{"doi":"10.1002/jha2.542","title":"Single nucleotide polymorphisms in <i>SAR1A</i> coding regions in sickle cell disease and their potential miRNA binding sites","abstract":"Sickle cell disease (SCD) is the most common severe monogenetic disorder and displays marked phenotypic heterogeneity. The clinical diversity of SCD derives from the inter-individual genetic background and other factors, including sociodemographic, socioeconomic, or environmental conditions [1]. For example, the variation of fetal hemoglobin (HbF) levels in SCD patients is influenced by the genetic loci inside or outside the β-globin gene cluster, such as single nucleotide polymorphisms (SNPs) in the quantitative trait loci XmnI-HBG2, BCL11A, and HBS1L-MYB [2]. Hydroxyurea or hydroxycarbamide (HU) is a major therapeutic option for homozygous SCD and is well established as an agent for inducing HbF levels [3, 4]. An increase in the levels of HbF lessens the clinical severity of SCD. However, the increase in HbF in response to HU therapy varies considerably among SCD patients [5]. We have previously reported that SNPs in the secretion-associated RAS-related GTPase 1A (SAR1A) gene promoter contribute to interindividual differences in regulation of HbF expression, as well as response to HU, in SCD patients [6]. SAR1A is a member of the small GTPase protein family and regulates the formation or assembly of the endoplasmic reticulum (ER)-derived coat protein complex II vesicles involved in the ER-to-Golgi apparatus export of proteins [7]. Interestingly, we found that SAR1A was a specific HU-inducible gene and also demonstrated that HU-induced SAR1A activates γ-globin expression through the induction of GATA-2 and the Giα/JNK/Jun pathway in human erythroid cells [8, 9]. Furthermore, the SNPs in the SAR1A promoter were found to be significantly associated with changes in HbF levels in both adults and children with SCD following HU treatment [6, 10]. Collectively, these observations suggest that SAR1A plays a pivotal role in HbF expression. In this study, we hypothesized that SNPs in SAR1A coding regions affect HU-induced HbF levels in SCD patients and determined the SNPs within the SAR1A 3ʹ untranslated region (UTR) as potential microRNA (miRNA) binding sites. Therefore, we expanded on our previous study [6] to investigate the association of SNPs in SAR1A coding regions with hematologic laboratory values in adults with SCD treated with HU. miRNAs are small noncoding RNAs that induce translational repression or decay, primarily by targeting the mRNA 3ʹ UTR [11]. Recently, Das et al. demonstrated that SNPs within miRNA binding sites can affect HbF expression [12]. miRNAs have also been shown to play an important role in HU-mediated HbF induction, as well as to be related to the clinical heterogeneity of SCD [13, 14]. Furthermore, we examined SNPs within the SAR1A 3ʹ UTR as potential miRNA binding sites. To identify SNPs in SAR1A-coding regions, we sequenced all eight SAR1A exons in 32 adults with SCD undergoing HU therapy. Three (rs56090714, rs3812693, and rs56381518) and 15 (rs78341510, rs114346554, rs72807054, rs201493587, rs1470556171, rs2394643, rs80028936, rs7919647, rs115340990, rs15801, rs1046747, rs79535872, rs7653, rs1280408553, and rs10586) variants were identified in exons 1 and 8, respectively (Figure 1A). No SNPs were detected in exons 2–7. Among these, rs7919647 in exon 8 had the highest frequency (24.4%) in the cohort examined (Figure 1B). Next, we analyzed these 18 SAR1A exon SNPs for association with hematological laboratory values determined in our cohort prior to and following HU treatment. We limited our statistical analysis to the 28 cohort members with an HbSS genotype (Table S1). Prior to multiple-linear regression analyses in our cohort, we evaluated the correlation between age, gender, HU dose, or HU duration and hematologic laboratory values. Only age was associated with a change in total hemoglobin levels (p = 0.003) and with a change in absolute HbF levels (p = 0.009) after HU treatment. We therefore did not pursue using age, gender, HU dose, or HU duration status in our model, except we added age when analyz","journal":"eJHaem","year":2022,"id":293160,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":349062,"name":"Christine Kim","orcid":"0000-0002-1424-4263","position":1,"is_corresponding":false},{"id":977938,"name":"Gulriz Kurban","orcid":null,"position":2,"is_corresponding":false},{"id":386790,"name":"Jianqiong Zhu","orcid":null,"position":3,"is_corresponding":false},{"id":911945,"name":"Wulin Aerbajinai","orcid":null,"position":4,"is_corresponding":false},{"id":19959,"name":"James G. Taylor","orcid":"0000-0002-4421-1809","position":5,"is_corresponding":false},{"id":385547,"name":"Griffin P. Rodgers","orcid":"0000-0002-4710-0012","position":6,"is_corresponding":false},{"id":505149,"name":"Chutima Kumkhaek","orcid":"0000-0002-4693-9078","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-19T00:30:50.076284Z","pmid":"36467826","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}