Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Evaluation of an HMGA2 variant contribution to height and basal insulin concentrations in ponies

Background: The HMGA2:c.83G>A variant was identified in Welsh ponies having pleiotropic effects on height and insulin concentration. Objective: Determine whether the HMGA2:c.83G>A variant is associated with decreased height and higher basal insulin concentrations across pony breeds. Animals: Two hundred thirty-six ponies across 6 breeds. Methods: Cross-sectional study. Ponies were genotyped for the HMGA2:c.83G>A variant and phenotyped for height and basal insulin concentrations. Stepwise regression was performed for model analysis using a linear regression model for height and mixed linear model for insulin with farm as a random effect. Coefficient of determination, pairwise comparison of the estimated marginal means and partial correlation coefficients (parcor) were calculated to assess the relationship between HMGA2 genotype and height or insulin. Results: Breed and genotype accounted for 90.5% of the variation in height across breeds, and genotype explained 21% to 44% of the variation within breeds. Breed, genotype, cresty neck score, sex, age, and farm accounted for 45.5% of the variation in insulin, with genotype accounting for 7.1%. The HMGA2 A allele frequency was 62% and correlated with both height (parcor = −0.39; P 10 cm shorter than other genotypes. Compared with G/G individuals, A/A and G/A individuals had 4.3 μIU/mL (95% confidence interval [CI]: 1.8-10.5) and 2.7 μIU/mL (95% CI: 1.4-5.3) higher basal insulin concentrations, respectively. Conclusions and Clinical Importance: These data demonstrate the pleiotropic effects of the HMGA2:c.83G>A variant and its role in identifying ponies at increased risk for insulin dysregulation. © 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Epidemiological investigation of insulin dysregulation in Shetland and Welsh ponies in Australia

Background: Insulin dysregulation (ID) is central to equine metabolic syndrome. There are limited epidemiological studies investigating dynamic testing of ID in ponies. Objectives: To evaluate prevalence and risk factors for ID through dynamic testing of hyperinsulinaemia (DHI) and insulin resistance (IR). Study design: Cross-sectional. Methods: Sex, age, breed, height, cresty neck score (CNS), body condition score (BCS), laminitis, HMGA2:c.83G>A genotype and pituitary pars intermedia dysfunction (PPID) status were documented. Dynamic hyperinsulinaemia was diagnosed with an oral sugar test (OST) and IR with an insulin tolerance test (ITT). Owners completed surveys reporting activity, laminitis history and perception of body condition using a (1–9) visual analogue scale (VASo). Ordinal scores were converted to binary outcomes for CNS (≤2/5 or ≥3/5), BCS and VASo (≤6/9 or ≥7/9). Variables associated with insulin concentrations, glucose reduction after the ITT and laminitis were evaluated with mixed effects regression models accounting for random effects of farms. Results: Among 167 ponies tested, median (range) age was 9 (4–21) years and BCS was 6 (4–8). Prevalence (95% confidence interval [CI]) of ID was 61 (53–68)%. Factors associated with insulin concentrations (estimate [95% CI]; μIU/mL) 60 min post-OST were: age (1.07 [1.02–1.11]), CNS (≥3/5, 1.52 [1.04–2.23]) and VASo (≥7/9, 1.75 [1.09–2.79]); and 90 min post-OST were: age (1.08 [1.03–1.12]), CNS (≥3/5, 1.80 [1.22–2.64]), VASo (≥7/9, 2.49 [1.52–4.08]) and sex (male, 0.64 [0.45–0.91]). Factors associated with glucose reduction after the ITT (estimate [95% CI]; %) were: age (−1.34 [−2.01 to −0.67]), sex (female, −6.21 [−11.68 to −0.74]) and VASo (≥7/9, −1.74 [−18.89 to −4.78]). Factors associated with laminitis (odds ratio [95% CI]) were DHI (4.60 [1.68–12.58]), IR (3.66 [1.26–10.61]) and PPID (11.75 [1.54–89.40]). Main limitations: Single time-point sampling, laminitis definition and diet analysis. Conclusions: Ageing, being female and owner-perceived obesity were associated with ID. © 2024 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]