Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

Funder: All funders per study are acknowledged in the Supplementary FileA new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Concurrent Milk Ingestion Decreases Absorption of Levothyroxine

BACKGROUND:Levothyroxine is the most commonly prescribed medication in the United States. Many foods and medications, including calcium supplements, can interfere with levothyroxine absorption. No studies have investigated the effect of cow's milk, a common breakfast staple, on the absorption of oral levothyroxine. Cow's milk contains approximately 450 mg of elemental calcium per 12 oz (355 mL) serving. METHODS:A pharmacokinetic study was conducted in healthy euthyroid subjects to assess levothyroxine absorption with and without concurrent cow's milk consumption. Following an overnight fast, serum total thyroxine (TT4) concentrations were measured at baseline and at one, two, four, and six hours after ingestion of 1000 μg of oral levothyroxine alone or when co-administered with 12 oz (355 mL) of 2% milk. There was a four-week washout period between the two assessments in each subject. RESULTS:Ten subjects (Mage ± SD = 33.7 ± 10.2 years; 60% male) completed the study. The area under the curve (AUC) of TT4 concentrations was significantly lower when levothyroxine was ingested along with 12 oz (355 mL) of 2% cow's milk (M ± SD = 67.3 ± 12.1) compared to that with levothyroxine alone (73.5 ± 17.0; p = 0.02). Also, peak serum TT4 concentrations were significantly lower when cow's milk was co-administered with levothyroxine (M ± SD = 14.1 ± 0.8 μg/dL) than with levothyroxine alone (13.0 ± 0.9 μg/dL; p = 0.04). CONCLUSIONS:This is the first study to demonstrate that concurrent cow's milk ingestion reduces oral levothyroxine absorption. The findings support previous literature showing the interference of elemental calcium and food with thyroid hormone absorption. Patients managed with thyroid hormone should be advised to avoid taking their levothyroxine simultaneously with cow's milk

Association of fasting insulin and C peptide with diabetic retinopathy in Latinos with type 2 diabetes.

ObjectiveResidual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested in type 2 diabetes whether markers of residual beta-cell function are associated with the development of diabetic retinopathy, an important microvascular complication of diabetes.DesignProspective, cross-sectional, family-based study.Participants585 Latino type 2 diabetic participants, ascertained in families via a proband either with known diabetes duration of greater than 10 years and/or with diabetic retinopathy.Outcome measuresCIRCULATING LEVELS OF FASTING INSULIN AND C PEPTIDE MEASURED AND CORRELATED TO DEGREE OF DIABETIC RETINOPATHY, ASSESSED BY DIGITAL FUNDUS PHOTOGRAPHY AND GRADED USING THE MODIFIED AIRLIE HOUSE CLASSIFICATION AND THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY SCALE (RANGE: levels 10-85).ResultsFasting plasma insulin (β=-0.29; 95% CI -0.38 to -0.20; p<0.0001) and C peptide (β=-0.21; 95% CI -0.30 to -0.13; p<0.0001) concentrations in these diabetic participants were significantly correlated with retinopathy and its degree of severity. This relationship remained significant after adjusting for potential covariates including age, gender, glycosylated hemoglobin, duration of diabetes, blood pressure, and renal function.ConclusionsThese data suggest that residual endogenous insulin secretion is associated with the presence of diabetic retinopathy and its severity in Latinos with familial type 2 diabetes. It remains to be proven whether beta-cell targeted therapies, to maintain beta-cell mass and/or function in addition to glycemic control, will further the goal of preventing diabetic microvascular disease

Association of fasting insulin and C peptide with diabetic retinopathy in Latinos with type 2 diabetes.

ObjectiveResidual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested in type 2 diabetes whether markers of residual beta-cell function are associated with the development of diabetic retinopathy, an important microvascular complication of diabetes.DesignProspective, cross-sectional, family-based study.Participants585 Latino type 2 diabetic participants, ascertained in families via a proband either with known diabetes duration of greater than 10 years and/or with diabetic retinopathy.Outcome measuresCIRCULATING LEVELS OF FASTING INSULIN AND C PEPTIDE MEASURED AND CORRELATED TO DEGREE OF DIABETIC RETINOPATHY, ASSESSED BY DIGITAL FUNDUS PHOTOGRAPHY AND GRADED USING THE MODIFIED AIRLIE HOUSE CLASSIFICATION AND THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY SCALE (RANGE: levels 10-85).ResultsFasting plasma insulin (β=-0.29; 95% CI -0.38 to -0.20; p<0.0001) and C peptide (β=-0.21; 95% CI -0.30 to -0.13; p<0.0001) concentrations in these diabetic participants were significantly correlated with retinopathy and its degree of severity. This relationship remained significant after adjusting for potential covariates including age, gender, glycosylated hemoglobin, duration of diabetes, blood pressure, and renal function.ConclusionsThese data suggest that residual endogenous insulin secretion is associated with the presence of diabetic retinopathy and its severity in Latinos with familial type 2 diabetes. It remains to be proven whether beta-cell targeted therapies, to maintain beta-cell mass and/or function in addition to glycemic control, will further the goal of preventing diabetic microvascular disease

Implementation findings from a hybrid III implementation-effectiveness trial of the Diabetes Prevention Program (DPP) in the Veterans Health Administration (VHA).

BackgroundThe Diabetes Prevention Program (DPP) is an effective lifestyle intervention to reduce incidence of type 2 diabetes. However, there are gaps in knowledge about how to implement DPP. The aim of this study was to evaluate implementation of DPP via assessment of a clinical demonstration in the Veterans Health Administration (VHA).MethodsA 12-month pragmatic clinical trial compared weight outcomes between the Veterans Affairs Diabetes Prevention Program (VA-DPP) and the usual care MOVE!® weight management program (MOVE!). Eligible participants had a body mass index (BMI) ≥30 kg/m2 (or BMI ≥ 25 kg/m2 with one obesity-related condition), prediabetes (glycosylated hemoglobin (HbA1c) 5.7-6.5% or fasting plasma glucose (FPG) 100-125 mg/dL), lived within 60 min of their VA site, and had not participated in a weight management program within the last year. Established evaluation and implementation frameworks were used to guide the implementation evaluation. Implementation barriers and facilitators, delivery fidelity, participant satisfaction, and implementation costs were assessed. Using micro-costing methods, costs for assessment of eligibility and scheduling and maintaining adherence per participant, as well as cost of delivery per session, were also assessed.ResultsSeveral barriers and facilitators to Reach, Adoption, Implementation, Effectiveness and Maintenance were identified; barriers related to Reach were the largest challenge encountered by site teams. Fidelity was higher for VA-DPP delivery compared to MOVE! for five of seven domains assessed. Participant satisfaction was high in both programs, but higher in VA-DPP for most items. Based on micro-costing methods, cost of assessment for eligibility was $68/individual assessed, cost of scheduling and maintaining adherence was$328/participant, and cost of delivery was $101/session.ConclusionsMulti-faceted strategies are needed to reach targeted participants and successfully implement DPP. Costs for assessing patients for eligibility need to be carefully considered while still maximizing reach to the targeted population