Associations between parental type 2 diabetes risk and offspring birthweight and placental weight: a survival analysis using the Walker cohort.

AIMS/HYPOTHESIS: Low birthweight (BW) is associated with the development of type 2 diabetes. Genome-wide analyses have identified a strong genetic component to this association, with many BW-associated loci also involved in glucose metabolism. We hypothesised that offspring BW and placental weight (PW) are correlated with parental type 2 diabetes risk, reflecting the inheritance of diabetes risk alleles that also influence fetal growth. METHODS: The Walker cohort, a collection of birth records from Dundee, Scotland, from the 1950s and the 1960s was used to test this hypothesis by linking BW and PW measurements to parental health outcomes. Using data from SCI-Diabetes and the national death registry, we obtained health records for over 20,000 Walker parents. We performed Fine-Gray survival analyses of parental type 2 diabetes risk with competing risk of death, and Cox regression analyses of risk of death, independently in the maternal and paternal datasets, modelled by offspring BW and PW. RESULTS: We found significant associations between increased paternal type 2 diabetes risk and reduced offspring BW (subdistribution hazard ratio [SHR] 0.92 [95% CI 0.87, 0.98]) and PW (SHR 0.87 [95% CI 0.81, 0.94]). The association of maternal type 2 diabetes risk with offspring BW or PW was not significant. Lower offspring BW was also associated with increased risk of death in both mothers (HR 0.91 [95% CI 0.89, 0.94]) and fathers (HR 0.95 [95% CI 0.92, 0.98]), and higher offspring PW was associated with increased maternal mortality risk (HR 1.08 [95% CI 1.04, 1.13]) when adjusted for BW. CONCLUSIONS/INTERPRETATION: We identified associations between offspring BW and reduced paternal type 2 diabetes risk, most likely resulting from the independent effects of common type 2 diabetes susceptibility alleles on fetal growth, as described by the fetal insulin hypothesis. Moreover, we identified novel associations between offspring PW and reduced paternal type 2 diabetes risk, a relationship that might also be caused by the inheritance of diabetes predisposition variants. We found differing associations between offspring BW and PW and parental risk of death. These results provide novel epidemiological support for the use of offspring BW and PW as predictors for future risk of type 2 diabetes and death in mothers and fathers.

Development of a high number, high coverage dog rabies vaccination programme in Sri Lanka.

BACKGROUND: Rabies is estimated to cause 59,000 deaths and economic losses of US$8.6 billion every year. Despite several years of rabies surveillance and awareness programmes, increased availability of post-exposure prophylaxis vaccinations and dog population control, the disease still remains prevalent in Sri Lanka. This study reports the roll-out of a high number, high coverage canine rabies vaccination campaign in Sri Lanka, providing estimates for the vaccination coverage achieved, analysing the local dog demographics, and identifying barriers of attendance to static vaccination clinics. METHODS: A mass dog vaccination campaign was undertaken in Negombo, Sri Lanka. The campaign was composed of static point and door-to-door vaccination stages, with a final survey of vaccination coverage. A large volume of data on the distribution, health, and signalment of vaccinated dogs was collected through a mobile phone application. A logistic regression model was developed to investigate which socio-spatial and dog-related factors influenced attendance of owners to static vaccination points. RESULTS: The campaign vaccinated over 7800 dogs achieving a vaccination coverage of 75.8%. A dog:human ratio of 1:17 was estimated. Most dogs were owned, and the dog population was mostly male, adult, and non-sterilized. Unawareness, unavailability and handling problems were the most common reasons given by owners to explain failure to attend a static vaccination point. The regression analysis showed that increasing distance to a static point, in addition to young age and poor health of the dog, were associated with a decrease in the likelihood of attendance to a static vaccination points. CONCLUSION: This study demonstrates the feasibility of high number, high coverage vaccination campaigns in Sri Lanka. The information on dog ecology and barriers of attendance to static point vaccination clinics will facilitate development of future vaccination campaigns.

Associations of offspring birthweight and placental weight with subsequent parental coronary heart disease: survival regression using the walker cohort.

Low birth weight (BW) is consistently correlated with increased parental risk of subsequent cardiovascular disease, but the links with offspring placental weight (PW) are mostly unexplored. We have investigated the associations between parental coronary heart disease (CHD) and offspring BW and PW using the Walker cohort, a collection of 48,000 birth records from Dundee, Scotland, from the 1950s and 1960s. We linked the medical history of 13,866 mothers and 8,092 fathers to their offspring's records and performed Cox survival analyses modelling maternal and paternal CHD risk by their offspring's BW, PW, and the ratio between both measurements. We identified negative associations between offspring BW and both maternal (hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.88-0.95) and paternal (HR: 0.96, 95% CI: 0.93-1.00) CHD risk, the stronger maternal correlation being consistent with previous reports. Offspring PW to BW ratio was positively associated with maternal CHD risk (HR: 1.14, 95% CI: 1.08-1.21), but the associations with paternal CHD were not significant. These analyses provide additional evidence for intergenerational associations between early growth and parental disease, identifying directionally opposed correlations of maternal CHD with offspring BW and PW, and highlight the importance of the placenta as a determinant of early development and adult disease.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

The role of genetics in fetal programming of adult cardiometabolic disease.

Disturbances affecting early development have broad repercussions on the individual's health during infancy and adulthood. Multiple observational studies throughout the years have shown that alterations of fetal growth are associated with increased cardiometabolic disease risks. However, the genetic component of this association only started to be investigated in the last 40 years, when single genes with distinct effects were investigated. Birth weight (BW), commonly reported as the outcome of developmental growth, has been estimated to be 20% to 60% heritable. Through Genome-Wide Association (GWA) meta-analyses, 190 different loci have been identified being associated with BW, and while many of these loci designate genes involved in glucose and lipid metabolism, with clear ties to fetal development, the role of others is not yet understood. In addition, due to its influence over the intrauterine environment, the maternal genotype also plays an important part in the determination of offspring BW, with the same loci having independent effects of different magnitude or even direction. There is still much to uncover regarding the genetic determinants of BW and the interactions between maternal, offspring, and even paternal genotype. To fully understand these, diverse and novel cohorts from multiple ancestries collecting extensive neonatal phenotype will be needed. This review compiles, chronologically, the main findings in the investigation of the genetics of BW.

Implementation of a mass canine rabies vaccination campaign in both rural and urban regions in southern Malawi.

Rabies is a devastating zoonotic disease causing nearly 60,000 deaths globally each year. The disease causes Malawi an economic loss of 13 million USD and kills almost 500 people annually. Domestic dogs are the main reservoir for rabies and vaccinating over 70% of the dog population is the most efficient method to reduce its incidence in both humans and canines. However, achieving such coverages is often difficult and depend on many geospatial factors. Rural and pastoral regions are considered difficult to vaccinate efficiently due to low dog densities, and reports of campaigns spanning large areas containing vastly different communities are lacking. This study describes a mass canine vaccination campaign covering rural and urban regions in southern Malawi. The campaign achieved an average vaccination coverage of 83.4% across 3 districts, and vaccinated over 89,000 dogs through a combined static point and door-to-door effort. A dog population of 107,574 dogs was estimated (dog:human ratio of 1:23). The canine population was found to be almost completely owned (99.2%) and mostly kept for security purposes (82.7%). The dogs were mainly adults, males, and not neutered. Regression analysis identified education level and proportion of young dogs as the only factors influencing (positively and negatively, respectively) whether vaccination coverage over 70% was achieved in a region, independently of variables such as population density or poverty. A second regression analysis was performed predicting absolute vaccination coverage. While education level and the proportion of confined dogs were associated with positive vaccination coverage, higher proportions of young animals and female dogs were associated with a decrease in coverage. This study confirms the feasibility of homogeneously vaccinating over 70% of the dogs in a large area including rural and urban communities. These findings can inform the logistics of future campaigns and might be used as a template to facilitate high-number, high-coverage vaccination campaigns to other regions in sub-Saharan Africa.