Longitudinal weight differences, gene expression and blood biomarkers in BMI-discordant identical twins

Abstract

Background: Body mass index (BMI) discordant monozygotic (MZ) twins allow an examination of the causes and consequences of adiposity in a genetically controlled design. Few studies have examined longitudinal BMI discordance in MZ pairs.

Objectives: The aim of this work was to study the development over time of BMI discordance in adolescent and adult MZ twin pairs and to examine lifestyle, metabolic, inflammatory and gene expression differences associated with concurrent and long-term BMI discordance in MZ pairs.

Subjects/methods: BMI data from 2775 MZ twin pairs, collected in eight longitudinal surveys and a biobank project between 1991 and 2011, were analyzed to characterize longitudinal discordance. Lifestyle characteristics were compared within discordant pairs (ΔBMI⩾3 kg m(-2)) and biomarkers (lipids, glucose, insulin, C-reactive protein, fibrinogen, interleukin (IL)-6, tumor necrosis factor-α and soluble IL-6 receptor and liver enzymes aspartate aminotransferase, alanine aminotransferase and gamma glutamyl transferase) and gene expression were compared in peripheral blood from discordant pairs who participated in the Netherlands Twin Register biobank project.

Results: The prevalence of discordance ranged from 3.2% in 1991 (mean age=17, s.d.=2.4) to 17.4% (N=202 pairs) in 2009 (mean age=35, s.d.=15) and was 16.5% (N=174) among pairs participating in the biobank project (mean age=35, s.d.=12). Of the 699 MZ pairs with BMI data from 3 to 5 time points, 17 pairs (2.4%) were long-term discordant (at all available time points; mean follow-up range=6.4 years). Concurrently discordant pairs showed significant differences in self-ratings of which twin eats most (P=2.3 × 10(-13)) but not in leisure time exercise activity (P=0.28) and smoking (P>0.05). Ten out of the 14 biomarkers showed significantly more unfavorable levels in the heavier of twin of the discordant pairs (P-values <0.001); most of these biomarker differences were largest in longitudinally discordant pairs. No significant gene expression differences were identified, although high ranking genes were enriched for Gene Ontology terms highlighting metabolic gene regulation and inflammation pathways.

Conclusions: BMI discordance is uncommon in adolescent identical pairs but increases with higher pair-mean of BMI at older ages, although long-term BMI discordance is rare. In discordant pairs, the heavier twin had a more unfavorable blood biomarker profile than the genetically matched leaner twin, in support of causal effects of obesity.

Figure 1. Flowchart of the selection procedure of MZ twin pairs included in each analysis

All numbers in this figure represent numbers of MZ twin pairs. GE= Gene expression. Each row (a to f) illustrates the available data and selection criteria for MZ pairs included in a particular analysis. a) Frequency of BMI discordance at one, two or more longitudinal time points in MZ pairs with longitudinal BMI data. b) Number of MZ pairs who are discordant across all projects and the number of pairs who are still discordant at the first next available follow-up time point. c) Discordant pairs included in the analyses of life style data. d) MZ pairs who were discordant at blood draw and were included in the analyses of biomarkers and gene expression. e). MZ pairs who were discordant at all time points of participation and were included in the analyses of biomarkers and gene expression. f) MZ pairs who became discordant after blood draw and who were studied to examine biomarkers and gene expression difference before BMI discordance onset.

Figure 2. BMI of MZ twin pairs who participated in the NTR biobank project (N=1055 pairs) and longitudinal BMI of 17 longitudinally discordant MZ pairs

a) Concordant pairs (Δ BMI < 3) are denoted by filled circles (N=881) and discordant pairs (Δ BMI ≥ 3 kg/m²) are indicated by other symbols (N=174). The grey lines indicate the threshold for discordance. B) Mean BMI of longitudinally discordant twins across NTR projects, with data from the heavier twins denoted by triangles and data from the leaner twins denoted by circles. c) Mean age of longitudinally discordant twins across NTR projects. Error bars represent standard errors. Time points 4-7 and 9 are surveys and time point 8 represents the time point of blood draw (NTR biobank). Note: None of these pairs participated in surveys 1-3. The following number of twins participated at each time point (N=leaner twin/heavier twin): 4: N=3/3, 5: N=10/10, 6: N=7/10, 7: N=15/15, 8: N=17/17, 9: N=14/11.