Causal relationship between body mass index and fetuin-A level in the asian population: a bidirectional Mendelian randomization study.

OBJECTIVE: Fetuin-A is associated with body mass index (BMI) as well as components of the metabolic syndrome. However, it is unclear if fetuin-A affects BMI or the other way around. We therefore assessed the causal association between fetuin-A and BMI or vice versa, utilizing a bidirectional Mendelian randomization approach.

DESIGN AND METHODS: This was a study of 2558 subjects from the Electricity Generating Authority of Thailand (EGAT) cohort. Two polymorphisms, that is, rs2248690 in the alpha2-Hereman-Schmid glycoprotein (AHSG) gene and rs9939609 in the fat mass and obesity-associated (FTO) gene were genotyped. Bidirectional causal models were constructed using a two-stage least-square instrumental variable (IV) regression. First, rs2248690 locus was used as the instrumental variable for the effect of circulating fetuin-A on BMI, and then, the FTO rs9939609 locus was used as the instrumental variable for the effect of BMI on circulating fetuin-A.

RESULTS: Among the 2558 subjects, the prevalence of the minor AHSG (T) and FTO (A) alleles was 17.9% and 22.1%, respectively. The AHSG rs2248690 locus was highly related to serum fetuin-A levels (P < 0.001). Likewise, the FTO rs9939609 locus and BMI were highly associated (P < 0.001). Mendelian randomization analyses showed that circulating fetuin-A, instrumented by the AHSG rs2248690 locus, was associated with BMI (coefficient = 2.26; 95% CI: 0.39, 4.12). In contrast, BMI, instrumented by the FTO rs9939609 locus, was not associated with circulating fetuin-A (coefficient = 0.0007; 95% CI: -0.0242, 0.0256).

CONCLUSION: Our findings suggest a causal association leading from circulating fetuin-A to BMI. There was no evidence of reverse causality from BMI to fetuin-A.