Association of Arachidonate 12-Lipoxygenase Genotype Variation and Glycemic Control With Albuminuria in Type 2 Diabetes

Yongmei Liu, Barry I. Freedman, Kathryn P. Burdon, Carl D. Langefeld, Timothy Howard, David Herrington, David C. Goff, Donald W. Bowden, Lynne E. Wagenknecht, Catherine C. Hedrick, Stephen S. Rich

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Background: Glycemic exposure activates 12-lipoxygenase (12LO) expression and formation of arachidonic acid-derived products. These products can induce cell hypertrophy, cell proliferation, and extracellular matrix deposition, potentially leading to diabetic nephropathy. Study Design: Cross-sectional study. Settings & Participants: 955 European-American siblings from 369 Diabetes Heart Study families. Participants were categorized as nondiabetic, diabetic with hemoglobin A1c level less than 6.5%, and diabetic with hemoglobin A1c level greater than 6.5% (uncontrolled type 2 diabetes mellitus). Predictor: Four haplotype-tagging variants in the arachidonate 12LO gene (ALOX12), glycemic control, and other covariates. Outcomes & Measurements: Albuminuria measured by means of urinary albumin-creatinine ratio (ACR). Results: Median ACR was 11.9 mg/g (interquartile range, 5.6 to 39.1). The overall test of the Arg261Gln genotypic association with ACR was significant (P = 0.009). Compared with 261Arg allele carriers, adjusted mean ACR was 42% greater in the 189 carriers of two 261Gln alleles (95% confidence interval, 10 to 83; P = 0.007). This association was confined to the group with uncontrolled type 2 diabetes mellitus (N = 623) with the greatest ACRs (P < 0.001). Adjustments for additional determinants of ACR yielded similar results. Limitations: Urine ACR was measured in duplicate on only a single occasion. This study was limited to European Americans. Conclusions: Consistent with animal and cellular studies, these results provide additional evidence of the importance of the 12LO pathway in the pathogenesis of human diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)242-250
Number of pages9
JournalAmerican Journal of Kidney Diseases
Issue number2
StatePublished - Aug 2008
Externally publishedYes


  • albuminuria
  • ALOX12 gene
  • diabetic nephropathy
  • genetics
  • Lipoxygenase
  • type 2 diabetes mellitus

ASJC Scopus subject areas

  • Nephrology


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