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Submitted on January 9, 2003
Accepted on April 18, 2003
1 Musculoskeletal Disease Center, JL Pettis VA Medical Center, Loma Linda, CA 92357, USA; Department of Medicine, Loma Linda University, Loma Linda, CA 92350; Department of Biochemistry, Loma Linda University, Loma Linda, CA 92350; Department of Physiology, Loma Linda University, Loma Linda, CA 92350
* To whom correspondence should be addressed. E-mail: mohans{at}lom.med.va.gov.
Recent studies using twins and inbred strains of mice reveal evidence for genetic mechanisms contributing to variation in circulating levels of IGF-I, IGF-II, and IGFBP-3. To examine the hypothesis that serum IGFBP-5 levels have a strong heritable component, we intercrossed two inbred strains of mice, MRL/MpJ and SJL, which exhibit 79% difference in serum IGFBP-5 levels (554 ± 68 vs. 309 ± 51 ng/ml respectively, P < 0.001). A genome wide scan was carried out using 137 polymorphic markers in 633 F2 female mice. Serum IGFBP-5 levels in the F2 progeny showed a normal distribution with an estimated heritability of 74%. Whole genome wide scans for co-segregation of genetic marker data with high or low serum IGFBP-5 levels revealed six different quantitative trait loci (QTL) in chromosomes 1, 9 (two), 10, and 11 (two), which together explained 26% of F2 variance. Chromosome 11 QTL exhibited the highest LOD score (7.5). Based on the past findings that IGFBP-5 is an important bone formation stimulator, we predicted IGFBP-5 to contribute to BMD variation in F2 mice. Accordingly, we found two of the six IGFBP-5 QTLs (Chrs 1, and 11) identified for serum IGFBP-5 phenotype also showed significant association with total body BMD phenotype (DEXA) in the F2 mice.
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