Dataset Information

Homocysteine and small vessel stroke: A mendelian randomization analysis.

ABSTRACT: OBJECTIVE:Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. METHODS:We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n?=?18), folate (n?=?3), vitamin B6 (n?=?1), and vitamin B12 (n?=?14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n?=?16,952 subtyped ischemic stroke cases and 404,630 noncases). RESULTS:Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p?=?6.7?×?10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p?=?1.3?×?10-4 ) and 0.70 (95% CI, 0.52-0.94; p?=?0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. INTERPRETATION:These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.

SUBMITTER: Larsson SC

PROVIDER: S-EPMC6594149 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Homocysteine and small vessel stroke: A mendelian randomization analysis.

Larsson Susanna C SC Traylor Matthew M Markus Hugh S HS

Annals of neurology 20190311 4

<h4>Objective</h4>Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization.<h4>Methods</h4>We used summary statistics data for single ...[more]

PMID: 30785218

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Project description:Background and purposeThe relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization.MethodsFive CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank.ResultsT2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P=0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P=0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P=0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P=0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P=0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P=0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P=0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P=0.008) after adjusting for potential confounders.ConclusionsOur Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA.

Project description: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 ?mol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 ?mol/L, Z?=?-5.29, P?<?0.01) and in healthy controls (median: 18.32 vs. 10.00 ?mol/L, Z?=?-8.76, P?<?0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 ?mol/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%, ??=?14.29, P?<?0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 ?mol/L, ??=?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, ??=?21.75, P?<?0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, ??=?2.97, P?=?0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, ??=?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%, ??=?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 (??=?0.76, P?=?0.02), systolic blood pressure (??=?0.26, P?=?0.02), diastolic blood pressure (??=?0.20, P?=?0.01), and pathologic T lesion (??=?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.

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Homocysteine and small vessel stroke: A mendelian randomization analysis.

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Homocysteine and small vessel stroke: A mendelian randomization analysis.

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