A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French-Canadian premenopausal women.
Genes are important BMD determinants. We studied the association of an ESRRA gene functional variant with BMD in 1335 premenopausal women. The ESRRA genotype was an independent predictor of L2-L4 BMD, with an effect similar to smoking and equivalent to a 10-kg difference in weight.


BACKGROUND
Several genetic polymorphisms have been associated with osteoporosis or osteoporosis fractures, but no functional effect has been shown for most of these gene variants. Because functional studies have implicated estrogen-related receptor alpha (ESRRA) in bone metabolism, we evaluated whether a recently described regulatory variant of the ESRRA gene is associated with lumbar and hip BMD as measured by DXA and with heel bone parameters as measured by quantitative ultrasound (QUS).


METHODS
Heel bone parameters were measured by right calcaneal QUS in 1335 healthy French-Canadian premenopausal women, and one-half of these women also had their BMD evaluated at two sites: femoral neck and lumbar spine (L2-L4) by DXA. All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance. The significance of the ESRRA contribution to the model was also assessed by two different permutation tests.


RESULTS
A statistically significant association between ESRRA genotype and lumbar spine BMD was observed: women carrying the long ESRRA genotype had a 3.9% (0.045 g/cm2) higher lumbar spine BMD than those carrying the short ESRRA genotype (p = 0.004), independently of other risk factors measured. This effect of ESRRA genotype is similar to the effect of smoking and equivalent to a 10-kg difference in weight. This association was confirmed by permutation tests (p = 0.004). The same trend was observed for femoral neck BMD (2.6%, p = 0.07). However, no association was observed between ESRRA and QUS heel bone measures.


CONCLUSIONS
These results support the genetic influence of this ESRRA regulatory variant on BMD.
Laflamme
Nathalie
N
Institut National de Santé Publique du Quebec, Ste-Foy, Quebec, Canada. nathalie.laflamme@inspq.qc.ca
Giroux
Sylvie
S
Loredo-Osti
J Concepción
JC
Elfassihi
Latifa
L
Dodin
Sylvie
S
Blanchet
Claudine
C
Morgan
Kenneth
K
Giguère
Vincent
V
Rousseau
François
F
D015502:Absorptiometry, Photon; D000328:Adult; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D002170:Canada; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005272:Femur Neck / Q000473:pathology; D015723:Gene Library; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008159:Lumbar Vertebrae / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D017697:Premenopause; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D014463:Ultrasonography; D000097983:ERRalpha Estrogen-Related Receptor
D018076:DNA, Complementary; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor