Childhood obesity leads to adult type 2 diabetes and coronary artery diseases: A 2-sample mendelian randomization study

Abstract

Observational studies have reported that childhood obesity is positively associated with risks of type 2 diabetes (T2D) and coronary artery disease (CAD) in adults; however, whether this association is causal is still unclear. In the present study, we conducted the 2-sample Mendelian randomization (MR) studies to investigate whether childhood obesity is causally associated with T2D and CAD in adults.Seven single-nucleotide polymorphisms (SNPs) that significantly associated with childhood obesity were used as instrumental variables. The 2-sample MR analyses were performed with the summary-level data of large-sample genome-wide association studies to evaluate the causal effects of childhood obesity on adult T2D and CAD and the levels of cardiometabolic traits.The 2-sample MR analyses suggested that each 1-unit increase in the log-odds of having childhood obesity was causally associated with an increased risk of adult T2D (odds ratio [OR] = 1.16, 95% confidential interval [CI] = 1.06-1.28; P = 1.0 × 10) and CAD (OR = 1.07, 95% CI = 1.02-1.12; P = 4.0 × 10) based on the inverse-variance weighted method. The MR analyses also suggested that childhood obesity was positively associated with the levels of adult body mass index, waist circumference, hip circumference, waist and hip ratio, log-transformed fasting glucose, log-transformed homeostatic model assessment (HOMA) of insulin resistance (%), and triglycerides. The childhood obesity was negatively associated with the adult high-density lipoprotein cholesterol level; however, there was no evidence of a causal association between childhood obesity and the levels of fasting glucose, 2-hour glucose, HbA1c (%), log-transformed HOMA of ß-cell function (%), low-density lipoprotein cholesterol, or total cholesterol in adults.In conclusion, a genetic predisposition to childhood obesity was associated with an increased risk of adult T2D and CAD, providing causal relations between childhood obesity and the risks of T2D and CAD in adults; however, the results need to be validated with larger-scale intervention studies.

Figure 1

Study design and the assumptions for the 2 sample Mendelian randomization. Three assumptions including: (1) the genetic variants should be robustly associated with the exposure; (2) the genetic variants should not be associated with the confounders of the exposure-outcome association; (3) the genetic variants must influence the outcomes through the exposure only and not through any other indirect pathways. The dash lines represent pathways that violate the assumptions. The primary outcomes of the study were adult T2D and CAD, while the secondary outcomes were BMI, WC, HC, WHR, fasting glucose, 2-hour glucose, fasting insulin, HbA1c, log-transformed HOMA-B, log-transformed HOMA-IR, HDL-c, LDL-c, TC and TG levels. BMI = body mass index, CAD = coronary artery disease, HC = hip circumference, T2D = type 2 diabetes, WC = waist circumference, WHR = waist and hip ratio.

Figure 2

MR analysis results of childhood obesity and the risk of T2D and CAD using the conventional inverse variance weighted (IVW), penalized robust IVW and the weighted median methods under the IV1 model. Results are standardized to a unit increase in the log-odds of having childhood obesity. CAD = coronary artery disease, T2D = type 2 diabetes.