OPG and RANK polymorphisms are both associated with cortical bone mineral density: findings from a metaanalysis of the Avon longitudinal study of parents and children and gothenburg osteoporosis and obesity determinants cohorts.
BACKGROUND
Several single-nucleotide polymorphisms (SNPs) have been reliably associated with areal bone mineral density (aBMD) in genome-wide association studies of mostly older subjects.


OBJECTIVE
We aimed to test those SNPs for an association with peripheral quantitative computed tomography (pQCT) bone measures in two young cohorts.


METHODS
We genotyped nine SNPs from the most promising aBMD candidates in a cohort of 15-yr-olds [in the Avon Longitudinal Study of Parents and Children (ALSPAC)] and carried out association analysis with several tibial pQCT measures to determine whether these candidates were important during adolescent growth and which particular skeletal parameters each of the candidates were acting upon. We also carried out a metaanalysis of the SNPs for association with cortical bone mineral density (BMDC) in ALSPAC and a similar male-only study (Gothenburg Osteoporosis and Obesity Determinants).


RESULTS
In the ALSPAC cohort, we found a significant association between RANK SNP (rs3018362) and BMDC but not any of the other pQCT bone measures. In the metaanalysis, we found the OPG SNP (rs4355801) and the RANK SNP (rs3018362) to be significantly associated with BMDC. We also found suggestive evidence of an association between the MARK3 SNP (rs2010281) and BMDC but with a direction of effect opposite to that previously reported.


CONCLUSIONS
The association of genes from the RANK/RANKL/OPG pathway and BMDC provides new insight into how this system might affect the skeleton, confirming it to be associated with volumetric cortical bone density but observing no relationship with bone size.
Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. l.paternoster@bristol.ac.uk
L
L
Paternoster
C
C
Ohlsson
A
A
Sayers
L
L
Vandenput
M
M
Lorentzon
D M
DM
Evans
J H
JH
Tobias
D000293:Adolescent; D000328:Adult; D015519:Bone Density / Q000235:genetics*; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009765:Obesity / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics*; D053244:Osteoprotegerin / Q000235:genetics*; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*
D053244:Osteoprotegerin; D053246:Receptor Activator of Nuclear Factor-kappa B