Association of arachidonate 12-lipoxygenase genotype variation and glycemic control with albuminuria in type 2 diabetes.
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.


METHODS
Cross-sectional study.


METHODS
955 European-American siblings from 369 Diabetes Heart Study families. Participants were categorized as nondiabetic, diabetic with hemoglobin A(1c) level less than 6.5%, and diabetic with hemoglobin A(1c) level greater than 6.5% (uncontrolled type 2 diabetes mellitus).


METHODS
Four haplotype-tagging variants in the arachidonate 12LO gene (ALOX12), glycemic control, and other covariates.


METHODS
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.


CONCLUSIONS
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.
Liu
Yongmei
Y
Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, UAS. yoliu@wfubmc.edu
Freedman
Barry I
BI
Burdon
Kathryn P
KP
Langefeld
Carl D
CD
Howard
Timothy
T
Herrington
David
D
Goff
David C
DC
Bowden
Donald W
DW
Wagenknecht
Lynne E
LE
Hedrick
Catherine C
CC
Rich
Stephen S
SS
D000328:Adult; D000419:Albuminuria / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D015995:Prevalence; D044469:Racial Groups; D012189:Retrospective Studies; D014481:United States / Q000453:epidemiology
D001092:Arachidonate 12-Lipoxygenase; D001786:Blood Glucose; D004247:DNA; D006442:Glycated Hemoglobin