Higher amino acid levels in maternal hyperglycemia: role of genetic variation in enzymatic degradation pathways?

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 806-823-Gestational Diabetes
Basic/Clinical
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-822
Jacklyn Karban*1, Loren Lynette Armstrong1, Sylvia Badon2, Denise Scholtens2, Lynn P. Lowe2, Boyd E. Metzger1, M. Geoffrey Hayes1 and William L. Lowe Jr.*1
1Feinberg School of Medicine, Northwestern University, Chicago, IL, 2Feinberg School of Medicine, Northwestern University
Maternal hyperglycemia during pregnancy is associated with greater offspring adiposity and increased childhood obesity and metabolic disorders.  The mechanisms for these associations are unknown, but the intrauterine environment is likely impacted by metabolites in addition to glucose that cross the placenta and impact fetal growth.  To address this, we have taken advantage of genome wide association (GWAS) data from mothers who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, an epidemiologic study which examined associations of glucose tolerance during pregnancy and risk of adverse pregnancy outcomes.

In a previous study, we demonstrated that 50 HAPO mothers of Northern European ancestry with high (>90th percentile) fasting plasma glucose (FPG) at 28 weeks gestation had significantly higher levels of alanine and proline compared to 50 HAPO mothers with low (<10th percentile) FPG.  A trend towards higher levels of the branched chain amino acids (BCAA) was also seen in the high FPG group.  The mechanisms underlying these differences are not known but could relate to secondary changes due to metabolic differences between groups, environmental differences, and/or genetic variation. To address the latter possibility, we addressed the hypothesis that higher levels of the above amino acids in the high FPG group are due to variation in the genes encoding enzymes involved in their degradation pathways.  SNPs were identified in loci (coding region plus 50 kb 5’ and 3’ to the gene) encoding nine enzymes important in the degradation pathways: protein phosphatase PP2C domain-containing 1K (PPM1K), branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK), branched chain aminotransferase 2 mitochondrial (BCAT2), dihydrolipoamide branched chain transacylase (DBT), dihydrolipoamide dehydrogenase (DLD), branched chain keto acid dehydrogenase E1 alpha polypeptide (BCKDHA), branched chain keto acid dehydrogenase E1 beta polypeptide (BCKDHB), proline dehydrogenase (PRODH) and alanine transaminase (GPT).  After controlling for HAPO field center, ancestry, and maternal age, mean arterial pressure, BMI, and height, 1,401 genotyped and imputed SNPs were tested for association with maternal FPG and fasting C-peptide (as a measure of insulin resistance given the association of BCAA with insulin resistance) or FPG alone (PRODH and GPT) in 4,382 HAPO mothers (1,351 European ancestry, 1,035 Afro-Caribbean, 804 Mexican American, and 1,192 Thai).

Accounting for linkage disequilibrium, a p-value of 10-3 was considered significant.  Several SNPs reached borderline significance, but none reached the pre-set level of significance.  These data suggest that it is unlikely that genetic variation in enzymes involved in amino acid degradation account for higher levels of the amino acids in mothers with high FPG and insulin resistance.

Nothing to Disclose: JK, LLA, SB, DS, LPL, BEM, MGH, WLL Jr.

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm