title: Relative influence of heritability, environment and genetics on serum sclerostin.
abstract: CONCLUSIONS
  We determined factors associated with serum sclerostin in 446 Afro-Caribbean family members. Age, weight, sex, diabetes and kidney function were associated with sclerostin. Sclerostin was heritable, and nine SNPs in the SOST gene region were associated with sclerostin. Variation in serum sclerostin is a heritable factor that is determined by both genetic and environmental factors.
  
  
  BACKGROUND
  Sclerostin, encoded by the SOST gene, is a Wnt inhibitor that regulates bone mineralization and is a candidate gene locus for osteoporosis. However, little is known about the genetic and non-genetic sources of inter-individual variation in serum sclerostin levels.
  
  
  METHODS
  Serum sclerostin was measured in 446 Afro-Caribbean men and women aged 18+ from seven large, multigenerational families (mean family size, 64; 3,840 relative pairs). Thirty-six common single nucleotide polymorphisms (SNP) were genotyped within a 100 kb region encompassing the gene encoding sclerostin (SOST). Genetic and non-genetic factors were tested for association with serum sclerostin.
  
  
  RESULTS
  Mean serum sclerostin was 41.3 pmol/l and was greater in men than in women (P < 0.05). Factors associated with higher serum sclerostin were increased age and body weight, male sex, diabetes and decreased glomerular filtration rate, which collectively accounted for 25.4 % of its variation. Residual genetic heritability of serum sclerostin was 0.393 (P < 0.0001). Nine SNPs reached nominal significance with sclerostin. Three of those nine SNPs represented independent association signals (rs851056, rs41455049 and rs9909172), which accounted for 7.8 % of the phenotypic variation in sclerostin, although none of these SNPs surpassed a Bonferroni correction for multiple comparisons.
  
  
  CONCLUSIONS
  Serum sclerostin is a heritable trait that is also determined by environmental factors including age, sex, adiposity, diabetes and kidney function. Three independent common SNPs within the SOST region may collectively account for a significant proportion of the variation in serum sclerostin.
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA, kuipers@pitt.edu.
authors.forename: A L
authors.initials: AL
authors.lastname: Kuipers
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.forename: C M
authors.initials: CM
authors.lastname: Kammerer
authors.forename: C S
authors.initials: CS
authors.lastname: Nestlerode
authors.forename: Y
authors.initials: Y
authors.lastname: Chu
authors.forename: C H
authors.initials: CH
authors.lastname: Bunker
authors.forename: A L
authors.initials: AL
authors.lastname: Patrick
authors.forename: V W
authors.initials: VW
authors.lastname: Wheeler
authors.forename: I
authors.initials: I
authors.lastname: Miljkovic
authors.forename: J M
authors.initials: JM
authors.lastname: Zmuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood; D000886:Anthropometry / Q000379:methods; D019485:Bone Morphogenetic Proteins / Q000097:blood* / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood; D005260:Female; D059647:Gene-Environment Interaction; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human