The influence of genes, diet and their interaction on body mass index and blood pressure in children and adolescents

Overweight and hypertension, defined by their underlying continuous traits of body mass index (BMI) and blood pressure (BP), are risk factors for cardiovascular diseases (CVDs), the first cause of death globally. Obesity and hypertension in adulthood can be traced back to related alterations in childhood and adolescence. Measuring BMI and blood pressure in children and adolescents is meaningful for the primary prevention of long-term CVD risk. In children and adolescents aged 5-19 years, the global age-standardized prevalence of obesity was 5.6% in girls and 7.8% in boys in 2016. The pooled prevalence derived from a meta-analysis in children and adolescents 3-19 years of age was 4.0% for hypertension, and 9.7% for prehypertension. The prevalence of obesity and hypertension occurring in children and adolescents has about doubled during the past decade, and the increasing trend may persist in the future. In response to the increasing prevalence, accurate prediction and early intervention of overweight and hypertension should be taken seriously. It is necessary to explore in-depth the multiple factors influencing BMI and BP in children and adolescents. The present study aims to investigate the influence of genetic and dietary factors and their interaction on BMI and BP trajectories in childhood. Identifying whether the impact of genetic susceptibility is moderated by dietary quality during critical developmental periods is important for targeted prevention of obesity and hypertension.
BMI and BP are influenced by genetic factors. There were 941 near-independent SNPs associated with BMI and 901 loci associated with blood pressure in adults discovered by GWAS. However, meta-GWAS in children only identified 25 SNPs associated with childhood BMI and 2 independent SNPs associated with childhood BP. Moreover, the overlaps in BMI- and BP-associated SNPs across childhood and adulthood were low. It indicated more need for children-specific GWAS for the specific intervention of long-term obesity and hypertension. To evaluate the overall contribution of identified genetic variants on traits, polygenic risk score (PRS) and genetic risk score (GRS) can be constructed, explaining a significant portion of the traits’ variation. 
BMI and BP are also influenced by dietary factors. Childhood BMI has been observed to be associated with diet factors including breastfeeding/formula feeding, protein intake, fat intake, sugar intake, supplementation with prebiotics and probiotics, and timing of complementary food. The influence of dietary factors on BMI was age-specific and remained in adulthood from childhood. Childhood and adolescent hypertension had been reported to be associated with dietary factors including non-breastfeeding, fructose intake, sugary soft drinks, and low-potassium intake. Several dietary factors in childhood can influence BP in the following years but others do not. Overall, there is a need for studies on the longitudinal effect of childhood overall diet quality on BMI and BP. 
Gene-diet interactions for BMI and BP have been reported in adults and children, not only between individual genes and several dietary factors, but also between GRS/PRS and overall dietary quality. Most of them suggested that healthy dietary patterns attenuated genetic predisposition to obesity and hypertension. However, the opposite or insignificant interaction between genetic and dietary factors for BMI or BP has been also found in several studies. BMI and BP, as well as their related genetic influences and dietary factors, develop across childhood, adolescence, and adulthood. Low overlaps in BMI- and BP-associated SNPs across childhood and adulthood may be partly attributed to different environmental factors, including dietary factors, modifying the effect of genetic factors between childhood and adulthood, calling for further longitudinal studies on gene-diet interaction and long-term dietary interventions for obesity and hypertension in children. 
We hypothesize that a healthy diet in childhood offsets genetic susceptibility to obesity and hypertension across childhood and adolescence. In the present study, characterizing when and how diet influences the associations of genetic variants with BMI and BP in childhood and adolescence may help determine the extent and the timing that dietary interventions in early life offset the genetic susceptibility to obesity and hypertension. Investigating gene-diet interaction for longitudinal development of obesity and hypertension in childhood and adolescence will help to find optimal windows of opportunity in early life for long-term prevention of obesity and hypertension, especially for those who have a higher genetic susceptibility. Our study will suggest targeted dietary interventions for obesity and hypertension tailored to genetic susceptibility and developmental stage.