TGF-beta 1 as a genetic susceptibility locus for advanced diabetic nephropathy in type 1 diabetes mellitus: an investigation of multiple known DNA sequence variants.
BACKGROUND
Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine suspected to be a crucial factor underlying glomerulosclerosis in advanced diabetic nephropathy. However, its potential role as a susceptibility gene for the development of this microvascular complication is unresolved.


METHODS
We examined whether DNA sequence variants in the TGF-beta1 gene are associated with advanced diabetic nephropathy among Caucasians with type 1 diabetes mellitus. These variants included three coding (Leu10Pro, Arg25Pro, and Thr263Ile) and two noncoding single-nucleotide polymorphisms (-800 and -509), as well as an insertion/deletion of a cytosine residue in intron 4. A large case-control study design was used in which cases were patients with type 1 diabetes with advanced diabetic nephropathy (presence of persistent proteinuria or end-stage renal disease [ESRD]; n = 298) and controls were patients who remained normoalbuminuric despite greater than 15 years of type 1 diabetes (n = 263).


RESULTS
Genotype frequencies for all polymorphisms were in Hardy-Weinberg equilibrium. Genotype distributions of all six DNA sequence variants were very similar between cases and controls (P = not significant). There was no significant difference in genotype distributions among cases regardless of whether these individuals with diabetes were proteinuric at the time of examination or had already developed ESRD secondary to diabetic nephropathy. Stratified analyses according to diabetes duration and glycemic control likewise did not detect an association between DNA sequence variants and advanced diabetic nephropathy.


CONCLUSIONS
Genetic variation at the TGF-beta1 locus is unlikely to confer significant susceptibility to advanced diabetic nephropathy in patients with type 1 diabetes mellitus.
Ng
Daniel P K
DP
Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA 02215, USA.
Warram
James H
JH
Krolewski
Andrzej S
AS
D000293:Adolescent; D000328:Adult; D000419:Albuminuria / Q000235:genetics; D016022:Case-Control Studies; D003404:Creatinine / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000652:urine; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics; D012709:Serum Albumin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D044465:White People / Q000235:genetics
D005819:Genetic Markers; D007328:Insulin; D012709:Serum Albumin; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003404:Creatinine