Abstract
Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases. Here, we conducted genome-wide association studies (GWASs) to identify the MUHNW and MHO genetic indices. The study dataset comprised genome-wide single-nucleotide polymorphism genotypes and epidemiological data from 49,915 subjects categorised into four phenotypes—metabolically healthy normal weight (MHNW), MUHNW, MHO, and metabolically unhealthy obese (MUHO). We conducted two GWASs using logistic regression analyses and adjustments for confounding variables (model 1: MHNW versus MUHNW and model 2: MHO versus MUHO). GCKR, ABCB11, CDKAL1, LPL, CDKN2B, NT5C2, APOA5, CETP, and APOC1 were associated with metabolically unhealthy phenotypes among normal weight individuals (model 1). LPL, APOA5, and CETP were associated with metabolically unhealthy phenotypes among obese individuals (model 2). The genes common to both models are related to lipid metabolism (LPL, APOA5, and CETP), and those associated with model 1 are related to insulin or glucose metabolism (GCKR, CDKAL1, and CDKN2B). This study reveals the genetic architecture of the MUHNW and MHO phenotypes in a Korean population-based cohort. These findings could help identify individuals at a high metabolic risk in normal weight and obese populations and provide potential novel targets for the management of metabolically unhealthy phenotypes.
Highlights
Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases
Determining the genetic characteristics associated with the MHO and MUHNW phenotypes will enable us to pinpoint the biological mechanisms driving these two paradoxical conditions and develop approaches to prevent cardiometabolic diseases
Several genomic studies have identified numerous genetic variants associated with adiposity in the context of a favourable cardiometabolic profile; many of these loci are located in or near genes involved in adipogenesis, fat distribution, and insulin s ignalling[18,19]
Summary
Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases. The mechanisms that determine why some individuals with obesity remain free from metabolic complications while others with normal weight are susceptible to metabolic complications are not fully understood, previous studies have shown the biological mechanisms possibly associated with the MHO and MUHNW phenotypes, apart from demographic factors (e.g., age, sex, and ethnicity) and environmental factors (e.g., physical activity, smoking, and alcohol intake) These studies indicated that reduced abdominal fat mass and increased gluteofemoral fat mass are associated with the metabolically healthy phenotype, whereas elevated abdominal fat mass and lower gluteofemoral fat mass contribute to the metabolically unhealthy phenotype[12,13,14]. We conducted GWASs to identify candidate genes harbouring single-nucleotide polymorphisms (SNPs) associated with the MHO and MUHNW phenotypes in a large Korean population-based cohort
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
