The obesity-risk variant of FTO is inversely related with the So-Eum constitutional type: genome-wide association and replication analyses

BACKGROUND Body constitutional types described in the traditional Korean medicine system, Sasang constitutional medicine, are heritable, as has been revealed by twin and family studies. Thus, individuals with the same constitution type usually have similar pathophysiological and psychological traits. In several recent genome-wide association (GWA) analyses performed to identify constitution-associated variants, the association signals were not replicated due to small sample size and dissimilar, non-objective methods for classification of the constitutional types. METHODS We conducted GWA analysis and followed replication analysis in two large populations (5,490 subjects: 3,810 subjects at discovery stage and 1,680 subjects at replication stage) to identify the replicable constitution-associated variants, wherein subjects with the highest tertile of constitution probability values versus the reference with the lowest tertile of the values obtained from a recently developed constitution analysis tool were compared. RESULTS We found that the obesity-risk variant in intron 1 of the fat mass and obesity-associated (FTO) gene was replicably inversely associated with the So-Eum (SE) type, characterized by reduced appetite, slim body, and cautious personality (rs7193144 in combined samples: odds ratio = 0.729, p = 1.47 × 10(-7)), and substantial association signal remained after controlling for body mass index (BMI). In contrast, the association of the variant with the Tae-Eum type, characterized by high body mass, disappeared after controlling BMI. CONCLUSIONS In summary, the obesity-risk variant in FTO intron 1 was inversely associated with the SE type, independent of BMI, which corresponded well with the characteristics of the SE type, such as the lowest body mass and lowest susceptibility to metabolic disorders among the constitutional types. Therefore, the obesity-risk variant of FTO associated with body mass increase might be involved in the determination of body constitution type.