Measures of insulin sensitivity, leptin, and adiponectin concentrations in cats in diabetic remission compared to healthy control cats

Objectives: Firstly, to compare differences in insulin, adiponectin, leptin, and measures of insulin sensitivity between diabetic cats in remission and healthy control cats, and determine whether these are predictors of diabetic relapse. Secondly, to determine if these hormones are associated with serum metabolites known to differ between groups. Thirdly, if any of the hormonal or identified metabolites are associated with measures of insulin sensitivity. Animals: Twenty cats in diabetic remission for a median of 101 days, and 21 healthy matched control cats. Methods: A casual blood glucose measured on admission to the clinic. Following a 24 h fast, a fasted blood glucose was measured, and blood sample taken for hormone (i.e., insulin, leptin, and adiponectin) and untargeted metabolomic (GC-MS and LC-MS) analysis. A simplified IVGGT (1 g glucose/kg) was performed 3 h later. Cats were monitored for diabetes relapse for at least 9 months (270 days). Results: Cats in diabetic remission had significantly higher serum glucose and insulin concentrations, and decreased insulin sensitivity as indicated by an increase in HOMA and decrease in QUICKI and Bennett indices. Leptin was significantly increased, but there was no difference in adiponectin (or body condition score). Several significant correlations were found between insulin sensitivity indices, leptin, and serum metabolites identified as significantly different between remission and control cats. No metabolites were significantly correlated with adiponectin. No predictors of relapse were identified in this study. Conclusion and clinical importance: Insulin resistance, an underlying factor in diabetic cats, persists in diabetic remission. Cats in remission should be managed to avoid further exacerbating insulin resistance

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with kno

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs ofMMin 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better captureMMrisk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA

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

Reference values for glucose tolerance and glucose tolerance status in cats

To determine the reference range for glucose tolerance, using a simplified glucose tolerance test (GTT), and to evaluate glucose tolerance status in cats.Prospective study.57 clinically normal cats.2 catheters were placed in the cephalic veins of nonsedated cats at least 3 hours before the test. Blood samples were obtained before (0 minutes) and 2, 5, 10, 15, 30, 45, 60, 90, and 120 minutes after glucose (0.5 g/kg [0.23 g/lb] of body weight) was injected i.v. Blood glucose concentration was measured by a glucose meter. Glucose half-life (t1/2) and disappearance of glucose (Kglucose) were calculated.Glucose tolerance in cats was considered normal when upper limits for glucose concentration were or = 0.41%/min. Impaired glucose tolerance in cats was defined as a glucose concentration > or = 160 mg/dl at 0 minutes, > or = 323 mg/dl at 60 minutes, > or = 239 mg/dl at 90 minutes, or > or = 172 mg/dl at 120 minutes. The frequency of impaired glucose tolerance was 2%. Five cats had stress-affected GTT. Significant differences in glucose t1/2 or Kglucose between cats or = 7 years old were not found.The simplified GTT and measurement of glucose concentration by a glucose meter provides a simple and low-cost method of assessing glucose tolerance status in cats that are normoglycemic after food is withheld. Use of absolute glucose concentrations overcomes the need to calculate glucose t1/2 values. The high glucose concentration at 0 minutes found in this study may reflect a more realistic concentration to use in assessing client-owned cats in a hospital environment