PubMed · 11627893
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D A Depalma. 1976-08-12. [Not Available].. https://pubmed.ncbi.nlm.nih.gov/11627893/
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BACKGROUND: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory β₁-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. METHODS: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). RESULTS: The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). CONCLUSIONS: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.
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We have analyzed the steady-state levels of cytochrome P-450 1A1 (CYP1A1) mRNA in peripheral blood lymphocytes of 177 individuals with various CYP1A1 genotypes using a quantitative reverse transcriptase-polymerase chain reaction technique that makes use of a homologous internal standard for accurate quantitation. We found no effects of ethnicity, age, or smoking status on CYP1A1 gene expression in this population. We did see a significant 2-fold increase in the mean level of CYP1A1 mRNA in women compared with men for both Caucasians and African Americans. We observed no effect of the African American-specific polymorphism (CYP1A1(*)3) on expression of the gene. However, we found a significant 3-fold decrease in expression associated with the homozygous MspI restriction fragment length polymorphism (CYP1A1(*)2A/(*)2A).