Homocysteine and IgA nephropathy: observational and Mendelian randomization analyses

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(>10μmol/L).Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients(median:18.32 vs.11.15μmol/L,Z=-5.29,P<0.01)and in healthy controls(median:18.32 vs.10.00μmol/L,Z=-8.76,P<0.01),but comparable with those in LN patients(median:18.32 L vs.14.50μmol/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%,χ2=14.29,P<0.01),serum creatinine(median:77.00 vs.100.00 vs.129.00 vs.150.00μmol/L,χ2=34.06,P<0.01),estimated glomerular filtration rate(median:100.52 vs.74.23 vs.52.68 vs.42.67 mL·min-1·1.73 m-2,χ2=21.75,P<0.01),systolic blood pressure(median:120.00 vs.120.00 vs.125.00 vs.130.00 mmHg,χ2=2.97,P=0.05),diastolic blood pressure(median 80.00 vs.75.00 vs.80.00 vs.81.00 mmHg,χ2=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%,χ2=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.