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Diabetes 54:1214-1221, 2005
© 2005 by the American Diabetes Association, Inc.

A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc–selective N-Acetyl-ß-D Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans

Donna M. Lehman1, Dong-Jing Fu2, Angela B. Freeman2, Kelly J. Hunt1, Robin J. Leach3,4, Teresa Johnson-Pais4, Jeanette Hamlington1, Thomas D. Dyer5, Rector Arya1, Hanna Abboud1, Harald H.H. Göring6, Ravindranath Duggirala6, John Blangero6, Robert J. Konrad5, and Michael P. Stern1

1 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
2 Lilly Research Laboratories, Indianapolis, Indiana
3 Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas
4 Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
5 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
6 Department of Nephrology, University of Texas Health Science Center, San Antonio, Texas

Excess O-glycosylation of proteins by O-linked ß-N-acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc–selective N-acetyl-ß-D glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes (P = 0.0128, relative risk = 2.77) and age at diabetes onset (P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for ~25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans.

Address correspondence and reprint requests to Donna M. Lehman, Department of Medicine/Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, Texas 78229. E-mail: lehman{at}uthscsa.edu


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