Haplotype effect in the IGF1 promoter accounts for the association between microsatellite and serum IGF1 concentration

P>Objective Systemic insulin-like growth factor 1 (IGF1) level is an important risk factor for various diseases. The inter-individual variation of serum IGF1 is determined by environmental and genetic factors, which are attributed to a microsatellite in IGF1 promoter. However, the exact nature of the underlying regulatory elements accounting for this association has not been characterized. Here, we defined the haplotype patterns, including both SNPs and the microsatellite, in the Chinese population, and investigated their regulatory effect on serum IGF1 level. This is the first study in which haplotype patterns of the microsatellite and SNPs in the IGF1 promoter are examined together. Methods The linkage disequilibrium (LD) patterns of IGF1 were examined using tagSNPs of the IGF1 regulatory region. The microsatellite, three tagSNPs and haplotypes were correlated with serum IGF1 concentration in 450 normal premenopausal Chinese women. Results Common alleles of the microsatellite were in strong LD with the three tagSNPs and were associated with particular haplotypes composed of SNPs. Neither the CA repeat number nor SNPs alone showed a robust association with serum IGF1 concentration. On the other hand, the haplotype T-19-A-T was significantly associated with serum IGF1 level. Conclusion No association was found between SNPs and microsatellite alone. However, the haplotype showed better correlation with serum IGF1 level. The results indicate that the previously observed correlation with microsatellite was because of a haplotype effect in the IGF1 promoter. Microsatellite or tagSNPs alone are not the primary regulatory elements of IGF1 expression. The exact regulatory genetic variant needs to be defined by functional genetic studies.