👤 Harald Staiger

The bovine digital cushion is a compression pad between the distal phalanx and sole and has been associated with claw horn disruption lesions. Digital cushion thickness (DCT) is estimated to be moderately heritable. Therefore, the objectives of our study were to examine influences of management and environment on DCT and to identify genetic markers and candidate genes associated with DCT. In a cohort of 502 Holsteins from 5 farms in New York State, DCT and body condition score (BCS) were collected twice, at <137 d prepartum and from 86 to 127 d in milk, corresponding to periods when the digital cushion is thickest and thinnest, respectively, as determined by previous research. Cows underwent sonographic examination of the digital cushion evaluated at the typical sole ulcer site for the right front and hind foot. Linear mixed models were conducted on DCT with the fixed effects of time point, digit, wither height, sacral height, BCS group, and multiple farm system variables separately and included random effects to control for the random subset of cows per farm, repeated measures, and multiple measurements from each cow. The phenotypic results indicated that DCT varied by sample time point, sacral height, parity, digit, BCS group, and wither height. For the genotypic study, 447 DNA samples were genotyped on the Illumina BovineHD 777K BeadChip (Illumina Inc., San Diego, CA). Quality assessment of markers and samples provided a final data set of 431 samples and 579,449 markers. Genome-wide association studies were conducted for DCT testing inheritance models and genetic variation of digit, foot, time point, and average thickness. One marker passed the Bonferroni correction threshold and 26 passed false discovery rate from 4 genome-wide association studies with covariates of sequencing batch plate, parity group, BCS, wither height, and sacral height. Ten candidate genes were identified, with 2 genes on Bos taurus autosomes 24 and 29 involved in biological functions related to the digital cushion: MC4R and DLG2 were related to fat deposition and bone growth, respectively. The genetic markers discovered in this study have the opportunity to be used in breeding programs using genomic selection to select against claw horn disruption lesions and lameness due to associations between the markers and DCT. Further studies on the biologically plausible candidate genes may identify causative genetic variants and how they relate to DCT through gene regulation, expression, structure, or copy number variation. Show less

Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism. In this cross-sectional study 1782 non-diabetic volunteers at increased risk for type 2 diabetes underwent an oral glucose tolerance test. Insulin, C-peptide and proinsulin were measured and genotyping was performed for 12 single nucleotide polymorphisms (SNP) in or near the genes GCK (rs4607517), DGKB (rs2191349), GCKR (rs780094), ADCY5 (rs11708067), MADD (rs7944584), ADRA2A (rs10885122), FADS1 (rs174550), CRY2 (rs11605924), SLC2A2 (rs11920090), PROX1 (rs340874), GLIS3 (rs7034200) and C2CD4B (rs11071657). Parameters of insulin secretion (AUC Insulin(0-30)/AUC Glucose(0-30), AUC C-peptide(0-120)/AUC Glucose(0-120)), proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin(0-120)/AUCInsulin(0-120)) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed. After adjustment for confounding variables, the effect alleles of the ADCY5 and MADD SNPs were associated with an impaired proinsulin-to-insulin conversion (p = 0.002 and p = 0.0001, respectively). GLIS3 was nominally associated with impaired proinsulin-to-insulin conversion and insulin secretion. The diabetogenic alleles of DGKB and PROX1 were nominally associated with reduced insulin secretion. Nominally significant effects on insulin sensitivity could be found for MADD and PROX1. By examining parameters of glucose-stimulated proinsulin-to-insulin conversion during an OGTT, we show that the SNP in ADCY5 is implicated in defective proinsulin-to-insulin conversion. In addition, we confirmed previous findings on the role of a genetic variant in MADD on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome. Show less

The liver X receptors (LXRs)-α and -β play a crucial role in control of insulin production and secretion in pancreatic β-cells. We hypothesized that common variants in the NR1H2 and NR1H3 genes, encoding LXR-β and -α, respectively, may alter pancreatic β-cell function. One thousand five hundred seventy-four subjects of European ancestry with elevated risk for type 2 diabetes were genotyped for the two NR1H2 single nucleotide polymorphisms (SNPs) rs2248949 and rs1405655 and for the four NR1H3 SNPs rs11039149, rs3758673, rs12221497 and rs2279238, and association studies with metabolic traits were performed. Metabolic characterization comprised an oral glucose tolerance test (OGTT) in all participants and, in addition, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test (IVGTT) in subsets. One hundred per cent of common genetic variation (minor allele frequency ≥1%) within the NR1H2 and NR1H3 loci (D' = 1.0; r² ≥ 0.8) were covered by the six chosen tagging SNPs. NR1H2 rs2248949 was nominally associated with OGTT-derived first-phase insulin secretion and proinsulin conversion to insulin and significantly associated with the AUC of insulin levels during the IVGTT (p = 0.007) after adjustment for age, gender, BMI and insulin sensitivity in the dominant model, with the minor allele conferring reduced pancreatic β-cell function to the carriers. In subjects of European ancestry at increased risk for type 2 diabetes, common variation within the NR1H2 gene impaired insulin secretion, which may facilitate the development of type 2 diabetes. Show less