ABSTRACT
BACKGROUND@#High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach.@*METHODS@#For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays.@*RESULTS@#Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = -5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = -8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/L, Z = -1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, χ = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN.@*CONCLUSIONS@#By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.
ABSTRACT
OBJECTIVE@#To compare the genetic architecture of susceptibility variants of IgA nephropathy (IgAN) in Chinese and Europeans.@*METHODS@#We selected the independent genome-wide significant variants of IgAN in European population as candidate variants. Their associations, risk alleles, risk allele frequencies, odds ratios and population attributable risk scores were derived and calculated, then compared with those in the current Chinese population, including 1 194 IgAN patients and 902 controls. Using the significant variants, genetic risk scores were calculated and compared between the East Asians and the Europeans. The correlation between the genetic risk scores and clinical manifestations was also evaluated.@*RESULTS@#There were 16 independent single nucleotide polymorphisms (SNPs) located in 11 loci showing significantly association with susceptibility to IgAN in the Europeans. 93.75% (15/16) of them also showed significant associations in the Chinese (P<0.05). The effects of all the associated SNPs were in the same direction, either risk or being protective for IgAN, between the Chinese and the Europeans. On the contrary, remarkable higher risk allelic odds ratio (P=1.94×10-2), higher risk allele frequency (P=3.09×10-2), and higher population attributable risk (P=3.03×10-4) were observed for most of the associated SNPs in the Chinese than in the Europeans. Furthermore, genetic risk scores were significantly larger in the Asian populations compared with the Europeans (P=1.78×10-163). While there was no significance among the subpopulations in both the East Asians and the Europeans. Compared with the healthy controls, the genetic risk score in the IgAN patients was significantly larger (P=3.60×10-27). Clinical analysis showed the genetic risk score was positively associated with serum levels of IgA and IgA1, phases of chronic kidney disease and Haas grades.@*CONCLUSION@#Our study provides further evidence in the shared genetic architecture between Chinese and Europeans, while differences with respect to the effect sizes and risk allele frequencies across ethnicities, contributing partially to the differences of disease prevalence.
Subject(s)
Humans , Asian People , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , Glomerulonephritis, IGA , Polymorphism, Single NucleotideABSTRACT
<p><b>OBJECTIVE</b>To study the clinicopathologic features of different variants of primary focal segmental glomerulosclerosis (FSGS).</p><p><b>METHODS</b>One hundred and two cases of FSGS were retrieved from the archival files of Peking University First Hospital during the past 6-year period. The pathologic findings were reviewed and the degrees of active and chronic changes were assessed by morphometric analysis. The histopathologic patterns were then correlated with clinical manifestations.</p><p><b>RESULTS</b>Amongst the 102 cases of primary FSGS studied, 55.9% belonged to the NOS (not other specified) variant, while the perihilar, cellular, tip and collapsing variants accounted for 6.9%, 25.5%, 4.8% and 6.9% respectively. The level of proteinuria in the cellular and tip variants were much higher than that in the NOS variant; and the incidence of nephrotic syndrome in the tip and collapsing variants was higher than that in the other three variants (chi(2) = 12.23, P < 0.05). The activity score of the cellular and collapsing variants was also higher than that of the other three variants (P < 0.05). The interval between disease onset and renal biopsy diagnosis in the perihilar variant was longer than that in the other variants. The chronicity score of this variant was higher than that of the tip and NOS variants (P < 0.05). On the other hand, the total scores of active and chronic changes of the tip variant was lower than that of the cellular and collapsing variants (P < 0.05); and its chronic score was lower than that of the NOS and perihilar variants (P < 0.05).</p><p><b>CONCLUSIONS</b>The NOS variant is the commonest morphologic pattern seen in primary FSGS. The cellular and collapsing variants are the patterns associated with active lesions, while perihilar variant is the pattern associated with chronic lesions. The tip variant shows mild pathological changes compared with the other patterns.</p>