TGF-beta1 gene variants in chronic kidney disease a candidate gene study

Background. The role of Transforming Growth Factor-beta 1 (TGF-beta1), a multifunctional cytokine with a key role in tissue repair and fibrosis, in progressive kidney injury has been well characterized in experimental as well as human studies.;Objective. We conducted a candidate gene association study to examine the role of genetic variants in the TGF-beta1 gene in the susceptibility to and severity of chronic kidney disease (CKD) addressing the limitations of prior studies in the field.;Methods. Variants in the TGF-a1 gene were studied in three independent populations with three study designs---a cohort study of patients with CKD, where we measured plasma and urinary TGF-beta1 levels, a case-control study of type 1 diabetic individuals with and without diabetic kidney disease (DKD) from the Genetics in Kidney Disease in Diabetes (GoKinD) study, and a family based association study in a parent-offspring trio population also from the GoKinD study. Genotyping was carried out by TaqMan PCR (Applied Biosystems 7900HT). Urinary and plasma TGF-beta1 levels were measured by immunoassay.;Results. Among 178 patients in the CKD cohort the presence of one or more T alleles in rs8179181 was associated with lower GFR at baseline (p=0.01), steeper decline in eGFR over time and higher risk of kidney disease progression (HR 3.0, 95%CI 1.2-7.9). No relationship was noted to plasma or urinary TGF-beta1 levels, but a doubling of plasma TGF-beta1 levels was independently associated with a HR of 1.84 (95%CI 1.2-5.1) for CKD progression. The family based association study of 254 case trios and 309 control trios showed significant overtransmission of the T allele of the SNP rs8179181 to cases and undertransmission to control offspring (p<0.01) indicating the presence of both linkage to and association with disease.;Bioinformatic analysis showed that the SNP rs8179181 located in the fifth intron, was a putative exon splicer enhancer or transcription factor binding site. Gene sequencing showed three novel variants, one being a synonymous SNP in the seventh exon of the gene, in proximity to the SNP rs8179181.;Conclusions. The SNP rs8179181 was associated with susceptibility to and progression of CKD. This SNP may have a regulatory function in mRNA splicing. Future study should undertake full functional characterization of this variant as well as explore novel variants in the 3' region of the gene. The discovery of genetic risk factors for CKD could play a major role in risk stratification of patients for targeted prevention and treatment strategies.