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Background Serum lipids are causally involved in the occurrence of atherosclerosis, but their roles in cerebral small vessel disease remain unclear. This study aimed to investigate the causal roles of lipid or apolipoprotein traits in cerebral small vessel disease and to determine the effects of lipid‐lowering interventions on this disease. Methods and Results Data on genetic instruments of lipids/apolipoproteins, as well as characteristic cerebral small vessel disease manifestations, including small vessel stroke (SVS) and white matter hyperintensity (WMH), were obtained from publicly genome‐wide association studies. Through 2‐sample Mendelian randomization analyses, it was found that decreased levels of high‐density lipoprotein cholesterol (odds ratio [OR], 0.85, P=0.007) and apolipoprotein A‐I (OR, 0.83, P=0.005), as well as increased level of triglycerides (OR, 1.16, P=0.025) were associated with a higher risk of SVS. A low level of high‐density lipoprotein cholesterol (OR, 0.93, P=0.032) was associated with larger WMH volume. Specifically, the genetically determined expressions of lipid fractions in various size‐defined lipoprotein particles were more closely related to the risk of SVS than WMH. Moreover, it was found that the hypertension trait ranked at the top in mediating the causal effect of hyperlipidemia on SVS and WMH by using Mendelian randomization‐based mediation analysis. For drug‐target Mendelian randomization, the low‐density lipoprotein cholesterol‐reducing genetic variation alleles at HMGCR and NL1CL1 genes and the high‐density lipoprotein cholesterol‐raising genetic variation alleles at the CETP gene were predicted to decrease the risk of SVS. Conclusions The present Mendelian randomization study indicates that genetically determined hyperlipidemia is closely associated with a higher risk of cerebral small vessel disease, especially SVS. Lipid‐lowering drugs could be potentially considered for the therapies and preventions of SVS rather than WMH.

BackgroundObservational researches have suggested a connection between iron deficiency anemia (IDA) and an increased likelihood of ischemic stroke (IS), yet establishing causality is challenging owing to the inherent limitations of such studies, including their vulnerability to confounding factors and the potential for reverse causation. This study employs a bidirectional two-sample Mendelian randomization (MR) approach to assess the causal linkage between IDA and IS and its subtypes.MethodsIdentifiable single nucleotide polymorphisms (SNPs) with significant links to either IDA or IS and its subtypes were employed as instrumental variables (IVs). The relationship between IDA and any IS, small vessel stroke (SVS), cardioembolic stroke (CES), and large artery stroke (LAS), was quantified using the inverse variance weighted (IVW) method. Complementary analyses utilizing MR-Egger and weighted median methods further supplemented the IVW findings. Moreover, the leave-one-out analysis, MR-Egger intercept test, MR-PRESSO global test, and Cochrane’s Q test were conducted for sensitivity analyses.ResultsThis study revealed no correlation between IDA and any IS (IVW method: OR [95% CI] = 0.977 [0.863–1.106]; p = 0.716), LAS (OR [95% CI] = 1.158 [0.771–1.740]; p = 0.479), CES (OR [95% CI] = 1.065 [0.882–1.285]; p = 0.512), or SVS (OR [95% CI] = 1.138 [0.865–1.498]; p = 0.357). Conducting a reverse MR analysis, it was determined that there is no causal connection between any IS, LAS, CES, SVS, and IDA (all p > 0.05). Sensitivity analysis indicated that heterogeneity was not significant and no evidence of horizontal pleiotropy was detected.ConclusionThis MR study suggested no causal effect of IDA on IS, LAS, CES, and SVS. Through reverse MR analyses, it was determined that IS and its subtypes did not exert a causal impact on IDA.

Abstract Introduction Stroke is one of the common diseases that pose a severe threat to human health, with immune cells playing a crucial role in its onset and recovery. However, the specific mechanisms and causal relationships of different immune cell groups in various clinical stroke subtypes are unclear. This study explored the causal relationship between immune cells and stroke and its subtypes using Mendelian randomization (MR) analysis. Methods Data from genome-wide association studies were analyzed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods for MR analysis, along with heterogeneity tests, sensitivity analysis, and pleiotropy analysis. Results CD45RA+CD28−CD8+ T cell %T cell (OR 1.002, 95% CI 1.001–1.003; P FDR = 0.02), CD27 on CD24+CD27+ B cell (OR 1.127, 95% CI 1.061–1.198; P FDR = 0.04), CD27 on IgD−CD38dim B cell (OR 1.138, 95% CI 1.076–1.203; P FDR = 0.005), and CD27 on switched memory B cell (OR 1.144, 95% CI 1.076–1.216; P FDR = 0.01) were found to increase the risk of large artery stroke. Switched memory B cell %lymphocyte (OR 1.206, 95% CI 1.103–1.318; P FDR = 0.02) increased the risk of small vessel stroke. Reverse MR analysis did not reveal any reverse causal associations. Furthermore, by substituting the outcome data, a secondary MR analysis was conducted to validate the primary findings. Conclusion Our study reveals several causal links between immune phenotypes and stroke and its different subtypes, highlighting the complex interactions between the immune system and stroke. These findings provide new directions for further uncovering the biological basis of stroke and assist in advancing research on early interventions and treatment strategies.

BackgroundStroke is a devastating global health issue, with high mortality and disability rates. The increasing prevalence of male infertility among reproductive-aged men has become a growing concern worldwide. However, the relationship between male infertility and stroke incidence remains uncertain. This study aimed to address this knowledge gap by employing a Mendelian randomization (MR) approach.MethodUtilizing genetic instrumental variables derived from a genome-wide association study (GWAS) on male infertility and stroke, a two-sample MR design was implemented. Five different analysis methods, with inverse-variance weighted as the primary approach, were used to examine the genetic causal associations between male infertility and various stroke subtypes. Heterogeneity analysis, pleiotropy tests, and leave-one-out validation were conducted to assess heterogeneity, evaluate pleiotropy, and ensure the robustness of the findings.ResultThe results indicate a potential lower risk of small vessel stroke associated with male infertility (odds ratio, 95% confidence interval: 0.82, 0.68 to 0.99, p=0.044), although no significant impact on other stroke subtypes was observed. The study exhibited low heterogeneity and no apparent pleiotropy; however, the stability of the results was not optimal.ConclusionMale infertility might potentially confer a protective effect against small vessel stroke risk. Caution is warranted due to potential confounding factors. Additional studies are necessary to confirm these findings and provide further validation.

Background Chitinase‐3 like protein 1 (CHI3L1, YKL‐40) was reported to be implicated in the development of ischemic stroke, but whether the association between them was causal remained unclear. We conducted a 2‐sample Mendelian randomization study to explore the associations of genetically determined plasma YKL‐40 with ischemic stroke and its subtypes (large artery stroke, small vessel stroke, and cardioembolic stroke). Methods and Results Based on genome‐wide association study data of 3394 European‐descent individuals, we selected 13 single‐nucleotide polymorphisms associated with plasma YKL‐40 as genetic instruments. Summary data about ischemic stroke and its subtypes were obtained from the Multiancestry Genome‐wide Association Study of Stroke Consortium, involving 34 217 ischemic stroke cases and 406 111 controls of European ancestry. We used the inverse‐variance weighted method followed by a series of sensitivity analyses to assess the causal associations of plasma YKL‐40 with ischemic stroke and its subtypes. The primary analysis showed that genetically determined high YKL‐40 levels were associated with increased risks of large artery stroke (odds ratio [OR], 1.08 [95% CI, 1.04–1.12]; P=1.73×10−4) and small vessel stroke (OR, 1.05 [95% CI, 1.01–1.09]; P=7.96×10−3) but not with ischemic stroke or cardioembolic stroke. Sensitivity analyses further confirmed these associations, and Mendelian randomization‐Egger indicated no evidence of genetic pleiotropy. In addition, supplementary analysis based on the summary data from the Olink proximity extension assay cardiovascular I (Olink CVD‐I) panel showed that high YKL‐40 levels were positively associated with the risks of large artery stroke (OR, 1.15 [95% CI, 1.08–1.22]; P=4.16×10−6) but not with small vessel stroke. Conclusions Genetically determined high plasma YKL‐40 levels were causal associated with increased risks of large artery stroke.

BackgroundPrevious studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed.ObjectWe intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis.MethodWe obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR–Egger method were adopted for sensitivity analyses.ResultsFor ICH or SVS, increased levels of phenylalanine (OR = 1.188, p