods passed basic performance quality checks. The analysis revealed a relatively low prevalence, with 4 out of 430 samples positive for FSHR-aAb in the control versus 11 out of 550 samples in the PCOS group, i.e., 0.9% versus 2.0%, respectively. Similarly, there were only 5 samples positive for LHR-aAb in the control versus 2 samples in the PCOS group, i.e., 1.2% versus 0.4%, respectively. Samples positive for FSHR-aAb displayed steroid hormones in the typical range of PCOS patients, whereas the two samples positive for LHR-aAb showed relatively elevated free testosterone in relation to total testosterone concentrations with unclear significance. We conclude that the FSHR and LHR constitute potential autoantigens in human subjects. However, the prevalence of specific autoantibodies to these receptors is relatively low, both in control subjects and in women with PCOS. It is therefore unlikely that autoimmunity to the LHR or FSHR constitutes a frequent cause of hyperandrogenemia or ovulatory dysfunction in PCOS

Dp-ucMGP as a Biomarker in Sarcopenia

Sarcopenia is linked with an increased risk of falls, osteoporosis and mortality and is an increasing problem for healthcare systems. No satisfying biomarkers for sarcopenia diagnosis exist, connecting bone, fat and muscle. Matrix-GLA-protein (MGP) is an adipokine that regulates bone metabolism and is associated with decreased muscle strength. Associations of dp-ucMGP were analyzed in the BioPersMed cohort (58 ± 9 years), including 1022 asymptomatic subjects at moderate cardiovascular risk. Serum measurements of dp-ucMGP in 760 persons were performed with the InaKtif MGP Kit with the IDS-iSYS Multi-Discipline Automated System. DXA data (792 persons) measured with the Lunar iDXA system and physical performance data (786 persons) were available. Dp-ucMGP plasma levels correlate with sarcopenia parameters like gait speed (ρ = −0.192, p < 0.001), appendicular skeletal muscle mass (ρ = 0.102, p = 0.005) and appendicular skeletal muscle mass index (ρ = 0.112, p = 0.001). They are lower in persons with sarcopenia (p < 0.001) and higher in persons with reduced physical performance (p = 0.019). Persons in the lowest dp-ucMGP quartile have the highest risk for reduced muscle mass, decreasing with each quartile, whereas persons in the highest quartile have the highest risk of reduced muscle strength. Dp-ucMGP might be a good biomarker candidate in sarcopenia characterization

DXA-Derived Indices in the Characterisation of Sarcopenia

Sarcopenia is linked with increased risk of falls, osteoporosis and mortality. No consensus exists about a gold standard “dual-energy X-ray absorptiometry (DXA) index for muscle mass determination” in sarcopenia diagnosis. Thus, many indices exist, but data on sarcopenia diagnosis agreement are scarce. Regarding sarcopenia diagnosis reliability, the impact of influencing factors on sarcopenia prevalence, diagnosis agreement and reliability are almost completely missing. For nine DXA-derived muscle mass indices, we aimed to evaluate sarcopenia prevalence, diagnosis agreement and diagnosis reliability, and investigate the effects of underlying parameters, presence or type of adjustment and cut-off values on all three outcomes. The indices were analysed in the BioPersMed cohort (58 ± 9 years), including 1022 asymptomatic subjects at moderate cardiovascular risk. DXA data from 792 baselines and 684 follow-up measurements (for diagnosis agreement and reliability determination) were available. Depending on the index and cut-off values, sarcopenia prevalence varied from 0.6 to 36.3%. Height-adjusted parameters, independent of underlying parameters, showed a relatively high level of diagnosis agreement, whereas unadjusted and adjusted indices showed low diagnosis agreement. The adjustment type defines which individuals are recognised as sarcopenic in terms of BMI and sex. The investigated indices showed comparable diagnosis reliability in follow-up examination

Urinary <i>C-</i>Peptide to Creatinine Ratio (UCPCR) as Indicator for Metabolic Risk in Apparently Healthy Adults—A BioPersMed Cohort Study

Background: C-peptide is produced in equimolar amounts with insulin from pancreatic beta cells, and thus is a fundamental biomarker for beta cell function. A non-invasive urinary C-peptide-to-creatinine ratio (UCPCR) has attracted attention as a biomarker for metabolic conditions. However, the UCPCR as an indicative risk predictor for prediabetes is still being investigated. Methods: We aimed to characterize UCPCRs in healthy people using American Diabetes Association (ADA) criteria and to evaluate their metabolic outcomes over time. A total of 1022 participants of the Biomarkers in Personalized Medicine cohort (BioPersMed) were screened for this study. Totals of 317 healthy with normal glucose metabolism, 87 prediabetic, and 43 diabetic subjects were included. Results: Prediabetic participants had a significantly higher UCPCR median value than healthy participants (p p p Conclusion: UCPCR measurements provide an indicative approach for metabolic risk, representing a potential use for prevention and monitoring of impaired glucose metabolism

Expression Profiles of miR-22-5p and miR-142-3p Indicate Hashimoto&rsquo;s Disease and Are related to Thyroid Antibodies

Hashimoto&rsquo;s thyroiditis (HT) is the most prevalent autoimmune disorder of the thyroid (AITD) and characterized by the presence of circulating autoantibodies evoked by a, to date, not fully understood dysregulation of the immune system. Autoreactive lymphocytes and inflammatory processes in the thyroid gland can impair or enhance thyroid hormone secretion. MicroRNAs (miRNAs) are small noncoding RNAs, which can play a pivotal role in immune functions and the development of autoimmunity. The aim of the present study was to evaluate whether the expression of 9 selected miRNAs related to immunological functions differ in patients with HT compared to healthy controls. MiRNA profiles were analysed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 24 patients with HT and 17 healthy controls. Systemic expressions of miR-21-5p, miR-22-3p, miR-22-5p, miR-142-3p, miR-146a-5p, miR-301-3p and miR-451 were significantly upregulated in patients with HT (p &le; 0.01) and were suitable to discriminate between HT and healthy controls in AUC analysis. Altered expressions of miR-22-5p and miR-142-3p were associated with higher levels of thyroid antibodies, suggesting their contribution to the pathogenesis of HT

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease