Recipient RAS gene variants and renal allograft function

BACKGROUND: Genetic variants of the renin-angiotensin system (RAS) have been implicated in the progression of native kidney diseases. A decreased long-term renal allograft function has also been associated with increased activity of RAS, which may be genetically determined. METHODS: The effect of the angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AGT1R), and aldosterone synthase (CYP11B2) genotypes on renal function was investigated in 223 first-allograft recipients. Graft function was estimated by yearly determinations of serum creatinine. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AGT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. RESULTS: The percentage of patients with preserved stable graft function up to 15 years after transplantation was higher when mean blood pressure was <97 mmHg, than when it was >117 mmHg (60 vs. 25% of patients). The CYP11B2 genotype predicted long-term stable graft function with more patients suffering from worsening renal function with the CYP11B2 TT than the CC genotype (P=0.002). There was a weak association between the AGT1R genotype (P=0.037), but not the AGT or ACE genotypes, and a preserved long-term graft function. Cox proportional hazards estimation showed no interactions between the observed effect of CYP11B2 genotype on renal function over time and the number of HLA class I and II matches, other RAS genotypes, graft function, or mean blood pressure at 1 year after transplantation. CONCLUSIONS: The rate of decline in renal allograft function is strongly associated with the CYP11B2 but not AGT, ACE, or AGT1R genotypes. This finding suggests that certain genetic factors related to the RAS are important determinants of long-term renal allograft function.     

Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans

TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P = 0.001-0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P = 4.2 x 10(-5), relative risk [RR] 0.69; P = 6.7 x 10(-6), respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P = 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations.