title: Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites.
abstract: Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites. A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006). Similarly, a G variant (f=0.40) in the van Buchem deletion region (SRP9) was associated with increased BMD in men at the FN (P=.007) and LS (P=.02). In both cases, differences between extreme genotypes reached 0.2 SD. We observed no genotype effects on fracture risk, for the 234 osteoporotic fractures validated during 8.2 years of follow-up and for the 146 vertebral prevalent fractures analyzed. We did not find association between any of several frequent haplotypes across the SOST gene region and BMD. We did find evidence of additive effects of SRP3 with the COLIA1 Sp1 polymorphism but not with haplotypes of 3' polymorphisms in the vitamin-D receptor gene. The SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST gene expression.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. a.g.uitterlinden@erasmusmc.nl
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Pascal P
authors.initials: PP
authors.lastname: Arp
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Paeper
authors.forename: Patrick
authors.initials: P
authors.lastname: Charmley
authors.forename: Sean
authors.initials: S
authors.lastname: Proll
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Yue
authors.initials: Y
authors.lastname: Fang
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: Theresa B
authors.initials: TB
authors.lastname: Britschgi
authors.forename: John A
authors.initials: JA
authors.lastname: Latham
authors.forename: Randall C
authors.initials: RC
authors.lastname: Schatzman
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
authors.forename: Mary E
authors.initials: ME
authors.lastname: Brunkow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000704:Analysis of Variance; D015519:Bone Density / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D017931:DNA Primers; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D016017:Odds Ratio; D010024:Osteoporosis / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012044:Regression Analysis; D017422:Sequence Analysis, DNA; D013124:Spinal Injuries / Q000235:genetics / Q000473:pathology; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D005819:Genetic Markers; C422903:SOST protein, human