Genetic variants associated with the risk of stroke in sickle cell disease: a systematic review and meta-analysis

Background Sickle cell disease (SCD) is the commonest cause of stroke in children. As it is a rare disease, studies investigating the association with complications like stroke in SCD have small sample sizes. Here, we performed a systematic review and meta-analysis of the studies exploring an association of genetic variants with stroke to get a better indication of their association with stroke. Methods PubMed and Google Scholar were searched to identify studies that had performed an association analysis of genetic variants for the risk of stroke in SCD patients. After screening of eligible studies, summary statistics of association analysis with stroke and other general information were extracted. Meta-analysis was performed using the fixed effect method on the tool METAL and forest plots were plotted using the R program. The random effect model was performed as a sensitivity analysis for loci where significant heterogeneity was observed. Results 408 studies were identified using the search term and after screening 39 studies that cumulatively analysed 11,780 SCD patients were included. These 39 studies included a total of 2,401 SCD patients with stroke, predominantly included individuals of African ancestry (N=16). Three of these studies performed whole exome sequencing while 36 performed single nucleotide-based genotyping. Though the studies reported association with 109 loci, meta-analyses could be performed only for 12 loci that had data from two or more studies. After meta-analysis we observed that four loci were significantly associated with risk for stroke: -α3.7kb Alpha-thalassemia deletion (P= 0.00000027), rs489347- TEK (P= 0.00081), rs2238432- ADCY 9 (P= 0.00085) and rs11853426- ANXA2 (P= 0.0034). Conclusion Ethnic representation of regions with a high prevalence of SCD like the Mediterranean basin and India needs to be improved for genetic studies on associated complications like stroke. Larger genome-wide collaborative studies on SCD and associated complications including stroke needs to be performed. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The research protocol of this systematic review and meta-analysis was registered on PROSPERO () web portal with registration number ?CRD42022311257?. ### Funding Statement No funding was received for this research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical clearance is not required as this is a systematic review and meta-analysis. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The raw data supporting the conclusions of this research work is presented in the article or in the supplementary material provided with the article. * SCD : sickle cell disease OR : odds ratio CI : confidence interval HbF : fetal hemoglobin GWAS : genome-wide association studies WES : Whole exome sequencing SNP : single nucleotide polymorphism AC : adenylyl cyclase WHO : World Health Organization