Structural analysis of the 11 beta-hydroxysteroid dehydrogenase type 2 gene in end-stage renal disease

Background. Mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 (1 1 beta HSD2) gene cause a rare form of low-renin hypertension leading to en d-stage renal disease (ESRD) in some affected subjects. To date, no search for mutations in the HSD11B2 gene was performed in a large population to ob tain an estimate its prevalence. Methods. The HSD11B2 gene was analyzed in 587 subjects, including 260 ESRD patients (either dialysis or transplanted) for mutations in the exons 2 thr ough 5 and corresponding intronic regions by polymerase chain reaction (PCR ) using appropriate overlapping primers, gel analysis by single strand conf ormational polymorphism (SSCP), and sequencing of identified migration vari ants. Results. The prevalence of single-nucleotide polymorphisms (SNPs) in ESRD p atients and controls was 26%. The following genetic variants were found amo ng all subjects investigated: exon 2 T442G (Leu(148)/Val, N = 70) and C470A (Thr(156)/Thr, N = 67), exon 3 G534A (Glu(178)/Glu, N = 69), and exon 5 C1 274T (Asp(388)/Asp, N = 2). Four SNPs were identified in intron 4 only. In the control population, the prevalence of the variants Leu(148) and Thr(156 ) was 14% each. Glu(178) was 11%, while no variants were found in exon 5. I n ESRD patients, the prevalence of the variant Leu(148) was 9%, and Thr(156 ) was 8%. Glu(178) was 13%, while the Asp(388) variant was 0.7%. In patient s with a short duration between the time of diagnosis of the renal disease and the onset of ESRD, the prevalence of the Leu(148) and Glu(178) variants was higher than in subjects with slowly progressing renal disease. The 11 beta HSD2 activity of all of these SNPs is predictably unaltered. Conclusions. There is a high prevalence of SNPs of the HSD11B2 gene, withou t causing exonic mutations generating a 11 beta HSD2 enzyme with altered ac tivity. Based on statistical analyses, the frequency of homozygosity for mu tated alleles of the HSD11B2 gene can be derived as <1/250,000 when a Cauca sian population is considered.