Tove Fall

Publications of Tove Fall

• Evaluation of circulating concentrations of glucose homeostasis biomarkers, progesterone, and growth hormone in healthy Elkhounds during anestrus and diestrus.

  Authors: Malin Mared, Brian Catchpole, Olle Kämpe, Tove Fall

  American journal of veterinary research. 02/2012; 73(2):242-7.

  To investigate whether circulating concentrations of biomarkers of glucose homeostasis, progesterone, and growth hormone in healthy female Elkhounds differ during diestrus and anestrus and to compareTo investigate whether circulating concentrations of biomarkers of glucose homeostasis, progesterone, and growth hormone in healthy female Elkhounds differ during diestrus and anestrus and to compare those findings with data from dogs of other breeds. 22 healthy female dogs of Elkhound breeds (known to have a high incidence of diestrus-associated diabetes mellitus) and 18 healthy female non-Elkhound dogs. For each dog, a blood sample (12 mL) was collected once during anestrus and once 2 to 8 weeks after cessation of estrual bleeding. Serum or whole blood samples were analyzed for glucose, growth hormone, insulin-like growth factor-1, C-peptide, fructosamine, and glycated hemoglobin A1c concentrations. Homeostasis model assessments (HOMAs) of pancreatic beta-cell function and insulin secretion were calculated. In Elkhounds, C-peptide concentration and the HOMA for beta-cell function (markers of insulin secretion) were higher in samples obtained during diestrus, compared with findings in samples obtained during anestrus. The HOMA for insulin sensitivity was lower (albeit not significantly) during diestrus than it was during anestrus in Elkhounds. Markers of insulin secretion and sensitivity were similar during anestrus and diestrus in the dogs of other breeds. Serum progesterone concentrations were greater during diestrus than during anestrus in Elkhounds and non-Elkhound dogs. All other variables did not differ between diestrus and anestrus within or between the 2 breed groupings. Results provided evidence that circulating insulin concentrations during diestrus are higher than those during anestrus in Elkhounds, which could contribute to development of diestrus-associated diabetes mellitus.

• Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

  Authors: Amaury Vaysse, Abhirami Ratnakumar, Thomas Derrien, Erik Axelsson, Gerli Rosengren Pielberg, Snaevar Sigurdsson, Tove Fall, Eija H Seppälä, Mark S T Hansen, Cindy T Lawley [......] Carles Vilà, Hannes Lohi, Francis Galibert, Merete Fredholm, Jens Häggström, Ake Hedhammar, Catherine André, Kerstin Lindblad-Toh, Christophe Hitte, Matthew T Webster

  PLoS genetics. 10/2011; 7(10):e1002316.

  The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysisThe extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

• Validation of a species-optimized enzyme-linked immunosorbent assay for determination of serum concentrations of insulin in dogs.

  Authors: Josefine Oberg, Tove Fall, Inger Lilliehöök

  Veterinary clinical pathology / American Society for Veterinary Clinical Pathology. 02/2011; 40(1):66-73.

  Measurement of canine serum insulin has relied on methods developed to measure human insulin. A species-optimized test for measurement of serum insulin in dogs is now commercially available. TheMeasurement of canine serum insulin has relied on methods developed to measure human insulin. A species-optimized test for measurement of serum insulin in dogs is now commercially available. The purpose of this study was to validate the canine ELISA for determination of serum insulin concentration in dogs. Precision was determined by evaluating intra- and interassay coefficient of variation (CV), and accuracy was determined by dilution and spike recovery studies. A method comparison study with samples from 34 clinically healthy dogs and 73 dogs examined for various illnesses and disorders ("patients") was performed using the canine ELISA and an ELISA for human insulin. Biologic relevance of the canine assay was evaluated by measuring insulin in samples collected from 8 healthy dogs after administration of glucagon. A stability study was preformed with 6 samples stored at 20°C, 4-8°C, and -20°C. For the canine ELISA, intra- and interassay CVs were 4.3-7.8% and 4.4-7.7%, respectively. Mean recovery after dilution was 99% and recovery after spiking with porcine insulin was 116%. The canine and human ELISAs correlated well (r(2) =.94 for healthy dogs, r(2) =.88 for patient samples). After glucagon injection serum insulin concentrations increased significantly in 8 dogs. Insulin was stable for 30 days in 6 serum samples stored at -20°C and in most samples for 8 days at 4-8°C. Insulin was stable for <3 days at room temperature (20°C). The new canine serum insulin ELISA had good precision and accuracy and correlated well with the previously used assay.

• Mammary Tumor Development in Dogs Is Associated with BRCA1 and BRCA2.

  Authors: Patricio Rivera, Malin Melin, Tara Biagi, Tove Fall, Jens Häggström, Kerstin Lindblad-Toh, Henrik von Euler

  Cancer research. 11/2009;

  Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown.Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer. [Cancer Res 2009;69(22):8770-4].

• Diabetes mellitus in a population of 180,000 insured dogs: incidence, survival, and breed distribution.

  Authors: Tove Fall, Helene Hansson-Hamlin, Ake Hedhammar, Olle Kämpe, Agneta Egenvall

  Journal of veterinary internal medicine / American College of Veterinary Internal Medicine. 21(6):1209-16.

  BACKGROUND: Canine diabetes mellitus (DM) is a common endocrinopathy with an unclear etiology. For a better understanding of the underlying mechanisms, there is a need for comprehensive epidemiologicBACKGROUND: Canine diabetes mellitus (DM) is a common endocrinopathy with an unclear etiology. For a better understanding of the underlying mechanisms, there is a need for comprehensive epidemiologic studies. Earlier studies have shown that the risk of disease is higher in certain dog breeds. HYPOTHESIS: Incidence, age of onset, survival and sex proportion of DM vary by breed. ANIMALS: Data from a cohort of 182,087 insured dogs aged 5-12 years accounting for 652,898 dog-years at risk were studied retrospectively. METHODS: Incidence rates by sex, breed, and geography were calculated with exact denominators. Age-specific incidence and survival after 1st DM claim were computed with Cox's regression and Kaplan-Meier survival function. Multivariable survival analysis was performed for the outcome diagnosis of DM with age, sex, and geography tested as fixed effects, previous endocrine or pancreatic diseases tested as time-dependent covariates, and breed tested as a random effect. RESULTS: The mean age at 1st insurance claim for the 860 DM dogs (72% females) was 8.6 years. The incidence of DM was 13 cases per 10,000 dog-years at risk. Australian Terriers, Samoyeds, Swedish Elkhounds, and Swedish Lapphunds were found to have the highest incidence. The proportion of females with DM varied significantly among breeds. Swedish Elkhounds, Beagles, Norwegian Elkhounds, and Border Collies that developed DM were almost exclusively females. The multivariable model showed that breed, previous hyperadrenocorticism, and female sex were risk factors for developing DM. Median survival time was 57 days after 1st claim. Excluding the 223 dogs that died within 1 day, the median survival time was 2 years after 1st claim of DM. CONCLUSION: The significant breed-specific sex and age differences shown in this study indicate that genetic variation could make breeds more or less susceptible to different types of DM.

• Characterisation of diabetes mellitus in dogs

  Authors: Tove Fall

  Diabetes mellitus is considered a common endocrine disorder in dogs. The underlying pathology is, however, poorly understood. Epidemiological, genetic and clinical research, as well as the clinicalDiabetes mellitus is considered a common endocrine disorder in dogs. The underlying pathology is, however, poorly understood. Epidemiological, genetic and clinical research, as well as the clinical management of diabetic dogs, requires an appropriate system of classification that provides a framework within which various forms and stages of diabetes mellitus can be identified and differentiated. The overall aim of this doctoral research was to further characterise the different subtypes of canine diabetes mellitus. In the first study, a population-based epidemiological study, breed- gender- and age-specific incidence rates were calculated, and survival after diagnosis was estimated. A major finding was that in some breeds such as elkhounds and border collies, only female dogs were affected by diabetes. In the second study, beta cell function was assessed in dogs through measurement of C-peptide before and after an intravenous injection of glucagon. Healthy dogs showed a marked increase in the serum concentration of C-peptide after glucagon stimulation, indicating that the test is suitable for the purpose. In most diabetic dogs, C-peptide did not increase after glucagon stimulation, indicating beta cell dysfunction. The test has a potential use for subtyping diabetes mellitus in newly diagnosed dogs. A specific subtype of diabetes, gestational diabetes mellitus, was clinically characterised in the third study. Gestational diabetes mellitus is rare in dogs, and the case series in this study is the largest one described to date. In the fourth study, diabetes mellitus was investigated in 63 Swedish and Norwegian elkhounds. From the latter two studies it was concluded that those elkhound breeds are predisposed to progesterone-related forms of diabetes mellitus (diœstrous and gestational diabetes mellitus), which have several characteristics in common with human gestational diabetes mellitus and may serve as a novel animal model for that disease. A new classification system for canine diabetes mellitus is proposed based on the basis of earlier studies and the newly gained knowledge. The following classes are proposed: juvenile; progesterone-related; secondary to pancreatic insult; endocrine tumours; iatrogenic; immune-mediated; and idiopathic.