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Evidence for Sex-Specific Associations between Variation in Acid Phosphatase Locus 1 (ACP1) and Insulin Sensitivity in Mexican-Americans

Department of Preventive Medicine, Division of Biostatistics (Y.-H.S., J.H., A.H.X., H.A., R.M.W.), Institute for Genetic Medicine (J.H., H.A., N.B.), and Department of Medicine, Division of Endocrinology (E.T., T.A.B.), Keck School of Medicine of the University of Southern California, Los Angeles, California 90033; Research and Evaluation (J.M.L.), Kaiser Permanente Southern California, Pasadena, California 91101; and Departments of Physiology and Biophysics (T.A.B., R.M.W.), and Biochemistry and Molecular Biology (N.B.), Keck School of Medicine of the University of Southern California, Los Angeles, California 90033

Address all correspondence and requests for reprints to: Richard M. Watanabe, Ph.D., Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, 1540 Alcazar Street, CHP-220, Los Angeles, California 90033. E-mail: rwatanab{at}usc.edu; or Nunzio Bottini, M.D., Ph.D., Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of USC, 2250 Alcazar Street, CSC-204, Los Angeles, California 90033. E-mail: nunzio{at}usc.edu.

Context: Acid phosphatase locus 1 (ACP1) is a low molecular weight tyrosine phosphatase that has been shown to be an important regulator of insulin receptor signaling.

Objective: We tested whether variation in ACP1 is associated with type 2 diabetes-related traits in 1035 individuals in 339 Mexican-American families of probands with or without a previous diagnosis of gestational diabetes mellitus (GDM).

Design: Study participants were phenotyped by oral glucose tolerance test (for glucose and insulin level) and iv glucose tolerance test (for insulin sensitivity and acute insulin response) and had dual-energy x-ray absorptiometry scans to assess body composition. Six tag single nucleotide polymorphisms (SNPs) were identified from among 15 SNPs genotyped across the ACP1 region. SNPs were tested for association with phenotypes using a likelihood ratio test under a variance components framework.

Results: After Bonferroni correction, none of the SNPs were associated with type 2 diabetes mellitus-related phenotypes. However, we observed a significant sex-specific effect of rs3828329. Among males, rs3828329 was significantly associated with fasting insulin (Bonferroni P = 0.007) and insulin sensitivity (Bonferroni P = 0.019) and marginally associated with 2-h insulin (Bonferroni P = 0.058) and percentage body fat (Bonferroni P = 0.09).

Conclusions: There were no significant associations in females. We conclude that variation in ACP1 is associated with fasting insulin and insulin sensitivity in a sex-specific manner.