Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men.
In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5' UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P = 0.004), and lower whole body BMD (P < 0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P < 0.01), and higher whole body BMD (P < 0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P < 0.05), and higher whole body BMD (P < 0.01). Significant gene-gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.
Hsu
Yi-Hsiang
YH
Program for Population Genetics, Harvard School of Public Health, 665 Huntington Avenue, FXB-101, Boston, MA, USA.
Niu
Tianhua
T
Terwedow
Henry A
HA
Xu
Xin
X
Feng
Yan
Y
Li
Zhiping
Z
Brain
Joseph D
JD
Rosen
Cliff J
CJ
Laird
Nan
N
Xu
Xiping
X
D000328:Adult; D000368:Aged; D000483:Alleles; D000886:Anthropometry; D015519:Bone Density / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D053244:Osteoprotegerin; D020641:Polymorphism, Single Nucleotide; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human