title: Causal relationship between the AHSG gene and BMD through fetuin-A and BMI: multiple mediation analysis.
abstract: Using mediation analysis, a causal relationship between the AHSG gene and bone mineral density (BMD) through fetuin-A and body mass index (BMI) mediators was suggested.
  
  
  BACKGROUND
  Fetuin-A, a multifunctional protein of hepatic origin, is associated with bone mineral density. It is unclear if this association is causal. This study aimed at clarification of this issue.
  
  
  METHODS
  A cross-sectional study was conducted among 1,741 healthy workers from the Electricity Generating Authority of Thailand (EGAT) cohort. The alpha-2-Heremans-Schmid glycoprotein (AHSG) rs2248690 gene was genotyped. Three mediation models were constructed using seemingly unrelated regression analysis. First, the ln[fetuin-A] group was regressed on the AHSG gene. Second, the BMI group was regressed on the AHSG gene and the ln[fetuin-A] group. Finally, the BMD model was constructed by fitting BMD on two mediators (ln[fetuin-A] and BMI) and the independent AHSG variable. All three analyses were adjusted for confounders.
  
  
  RESULTS
  The prevalence of the minor T allele for the AHSG locus was 15.2%. The AHSG locus was highly related to serum fetuin-A levels (P < 0.001). Multiple mediation analyses showed that AHSG was significantly associated with BMD through the ln[fetuin-A] and BMI pathway, with beta coefficients of 0.0060 (95% CI 0.0038, 0.0083) and 0.0030 (95% CI 0.0020, 0.0045) at the total hip and lumbar spine, respectively. About 27.3 and 26.0% of total genetic effects on hip and spine BMD, respectively, were explained by the mediation effects of fetuin-A and BMI.
  
  
  CONCLUSIONS
  Our study suggested evidence of a causal relationship between the AHSG gene and BMD through fetuin-A and BMI mediators.
authors.affiliation: Department of Diagnostic and Therapeutic Radiology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, chanika.sri@mahidol.edu.
authors.forename: C
authors.initials: C
authors.lastname: Sritara
authors.forename: A
authors.initials: A
authors.lastname: Thakkinstian
authors.forename: B
authors.initials: B
authors.lastname: Ongphiphadhanakul
authors.forename: L
authors.initials: L
authors.lastname: Chailurkit
authors.forename: S
authors.initials: S
authors.lastname: Chanprasertyothin
authors.forename: W
authors.initials: W
authors.lastname: Ratanachaiwong
authors.forename: P
authors.initials: P
authors.lastname: Vathesatogkit
authors.forename: P
authors.initials: P
authors.lastname: Sritara
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods; D000328:Adult; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006621:Hip Joint / Q000502:physiology; D006801:Humans; D008159:Lumbar Vertebrae / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D060749:alpha-2-HS-Glycoprotein / Q000032:analysis / Q000235:genetics* / Q000502:physiology*
chemical_list: C556354:AHSG protein, human; D060749:alpha-2-HS-Glycoprotein