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

Abstract

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: 407 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 35 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-ADCY9 (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.