Melbourne School of Population and Global Health - Theses
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ItemDevelopmental Origins of Cardiometabolic Health in Twins( 2021)Background Cardiometabolic diseases are the leading cause of death and disability in Australia and may have origins in early life. Unique insights into the developmental origins of health and disease (DOHaD) can be obtained from twin studies due to matching for shared genetic and environmental factors. As such, twin studies can provide greater insight into causes of disease, including genetic and environmental contributions, and are usually generalisable to non-twin populations. Despite these benefits, few twin studies have comprehensively explored the developmental origins of cardiometabolic health. Therefore, I aimed to better understand the developmental origins of cardiometabolic health in twins, by carefully and comprehensively exploring associations of gestational and birth exposures with childhood markers of cardiometabolic health. Methods To comprehensively evaluate the current knowledge of the developmental origins of cardiometabolic health in twins, I conducted three systematic reviews (Chapters 3, 10.2 and 11.2). I used the knowledge gained from these reviews to guide original data analyses using data from the Peri/Postnatal Epigenetic Twins Study (PETS, described in Chapter 5). Twin-specific regression models (described in Chapter 6) were fitted to assess the twins-as-individuals and within-between associations of birthweight (Chapter 12.2), gestational weight gain (GWG, Chapter 10.4), and gestational nutrition (Chapter 11.3) with childhood markers of cardiometabolic health. A mixed-effects model was then fitted to determine the genetic and environmental contributions to the variance of twin anthropometric measures (Chapter 12.3). Results My systematic reviews identified several limitations of previous twin studies: 1) DOHaD exposures are often limited to birthweight; 2) typically, only blood pressure or BMI are used as cardiometabolic outcomes; 3) most studies have failed to appropriately adjust for gestational age; 4) few studies used the extra information contained in data from twins; 5) twin-specific GWG recommendations are limited to women who deliver twins at greater than or equal to 37 weeks’ gestation and/or with a birthweight of at greater than or equal to 2500 grams. To address limitation #1, I explored the associations of GWG and gestational nutrition with twin cardiometabolic health, and found that GWG was associated with birth size, for example, birthweight z-scores (Beta: 0:32, 95%CI: 0:19, 0:45), and childhood growth in the PETS. Maternal macronutrient intake was also associated with birth size, for example, protein intake with birthweight z-scores (Beta: 0:25, 95%CI: 0:09, 0:41), but not with childhood markers of cardiometabolic health. To address limitations #3 and #4, I found that birthweight-for-gestational-age z-scores were associated with twins-as-individuals, within- and between-pair childhood anthropometrics, but not with blood pressure. This contradicts results from previous studies which have not adjusted for gestational age. The within-between models showed evidence for potentially causal associations of birthweight with childhood markers of cardiometabolic health. Genetic factors contributed most strongly to the variance of childhood height, weight and BMI in the PETS. Conclusion These results have improved our knowledge of the developmental origins of cardiometabolic health in twins by demonstrating that multiple early-life exposures, and not just birthweight, are associated with a range of childhood markers of cardiometabolic health. Further, these results demonstrate the value of twin studies in DOHaD research, highlight the importance of adjusting for gestational age when studying gestational exposures and birthweight, and illustrate the need for improved, twin-specific GWG and nutrition guidelines.