Abstract
BackgroundVariation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI).MethodsThe study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.ResultsIn cross-sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the A allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood.ConclusionsThere was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time.
Highlights
Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits
Population characteristics Genotypic and allelic frequencies for all eight single nucleotide polymorphism (SNP) in the Busselton Health Study (BHS) populations are given in Additional file 1: Electronic Supplementary Material (ESM) Table 1
In analyses using full covariate models, we observed that the T Type 2 diabetes (T2D)-risk allele at the IGF2BP2 SNP rs4402960 was associated with raised fasting glucose level (p = 0.045), and that the A obesity-risk allele at the fat mass and obesity associated (FTO) SNP rs9939609 was associated with raised body mass index (BMI) (p = 0.003)
Summary
Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. Variation in the effects of genetic variants at different stages of life could significantly alter the trajectories of traits and potentially the risks of certain diseases. Some of the intermediate traits of T2D, such as obesity and raised fasting plasma glucose, have complex determinants and both BMI and fasting plasma glucose tend to increase with age [6,7]. These observations raise the question of whether time- or age-varying genetic effects exist that could influence such intermediate traits and thereby T2D risk
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