Pasquale Zamboli

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹⁰), with heterogeneity detected only at the PSMB9/TAP1 locus (I² = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻⁴). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²⁸). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

BACKGROUND: Ambulatory blood pressure (BP) measurement allows a better risk stratification in essential hypertension compared with office blood pressure measurement, but its prognostic role in nondialysis chronic kidney disease has been poorly investigated. METHODS: The prognostic role of daytime and nighttime systolic BP (SBP) and diastolic BP (DBP) in comparison with office measurements was evaluated in 436 consecutive patients with chronic kidney disease. Primary end points were time to renal death (end-stage renal disease or death) and time to fatal and nonfatal cardiovascular events. Quintiles of BP were used to classify patients. RESULTS: The mean (SD) age of the patients was 65.1 (13.6) years, and the glomerular filtration rate was 42.9 (19.7) mL/min/1.73 m(2); 41.7% of the participants were women, 36.5% had diabetes, and 30.5% had cardiovascular disease. Office-measured SBP/DBP values were 146 (19)/82 (12) mm Hg; daytime SBP/DBP was 131 (17)/75 (11) mm Hg, and nighttime SBP/DBP was 122 (20)/66 (10) mm Hg. During follow-up (median, 4.2 years), 155 and 103 patients reached the renal and cardiovascular end points, respectively. Compared with a daytime SBP of 126 to 135 mm Hg, patients with an SBP of 136 to 146 mm Hg and those with an SBP higher than 146 mm Hg had an increased adjusted risk of the cardiovascular end point (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.13-4.41 and 3.07; 1.54-6.09) and renal death (1.72; 1.02-2.89 and 1.85; 1.11-3.08). Nighttime SBPs of 125 to 137 mm Hg and higher than 137 mm Hg also increased the risk of the cardiovascular end point (HR, 2.52; 95% CI, 1.11-5.71 and 4.00; 1.77-9.02) and renal end point (1.87; 1.03-3.43 and 2.54; 1.41-4.57) with respect to the reference SBP value of 106-114 mm Hg. Office measurement of BP did not predict the risk of the renal or cardiovascular end point. Patients who were nondippers and those who were reverse dippers had a greater risk of both end points. CONCLUSION: In chronic kidney disease, ambulatory BP measurement and, in particular, nighttime BP measurement, allows more accurate prediction of renal and cardiovascular risk; office measurement of BP does not predict any outcome.