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Association Between Serum Insulin Growth Factor-I (IGF-I) and a Simple Sequence Repeat in IGF-I Gene: Implications for Genetic Studies of Bone Mineral Density

The Jackson Laboratory (C.J.R., D.V.), Bar Harbor, Maine 04605; Department of Medicine (E.S.K., J.P.B.) and Department of Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Medical College of Virginia and McGuire Veterans Administration Hospital (R.A.A.), Richmond, Virginia 23249; Beth Israel Medical Center (P.J.R.), New York, New York 10003; Foundation for Blood Research (W.Y.C.), Scarborough, Maine 04070; and Southwest Foundation for Biomedical Research (S.W., J.R.), San Antonio, Texas 78228

Address all correspondence and requests for reprints to: Clifford J. Rosen, Maine Center for Osteoporosis Research and Education, St. Joseph Hospital, 360 Broadway, Bangor, Maine 04401. E-mail: crosen{at}maine.maine.edu

We recently demonstrated that insulin growth factor-I (IGF-I) cosegregates with bone mineral density (BMD) in progenitor crosses of two inbred strains of mice. Additionally, we reported that men with idiopathic osteoporosis (IOM) have low serum IGF-I levels, which can be related to BMD and bone turnover. In this study, we considered the possibility that serum IGF-I levels are influenced by molecular genetic variation in the IGF-I structural gene, and that a polymorphic microsatellite (CA repeat) in this locus can be used as a genetic marker for such comparisons. We studied 171 men and women, classified according to the trial in which they were participating. First, in 25 Caucasian men with IOM we noted a very high frequency (64%) of homozygosity for the most common allele (192 bp) in a dinucleotide repeat 1 kb upstream from the transcription start site of the IGF-I gene. This compared with a frequency of only 32% in healthy populations (both men and women) (P < 0.004). Next, we determined that for 116 healthy Caucasian men and women the 192/192 genotype was associated with lower serum IGF-I levels than all other genotypes (192/192: 129±7 ng/mL vs.. others: 154 ± 7 ng/mL, P = 0.03). We also noted that subjects possessing one 194-bp allele exhibited serum IGF-I levels 25% higher than those homozygous for 192 bp (192/192), (P < 0.005) even after correction for age and sex. Similarly, for men with the 192/192 genotype, serum IGF-I concentrations were lower than any other genotype (145 ± 10 ng/mL vs.. 183 ± 9 ng/ml P < 0.02). In conclusion, low serum IGF-I levels found in men with IOM are associated with homozygosity for a specific allele of the IGF-I microsatellite (192/192), and individual variation in serum IGF-I levels is influenced by genetic factors and may be specifically influenced by variation at the IGF-I structural locus. Further family and pedigree studies are needed to characterize the relationship of bone mass acquisition to the IGF-I genotype.

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