Genetic Effects on Longitudinal Changes from Healthy to Adverse Weight and Metabolic Status – The HUNT Study

Abstract

Introduction: The complexity of obesity and onset and susceptibility of cardio-metabolic disorders are still poorly understood and is addressed here through studies of genetic influence on weight gain and increased metabolic risk longitudinally.

Subjects/methods: Twenty seven previously identified obesity, eating disorder or metabolic risk susceptibility SNPs were tested for association with weight or metabolically related traits longitudinally in 3999 adults participating both in the HUNT2 (1995-97) and HUNT3 (2006-08) surveys. Regression analyses were performed with changes from normal weight to overweight/obesity or from metabolically healthy to adverse developments with regards to blood pressure, glucose, HDL cholesterol, triglycerides or metabolic syndrome as outcomes. Additionally, a sub-sample of 1380 adolescents was included for testing association of nine SNPs with longitudinal weight gain into young adulthood.

Results: The most substantial effect on BMI-based weight gain from normal to overweight/obesity in adults was observed for the DRD2 variant (rs6277)(OR: 0.79, 95% CI: 0.69-0.90, P = 3.9x10(-4), adj. P = 0.015). DRD2 was not associated with BMI on a cross-sectional level. In the adolescent sample, FTO (rs1121980) was associated with change to overweight at adulthood in the combined male-female sample (OR: 1.27, 95% CI: 1.09-1.49, P = 3.0x10(-3), adj. P = 0.019) and in females (OR: 1.53, 95% CI: 1.23-1.91, P = 1.8x10(-4), adj. P = 0.003). When testing for association to longitudinal adverse developments with regard to blood pressure, blood lipids and glucose, only rs964184 (ZNF259/APOA5) was significantly associated to unfavourable triglyceride changes (OR: 1.66, 95% CI: 1.36-2.03, P = 5.7x10(-7), adj. P = 0.001). Pleiotropic effects on metabolic traits, however, were observed for several genetic loci cross-sectionally, ZNF259/APOA5, LPL and GRB14 being the most important.

Conclusions: DRD2 exhibits effects on weight gain from normal weight to overweight/obesity in adults, while, FTO is associated to weight gain from adolescence to young adulthood. Unhealthy longitudinal triglyceride development is strongly affected by ZNF259/APOA. Our main finding, linking the DRD2 variant directly to the longitudinal weight gain observed, has not previously been identified. It suggests a genetic pre-disposition involving the dopaminergic signalling pathways known to play a role in food reward and satiety linked mechanisms.

Fig 1. Flow diagram of individuals included in the adult longitudinal study.

Overweight/obesity was defined as having a BMI ≥ 25 kg/m² or as ≥ 94 cm 102 cm (male) and ≥ 80 (female) with regards to waist circumference (WC). Unhealthy blood pressure (BP) was defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥ 85 mmHg, or antihypertensive drug treatment. Unhealthy blood glucose (GLU) level was defined as ≥7.0 mmol/l or use of or diabetes medical treatment and triglyceride (TG) level as ≥2.1 mmol/l (both cut-offs modified due to non-fasting measurements). An unhealthy HDL cholesterol (HDL-C) level was defined below <1.0 mmol/l (male) or <1.3 mmol/l (female). Metabolic syndrome (MetS) phenotype cut-offs were based on the original NCEP—ATP III definition taking into account WC, BP, GLU, HDL-C and TG levels. MetS-cases were those scoring below cut-off for all five measures at baseline, but above cut-off for at least three components at follow-up. Controls scored below cut-offs for all five measures both at base-line and at follow-up.

Fig 2. Cross-sectional associations between SNPs and metabolic syndrome (MetS) components.

MetS-components: waist circumference (WC), HDL cholesterol (HDL-C), triglycerides (TG), glucose (GLU), systolic and diastolic blood pressure (SBP, DBP) at baseline (HUNT2) and follow-up (HUNT3). The following markers included were all significantly (P<0.05) associated to at least one trait cross-sectionally: ZNF259/APOA5 (rs964184), G6PC2 (glucose-6-phosphatase catalytic 2, rs560887), LPL (rs268), GRB14 (rs10195252), FTO (rs1121980), OPRD1 (rs569356 and rs533123) and NTRK3 (neurotrophic tyrosine kinase receptor type 3, rs7180942).