Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Multifactorial analysis of changes in body mass index across the adult life course: a study with 65 years of follow-up.

BACKGROUND: Although the negative consequences on health of being obese are well known, most adults gain weight across the lifespan. The general increase in body mass index (BMI) is mainly considered to originate from behavioral and environmental changes; however, few studies have evaluated the influence of these factors on change in BMI in the presence of genetic risk. We aimed to study the influence of multifactorial causes of change in BMI, over 65 years. METHODS AND FINDINGS: Totally, 6130 participants from TwinGene, who had up to five assessments, and 536 from the Swedish Adoption/Twin Study of Aging, who had up to 12 assessments, ranging over 65 years were included. The influence of lifestyle factors, birth cohort, cardiometabolic diseases and an individual obesity genetic risk score (OGRS) based on 32 single nucleotide polymorphisms on change in BMI was evaluated with a growth model. For both sexes, BMI increased from early adulthood to age of 65 years, after which the increase leveled off; BMI declined after age of 80 years. A higher OGRS, birth after 1925 and cardiometabolic diseases were associated with higher average BMI and a steeper increase in BMI prior to 65 years of age. Among men, few factors were identified that influence BMI trajectories in late life, whereas for women type 2 diabetes mellitus and dementia were associated with a steeper decrease in BMI after the age of 65 years. CONCLUSIONS: There are two turning points in BMI in late adulthood, one at the age of 65 years and one at the age 80 years. Factors associated with an increase in BMI in midlife were not associated with an increase in BMI after the age of 65 years. These findings indicate that the causes and consequences of change in BMI differ across the lifespan. Current health recommendations need to be adjusted accordingly.

The role of obesity-related genetic loci in insulin sensitivity.

AIMS: Despite rapid advancements and many new diabetes susceptibility loci found in the past few years, few genetic variants associated with insulin sensitivity have been described, potentially attributable to the lack of larger cohorts examined with gold standard methods for insulin sensitivity assessment. There is a strong link between obesity and insulin sensitivity, and we hypothesized that known obesity susceptibility loci may act via effects on insulin sensitivity. METHODS: A cohort of 71-year-old men without diabetes (Uppsala Longitudinal Study of Adult Men) underwent a euglycaemic-hyperinsulinaemic clamp and genotyping for genetic variants representing 32 loci recently reported to be associated with BMI (n = 926). The effect of these loci on the insulin sensitivity index (M/I ratio) was examined using linear regression. An in silico replication was performed in publically available data for the three top single-nucleotide polymorphisms from the Meta-Analyses of Glucose and Insulin-related traits Consortium analyses of homeostasis model assessment of insulin resistance (n = 37,037). RESULTS: Three loci (SH2B1, MTCH2 and NEGR1) were associated with decreased insulin sensitivity at a nominal significance (P ≤ 0.05) after adjustment for BMI, but did not hold for multiple comparison correction. SH2B1 rs7359397 was also associated with homeostasis model assessment of insulin resistance in the Meta-Analyses of Glucose and Insulin-related traits Consortium data set (P = 3.9 × 10(-3)). CONCLUSIONS: Our study supports earlier reports of SH2B1 to be of importance in insulin sensitivity and, in addition, suggests potential roles of NEGR1 and MTCH2.

Regional occurrence, high frequency but low diversity of mitochondrial DNA haplogroup d1 suggests a recent dog-wolf hybridization in Scandinavia.

The domestic dog mitochondrial DNA (mtDNA)-gene pool consists of a homogenous mix of haplogroups shared among all populations worldwide, indicating that the dog originated at a single time and place. However, one small haplogroup, subclade d1, found among North Scandinavian/Finnish spitz breeds at frequencies above 30%, has a clearly separate origin. We studied the genetic and geographical diversity for this phylogenetic group to investigate where and when it originated and whether through independent domestication of wolf or dog-wolf crossbreeding. We analysed 582 bp of the mtDNA control region for 514 dogs of breeds earlier shown to harbour d1 and possibly related northern spitz breeds. Subclade d1 occurred almost exclusively among Swedish/Finnish Sami reindeer-herding spitzes and some Swedish/Norwegian hunting spitzes, at a frequency of mostly 60-100%. Genetic diversity was low, with only four haplotypes: a central, most frequent, one surrounded by two haplotypes differing by an indel and one differing by a substitution. The substitution was found in a single lineage, as a heteroplasmic mix with the central haplotype. The data indicate that subclade d1 originated in northern Scandinavia, at most 480-3000 years ago and through dog-wolf crossbreeding rather than a separate domestication event. The high frequency of d1 suggests that the dog-wolf hybrid phenotype had a selective advantage.

Diabetes mellitus in elkhounds is associated with diestrus and pregnancy.

BACKGROUND: Female Elkhounds are shown to be at increased risk for diabetes mellitus, and occurrence of diabetes during pregnancy has been described in several cases. HYPOTHESIS: Onset of diabetes mellitus in Elkhounds is associated with diestrus. ANIMALS: Sixty-three Elkhounds with diabetes mellitus and 26 healthy controls. METHODS: Medical records from 63 Elkhounds with diabetes were reviewed and owners were contacted for follow-up information. Blood samples from the day of diagnosis were available for 26 dogs. Glucose, fructosamine, C-peptide, growth hormone (GH), insulin-like growth factor-1, progesterone, and glutamate decarboxylase isoform 65-autoantibodies were analyzed and compared with 26 healthy dogs. Logistic models were used to evaluate the association of clinical variables with the probability of diabetes and with permanent diabetes mellitus after ovariohysterectomy (OHE). RESULTS: All dogs in the study were intact females and 7 dogs (11%) were pregnant at diagnosis. The 1st clinical signs of diabetes mellitus occurred at a median of 30 days (interquartile range [IQR], 3-45) after estrus, and diagnosis was made at a median of 46 days (IQR, 27-62) after estrus. Diabetes was associated with higher concentrations of GH and lower concentrations of progesterone compared with controls matched for time after estrus. Forty-six percent of dogs that underwent OHE recovered from diabetes with a lower probability of remission in dogs with higher glucose concentrations (odds ratio [OR], 1.2; P=.03) at diagnosis and longer time (weeks) from diagnosis to surgery (OR, 1.5; P=.05). CONCLUSIONS: Diabetes mellitus in Elkhounds develops mainly during diestrus and pregnancy. Immediate OHE improves the prognosis for remission of diabetes.

Gestational diabetes mellitus in 13 dogs.

BACKGROUND: There are few reports on the clinical appearance, prognosis, and risk factors for gestational diabetes mellitus (GDM) in dogs. OBJECTIVE: To describe the clinical characteristics of GDM in dogs. ANIMALS: Thirteen dogs with GDM. METHODS: Retrospective study. Medical records were reviewed and owners and referring veterinarians were contacted for follow-up information. RESULTS: Nordic Spitz breeds (11/13 dogs) were overrepresented in the case material. Diagnosis was established at a median of 50 days after mating (range, 32-64). Median glucose concentration at diagnosis was 340 mg/dL (18.9 mmol/L) (range, 203-587). One dog was euthanized at diagnosis, 5 bitches were treated with insulin until whelping, and in 7 dogs, pregnancy was terminated within 4 days of diagnosis. One dog died after surgery. Tight glycemic control was not achieved in any of the insulin-treated dogs during pregnancy. Diabetes mellitus (DM) resolved in 7 dogs at a median of 9 days after the end of their pregnancies and DM was permanent in 4 dogs. Puppy mortality was increased compared with offspring of healthy dams. CONCLUSION: This report suggests that GDM affects mainly middle-aged bitches in the 2nd half of pregnancy with a breed predisposition toward Nordic Spitz breeds. GDM may resolve within days to weeks after pregnancy has ended. Further research is needed to investigate optimal treatment regimens for dogs with GDM and risk factors for unsuccessful outcome.

Glucagon stimulation test for estimating endogenous insulin secretion in dogs.

Fifty-one dogs (27 diabetic dogs, four that had recovered from diabetes and 20 healthy control dogs) were given 0.5 or 1.0 mg glucagon intravenously. Blood samples were taken before the injection and 10 and 20 minutes after it. Samples were analysed to determine C-peptide, insulin and glucose concentrations, and one sample from each dog was analysed for fructosamine. The median (interquartile range) concentrations of C-peptide in the samples taken at 10 minutes were 0.5 (0.3 to 0.8) nmol/l in the control dogs, 0.1 (0 to 0.2) nmol/l in the diabetic dogs, and 0.3 (0.2 to 0.4) nmol/l in the dogs that had recovered from diabetes. Seven of the 51 dogs showed mild adverse reactions after the injection of glucagon.

Environmental Risk Factors for Diabetes Mellitus in Cats.

BACKGROUND: Diabetes in cats resembles type 2 diabetes in people. The etiology is not fully understood, but both genetic and environmental factors are believed to contribute. OBJECTIVES: To assess the associations of environmental risk factors with diabetes in cats. ANIMALS: Cats with a diagnosis of diabetes (n = 396) insured by a Swedish insurance company during years 2009-2013, and a control group (n = 1,670) matched on birth year. METHODS: A web-based questionnaire was used in a case-control study. An invitation to participate was sent to owners of 1,369 diabetic cats and 5,363 control cats. The survey contained questions related to the cat's breed, age, sex, neutering status, body condition, housing, access to the outdoors, activity level, diet, eating behavior, feeding routine, general health, stressful events, other pets in the household, medications, and vaccination status. Data were analyzed by multiple logistic regression. RESULTS: Response rate was 35% for the diabetic group and 32% for the control group. Indoor confinement, being a greedy eater, and being overweight were associated with an increased risk of diabetes. In cats assessed by owners as being normal weight, there was an association between eating predominantly dry food and an increased risk of diabetes (Odds ratio 3.8; 95% confidence intervals 1.3-11.2). CONCLUSIONS AND CLINICAL IMPORTANCE: Dry food is commonly fed to cats worldwide. The association found between dry food and an increased risk of diabetes in cats assessed as normal weight by owners warrants further attention.

Incidence of Diabetes Mellitus in Insured Swedish Cats in Relation to Age, Breed and Sex.

BACKGROUND: Diabetes mellitus (DM) is a common endocrinopathy in cats. Most affected cats suffer from a type of diabetes similar to type 2 diabetes in humans. An increasing prevalence has been described in cats, as in humans, related to obesity and other lifestyle factors. OBJECTIVES: To describe the incidence of DM in insured Swedish cats and the association of DM with demographic risk factors, such as age, breed and sex. ANIMALS: A cohort of 504,688 individual cats accounting for 1,229,699 cat-years at risk (CYAR) insured by a Swedish insurance company from 2009 to 2013. METHODS: We used reimbursed insurance claims for the diagnosis of DM. Overall incidence rates and incidence rates stratified on year, age, breed, and sex were estimated. RESULTS: The overall incidence rate of DM in the cohort was 11.6 cases (95% confidence interval [CI], 11.0-12.2) per 10,000 CYAR. Male cats had twice as high incidence rate (15.4; 95% CI, 14.4-16.4) as females (7.6; 95% CI, 6.9-8.3). Domestic cats were at higher risk compared to purebred cats. A significant association with breed was seen, with the Burmese, Russian Blue, Norwegian Forest cat, and Abyssinian breeds at a higher risk compared to other cats. No sex predisposition was found among Burmese cats. Several breeds with a lower risk of DM were identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results verify that the Burmese breed is at increased risk of developing DM. We also identified several previously unreported breeds with increased or decreased risk of DM.

[Effects of natural phosphate supplementation in the Gabra Zebu of Senegal]. / Effets de la complémentation en phosphates naturels chez le Zébu Gabra du Sénégal.

The authors contemplate using natural phosphates, despite their high fluorine content, as an economical supplement for tropical cattle's phosphate needs. Continuous and discontinuous distribution will be tried to better understand the effects of the fluorine. Tests were carried out in Senegal on 78 Gabra Zebu bullocks. Over a 2 year period, every day each animal received differing doses (50g. and 100g.) of differing phosphates (from Taiba or from Thies) resulting in dental lesions and some bone lesions because of the fluorine content. The dental lesions were the most noticeable. Only a minority of the bone and articulary lesions were serious. Furthermore, they were inconsistent. At the end of the experiment, the animals were in good general health. It had not been possible to dose fluorine prior to this publication.

Relationship among insulin resistance, growth hormone, and insulin-like growth factor I concentrations in diestrous Swedish Elkhounds.

BACKGROUND: In the dog, the normal estrous cycle includes a prolonged luteal phase. Progesterone stimulates local canine mammary growth hormone (GH) production, which may act systemically and contribute to insulin resistance. Swedish Elkhounds are predisposed to progesterone-related diabetes mellitus, and the relationship among insulin resistance, GH, and insulin-like growth factor I (IGF-I) is of particular interest. OBJECTIVE: To study insulin resistance in relation to GH and IGF-I in nondiabetic Swedish Elkhounds during diestrus. We also assessed whether alterations in these hormones could predict diestrus-linked diseases and all-cause mortality. ANIMALS: Eighty-four privately owned female intact Swedish Elkhounds >4 years of age. METHODS: Blood sampling and clinical examination during luteal phase, with a follow-up questionnaire after 20 months. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). RESULTS: In multivariable regression analysis, GH was positively associated with HOMA-IR (P = .009). An increase in GH of 1 ng/mL was associated with a 12.7% increase in HOMA-IR. Moreover, C-peptide was positively associated with IGF-I (P = .04), and an increase in C-peptide of 0.1 ng/mL was associated with a 6.9% increase in IGF-I. Structural equation modeling supported these results. Twenty-three animals were found to have previously unrecognized mammary masses and had higher GH (P < .0001) and IGF-I (P = .007) than dogs without mammary masses (n = 61). There was no association between high GH and IGF-I concentrations at sampling and future mammary masses. CONCLUSION: We showed that GH was strongly associated with insulin resistance in older Swedish Elkhounds during diestrus.

A common variant in the FTO locus is associated with waist-hip ratio in Indian adolescents.

BACKGROUND: Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups. Associations with obesity traits among Indian adolescents have not been determined. OBJECTIVE: To study the association of rs9939609 (FTO) and rs17782313 (MC4R) to obesity related anthropometric traits in Indian adolescents. METHODS: Subjects for the current study were recruited from a cross-sectional cohort of 1,230 adolescents (age mean ± SD: 17.1 ± 1.9 years) from South India. RESULTS: The variant at the FTO locus was found to be associated with waist-hip ratio (WHR) but not with overall obesity in this population. No significant association was observed for obesity-traits and Mc4R variant rs17782313. CONCLUSION: The common variant of FTO (rs9939609) is associated with body fat distribution during early growth in Indian adolescents and may predispose to obesity and metabolic consequences in adulthood.

Lifestyle risk factors for progesterone-related diabetes mellitus in elkhounds - a case-control study.

OBJECTIVES: This study aims to investigate lifestyle risk factors for the development of progesterone-related diabetes mellitus in female elkhounds. METHODS: Owners of 48 diabetic elkhounds and 58 healthy elkhounds were interviewed by phone concerning lifetime diet and exercise routines. A logistic model was developed to assess the impact of diet and exercise on diabetes diagnosis. The agreement between lifetime owner-perceived body condition score (BCS) and veterinary-perceived BCS at inclusion was estimated in healthy control dogs using the Kappa statistic. RESULTS: The model showed that diabetic dogs had increased odds for having been overweight (before diagnosis) compared with controls (OR=2·8, 95% confidence interval 1·1-7·5, P=0·034). Although feeding other food than commercial dog feed was associated with diabetes case status, the effect was not significant after BCS was entered into the model. The overall agreement between lifetime owner- and veterinary-perceived BCS at inclusion in the study was 75% and had a Kappa statistic of 0·16 (P=0·12). CLINICAL SIGNIFICANCE: This study indicates that a high owner-perceived lifetime BCS is associated with progesterone-related diabetes in elkhounds.