title: Causal relationship between body mass index and fetuin-A level in the asian population: a bidirectional Mendelian randomization study.
abstract: 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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Ammarin
authors.initials: A
authors.lastname: Thakkinstian
authors.forename: Laor
authors.initials: L
authors.lastname: Chailurkit
authors.forename: Daruneewan
authors.initials: D
authors.lastname: Warodomwichit
authors.forename: Wipa
authors.initials: W
authors.lastname: Ratanachaiwong
authors.forename: Sukit
authors.initials: S
authors.lastname: Yamwong
authors.forename: Suwannee
authors.initials: S
authors.lastname: Chanprasertyothin
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.forename: Piyamitr
authors.initials: P
authors.lastname: Sritara
authors.forename: Boonsong
authors.initials: B
authors.lastname: Ongphiphadhanakul
mesh_terms: D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D044466:Asian People; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D005260:Female; D060748:Fetuins / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D060749:alpha-2-HS-Glycoprotein / Q000378:metabolism*
chemical_list: C556354:AHSG protein, human; D060748:Fetuins; D011506:Proteins; D060749:alpha-2-HS-Glycoprotein; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human