A. L. Eriksson1, M. Suuriniemi2, A. Mahonen3, S. Cheng2, C. Ohlsson1. 1Centre for Bone Research at the Sahlgrenska Academy (CBS), Department of Internal Medicine, Göteborg University, Göteborg, Sweden, 2LIKES-Foundation for Sport and Health Sciences and Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland, 3Department of Medical Biochemistry, University of Kuopio, Kuopio, Finland.
Estrogen plays a vital role in the growth of adolescents. Catechol-O-Methyltransferase (COMT) is a key enzyme in the degradation of estrogens. A functional polymorphism in the COMT gene (val158met) decreases the activity of the enzyme by 60-75%. The aim of the present study was to investigate the influence of the COMT polymorphism on maturation and growth in early pubertal Finnish girls.
246 healthy 10-12 year old girls in Tanner stage 1-3 were genotyped for the COMT val158met polymorphism. They were classified as homozygous for the low activity genotype (COMTLL), heterozygous (COMTHL) or homozygous for the high activity genotype (COMTHH). The relationship between COMT genotype and height, bone phenotype, hormone levels and pubertal development was investigated.
Girls with COMTLL were 5,4 cm taller than girls with COMTHH and 2,4 cm taller than COMTHL (p ANOVA = 0,001). DEXA measurements showed an increase in BMC and bone area in total body, femur neck, total femur, and L2-L4 spine in COMTLL compared to COMTHH. COMTHL was an intermediate group. No major effect was seen on aBMD. pQCT measurements of the tibia showed an increased BMC in COMTLL. This was due to an increased cross sectional cortical area which in turn was caused by an increased periosteal circumference. No influence was seen on cortical or trabecular vBMD suggesting that the effects were caused by an increased longitudinal and radial growth.
COMTLL had higher levels of free estradiol and serum IGF-1, and they were more likely to be in Tanner stage 2 or 3 than COMTHH. Statistical regression models indicated that the effects of COMT genotype on bone parameters were exerted via a regulation of estrogen and/or IGF-1. The COMT genotype also influenced cross sectional muscle area. The effect on cortical bone vanished when the muscle area was included in a linear regression model suggesting that the COMT effect on cortical bone is mediated via increased muscle mass.
In conclusion the COMT polymorphism is highly associated with height, cortical bone mass and pubertal development in early pubertal girls. Most of these effects can be explained by altered estradiol and IGF-1 status. We propose that a low activity COMT phenotype results in increased estradiol levels which in turn increase the activity in the GH/IGF-1 axis, resulting in increased longitudinal and radial bone growth and earlier pubertal development.