Background & Aim:

Adolescence is characterised by pubertal development, changing body composition, decline in health-promoting behaviours and uptake of potentially harmful behaviours. Blood pressure (BP) increases in adolescence, and changes are observed in levels of circulating lipids, glucose and insulin. Adverse levels of BP and lipids in adolescence are associated with greater adult risk of cardiovascular diseases. Adolescence thus represents a potentially sensitive period in the development of cardiovascular risk. However, the causal mechanisms linking adolescence-related changes with cardiovascular risk are not well understood. We propose to study this in the Avon Longitudinal Study of Parents and Children. Specifically, we will assess whether pubertal development, genetic variants, adiposity and behavioural factors are associated with patterns of change in BP, lipids, glucose and insulin from 7-17 years; and explore how puberty and changes in BP, lipids, glucose and insulin are associated with cardiovascular structure and function measured at age 17.

Our key hypotheses (numbered) will each be addressed by relevant objectives (letters) as follows:

1. Age at puberty will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence, with earlier age at puberty resulting in a more adverse cardiovascular profile

a. To assess the association between age at puberty (measured using age at peak height velocity, measures derived from height for mid-parental-height and age at menarche) with patterns of change in SBP and DBP from 7 to 17 years (measures at 7, 9, 11, 13, 15 and 17 years), and patterns of change in lipids, glucose and insulin from 9 to 17 years (measures at 9, 15 and 17 years), and gender differences in these associations

b. To test the causality of associations between age at puberty and SBP, DBP, lipids, glucose and insulin, using genetic variants related to puberty in a Mendelian Randomisation analysis

c. To assess the age at which associations between genetic variants related to puberty and trajectories of SBP, DBP, lipids, glucose and insulin become apparent, and how these associations change across childhood and adolescence.

2. Changes in adiposity will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence

a. To assess the associations of changes in BMI (from age 7 to 17), DXA-assessed fat mass (age 9 to 17) and waist circumference (age 7 to 17) with changes in SBP, DBP, lipids, glucose and insulin across childhood and insulin (ages as in 1a above), and whether these differ between males and females

b. To assess the association of genetic variants related to BMI and waist circumference with changes in SBP, DBP, lipids, glucose and insulin across childhood and insulin

3. Modifiable behavioural risk factors will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence

a. To investigate the associations of dietary intake (ages 7 to 13), physical activity (ages 11 to 15) and smoking (ages 9 to 17) (and changes in these across childhood and adolescence) with changes in BP, lipids, glucose and insulin (ages as in 1a above, but starting at age 11 for physical activity and age 9 for smoking)

4. Genetic variants robustly associated in adult populations with BP, lipids, glucose and insulin will exhibit stronger associations with these traits later in adolescence (after puberty) compared with in childhood and earlier adolescence

a. To assess the relationship between an allelic score of BP-related SNPs and changes in BP

b. To assess the relationship between an allelic score of lipid-related SNPs and changes in lipids

c. To assess the relationship between allelic scores for i) type II diabetes, ii) fasting glucose levels and iii) circulating insulin levels and changes in glucose and insulin

5. Age at onset of puberty will be associated with cardiovascular structure and function

a. To assess the association of age at pubertal onset with measures of cardiovascular structure and function (measures detailed in section 4) at age 17

b. To determine the associations of changes in BP, lipids, glucose and insulin across childhood and adolescence with measures of cardiovascular structure and function at age 17

c. To assess the extent to which changes in BP, lipids, glucose and insulin across childhood and adolescence mediate the relationship of age at pubertal onset with measures of cardiovascular structure and function at age 17.

Statistical analysis will mainly involve multilevel models (including multivariate multilevel models) as well as standard regression techniques.