Genetic variation of glucose transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) study.
BACKGROUND
Evidence suggests glucose transporter-1 (GLUT1) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six GLUT1 single nucleotide polymorphisms(SNPs), particularly XbaI and the previously associated Enhancer-2 (Enh2) SNP.


METHODS
A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio (ACR). Cases comprised albuminuria (N = 825; ≥ 30 μg/mg) and macroalbuminuria (N = 173; ≥ 300 μg/mg). ACR < 30 μg/mg classified controls (n = 9453). Logistic regression and odds ratios (OR) assessed associations. The evaluation phase (stage 1, n = 2938) tested associations of albuminuria (n = 305) with six GLUT1 SNPs: rs841839, rs3768043, rs2297977, Enh2(rs841847) XbaI (rs841853), and rs841858. Enh2 was examined separately in the replication phase (stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes.


RESULTS
In European Americans, after adjusting for diabetes and other GLUT1 SNPs in stage 1, Enh2 risk genotype (TT) was more common in albuminuric cases (OR = 3.37, P = 0.090) whereas XbaI (OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the Enh2 association with albuminuria was significant among diabetic European Americans (OR = 2.36, P = 0.025). In African Americans, Enh2 homozygosity was rare (0.3%); XbaI was common (18.0% AA) and not associated with albuminuria. In stage 2 (n = 7,340), Enh2 risk genotype had increased but non-significant OR among diabetic European Americans (OR = 1.66, P = 0.192) and not non-diabetics (OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, Enh2 was associated with albuminuria (OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria (OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The Enh2 association with macroalbuminuria among non-diabetic European Americans with fasting insulin (OR = 1.84, P = 0.210) was stronger at the highest insulin quartile (OR = 4.08, P = 0.040).


CONCLUSIONS
As demonstrated with type 1 diabetic nephropathy, the GLUT1 Enh2 risk genotype, instead of XbaI, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the Enh2 risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Charles C
CC
Hsu
Wenhong L
WL
Kao
Michael W
MW
Steffes
Tejal
T
Gambir
Frederick L
FL
Brancati
Charles W
CW
Heilig
Alan R
AR
Shuldiner
Eric A
EA
Boerwinkle
Josef
J
Coresh
D001741:Black or African American; D000419:Albuminuria / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D051272:Glucose Transporter Type 1 / Q000235:genetics*; D006801:Humans; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide; D014481:United States; D044465:White People
D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human
J Biol Chem. 1997 Feb 28;272(9):5555-62
9038162
J Clin Invest. 1995 Oct;96(4):1802-14
7560072
Lab Invest. 1995 Nov;73(5):674-84
7474941
Diabetes Res Clin Pract. 1998 Aug;41(2):113-20
9789717
J Biol Chem. 1992 May 5;267(13):9300-6
1339457
Nature. 2001 Dec 13;414(6865):813-20
11742414
Ann Hum Biol. 2008 Sep-Oct;35(5):490-8
18821326
Hypertension. 2003 Jul;42(1):19-24
12771048
J Biol Chem. 1994 Nov 18;269(46):29265-70
7961896
Diabetes. 2002 Jul;51(7):2264-9
12086959
Am J Physiol. 1988 Mar;254(3 Pt 1):C411-6
3279808
Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1708-13
15205219
Adv Genet. 2008;60:293-308
18358325
Nephrol Dial Transplant. 2001 Aug;16(8):1653-6
11477169
Diabetes Care. 2004 Jan;27 Suppl 1:S79-83
14693934
Am J Epidemiol. 1989 Apr;129(4):687-702
2646917
Kidney Int. 2001 Mar;59(3):985-9
11231353
Kidney Int. 2001 Feb;59(2):631-6
11168944
Am J Hum Genet. 2001 Apr;68(4):978-89
11254454
Nat Genet. 2000 Mar;24(3):251-6
10700177
Genetics. 1964 Oct;50:757-82
14221879
Am J Kidney Dis. 2003 Oct;42(4):617-22
14520612
Genomics. 1995 Sep 20;29(2):311-22
8666377
J Diabetes Complications. 2005 Mar-Apr;19(2):65-9
15745834
Nat Genet. 2000 Apr;24(4):349-54
10742096
Mol Cell. 1998 Mar;1(4):575-82
9660941
Expert Rev Mol Med. 2006 Feb 06;8(4):1-18
16515729
Diabetes. 1997 Jun;46(6):1030-9
9166676
Kidney Int. 1999 May;55(5):1843-8
10231446
J Hum Genet. 2005;50(2):84-91
15682272
Biotechniques. 2002 May;32(5):1144-6, 1148, 1150 passim
12019788
J Biol Chem. 1995 Feb 10;270(6):2640-3
7852331
Am J Physiol. 1999 Jul;277(1):F97-104
10409302
Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266
11904577
Biochem J. 2001 Oct 15;359(Pt 2):273-84
11583573
Diabetes. 2005 Nov;54(11):3095-102
16249431
Am J Hum Genet. 2003 Nov;73(5):1162-9
14574645