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Height in Pre- and Postmenopausal Women Is Influenced by Estrogen Receptor Gene Polymorphisms

Departments of Internal Medicine (S.C.E.S., J.B.J.v.M., A.P.B., M.v.d.K., Y.F., J.P.T.M.v.L., A.G.U., H.A.P.P.) and Epidemiology and Biostatistics (S.C.E.S., A.P.B., M.v.d.K., A.H., A.G.U., H.A.P.P.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands; and Diagnostic Center Eindhoven (G.L., H.A.P.P.), 5611 NE Eindhoven, The Netherlands

Address all correspondence and requests for reprints to: Dr. André G. Uitterlinden, Genetic Laboratory, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: a.g.uitterlinden{at}erasmusmc.nl.

The estrogen receptor gene (ESR1) is known to be involved in metabolic pathways influencing growth. We have performed two population-based association studies using three common polymorphisms within this candidate gene to determine whether these are associated with variation in adult stature. In 607 women, aged 55–80 yr, from the Rotterdam Study, the ESR1 PvuII-XbaI haplotype 1 (px) and the L allele of the TA repeat polymorphism (<18 TA repeats) were significantly associated with an allele dose-dependent decrease in height. The per allele copy of ESR1 PvuII-XbaI haplotype 1 height was 0.9 cm shorter (P trend = 0.02) and 1.0 cm/allele copy of the TA repeat L allele (P trend = 0.003). These results were independent of age, age at menarche and menopause, and lumbar spine bone mineral density and remained significant after participants with vertebral fractures were excluded. In 483 men from the Rotterdam Study we found no association with height. In 1500 pre- and perimenopausal women from the Eindhoven Study a similar association was observed; women were 0.5 cm shorter per allele copy of the ESR1 haplotype 1 (P for trend = 0.03). In conclusion, we demonstrate a role for genetic variations in the estrogen receptor gene in determining adult stature in women.

This work was supported by The Netherlands Organization of Scientific Research Institute for Diseases in the Elderly (Grant 014-90-001).

Abbreviations: BMI, Body mass index; BMD, bone mineral density; DEXA, dual energy x-ray absorptiometry; LRH, long-range haplotype; RFLP, restriction fragment length polymorphism; VNTR, variable number of tandem repeat.

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