PubMed · 10843019
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R A Aronson. 2000. A work in progress.. https://pubmed.ncbi.nlm.nih.gov/10843019/
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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.
We examined age- and sex-standardized risk ratios (SRRs) in matched samples of 1,185 families of obese African-American and Caucasian women. Familial risk ratios increased with body mass index (BMI) of proband and BMI thresholds of relative. Ratios were higher in Caucasian than African-American families, apparently because Caucasian probands were more extreme relative to their population mean. Risk ratios for moderate obesity (BMI >/= 30) were around 2 for African-Americans and were a little higher in Caucasians. Ratios for extreme obesity (BMI >/= 40) ranged from 3 to 5 in African-Americans and from about 5 to 9 in Caucasians. Thin relatives were rare in families of both races. Risk ratios appear high enough in both racial groups to facilitate the identification of quantitative trait loci underlying common obesity phenotypes. The high population prevalence of obesity in African-American women will require particularly high selection thresholds to achieve risk ratios comparable to those for Caucasians. The scarcity of thin siblings in both groups will greatly increase the effort required in sample recruitment for discordant pair designs.
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