Table of Contents 21-4

COMT Polymorphism in Early Puberty

Estrogens are initially metabolized by a P450 hydroxylase to less biologically active catechol-estrogens and further degraded by catecholamine-O-methyltransferase (COMT) to inactive products. COMT transfers a methyl group from S-adenosylmethionine to the catechol-estrogen. Within the structure of COMT (OMIM 116790, chromosome 22q11) is a functional polymorphism that results in the substitution of methionine for valine in codon 158 (val158met). The COMT product containing val158 is 3 to 4 fold more biologically active than is that with met158.

Hypothesizing that the COMT val158met polymorphism effect on estrogen catabolism might be reflected in the biologic activity of endogenous estrogen, the investigators examined the relationship between linear growth, bone mineralization, and sexual development in prepubertal and early pubertal, 10-12 year old girls and the high (H) and low (L) polymorphic variants of COMT (COMT^HH and COMT^LL, n=43 and n=85, respectively). Although total serum estradiol concentrations were similar in COMT^HH and COMT^LL girls, levels of free estradiol as well as IGF-I were higher in COMT^LL subjects. The authors reported that at the time of study COMT^LL subjects were 5.4 cm taller than were COMT^HH girls, had greater lean body mass, and appeared to progress further into puberty at a more rapid rate than did COMT^HH girls. Total bone mineral content (BMC) by DEXA was 12.7% greater in COMT^LL than in COMT^HH girls due primarily to increased bone size; thus, volumetric bone mineral density was similar among groups. Cortical BMC and cortical cross-sectional area by peripheral quantitative computerized tomography (pQCT) were highest in COMT^LL subjects due primarily to increased periosteal circumference. There was no relationship between COMT variant and trabecular volume or mineralization. Serum free estradiol values were related to these varied aspects of growth and mineral metabolism and thus indirectly to the COMT polymorphic variants. The authors concluded that the val158met COMT polymorphism exerted significant effects on growth, pubertal development, and bone mineralization in pre- and early adolescent girls, primarily by increasing serum concentrations of free estradiol by altering the rate of catabolism of endogenous estrogens.

Eriksson A-L, Suuriniemi M, Mahonen A, Cheng S, Ohlsson C. The COMT val158met polymorphism is associated with early pubertal development, height and cortical bone mass in girls. Pediatric Res. 2005; 58:71-77.

Editor’s Comment: COMT may now be added to the growing list of recognized genes that influence the rates of growth and sexual development and bone mineralization; this report emphasized the extensive genetic variability in these processes. Although COMT LL girls were 5 cm taller than COMT HH subjects at 10-12 years of age, the effect of the COMT val158 met polymorphism on adult height is likely to be less impressive as the COMT LL subjects will probably complete their pubertal development and achieve their adult height at an earlier age than the COMT HH children. It would be of interest to learn the bone ages of the study subjects and later their ages of menarche and their adult heights. Similar studies relating COMT genotype and growth, pubertal maturation, and bone mineralization would also be of interest.

Allen W. Root, MD