Vasconcelos Ana Gabriela, Johnson Mari, Cai Yanwei, Hsu Li, Franceschini Nora, Auer Paul L, Kooperberg Charles, Raffield Laura M, Reiner Alex P
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Epigenetics. 2025 Dec;20(1):2539234. doi: 10.1080/15592294.2025.2539234. Epub 2025 Aug 4.
Sickle cell trait (SCT) is due to heterozygosity for the β-globin sickle cell mutation. SCT recently has been associated with increased risk of various adverse health outcomes. DNA methylation (DNAm) is one potential mechanism by which SCT may impact disease risk. To identify DNAm sites associated with SCT, we conducted an epigenome-wide association (EWAS) meta-analysis using whole blood Illumina EPIC array data available in a total of 3,677 African American participants (including 1,071 with SCT) from the Women's Health Initiative and Jackson Heart Study. We identified 103 differentially methylated CpGs and 119 differentially methylated regions associated with SCT. The strongest signals were hypermethylated cis loci within predicted regulatory elements within or near the β-globin gene cluster on chromosome 11. Beyond the globin locus, SCT-associated DMPs were enriched in genes involved in redox regulation and oxidative stress. We also demonstrate an association of SCT with differences in biological age and epigenetic age acceleration, though the pattern and strength of association differ according to the epigenetic clock used. Specifically, more recent epigenetic clocks that incorporate clinical phenotypes or laboratory biomarkers related to adverse health outcomes are associated with accelerated aging among individuals with SCT compared to African American controls. Our results lay the groundwork for future study of the role of DNAm in biologic aging and related health outcomes among individuals with SCT.
镰状细胞性状（SCT）是由于β-珠蛋白镰状细胞突变的杂合性所致。最近，SCT与各种不良健康结局风险增加相关。DNA甲基化（DNAm）是SCT可能影响疾病风险的一种潜在机制。为了鉴定与SCT相关的DNAm位点，我们使用来自女性健康倡议和杰克逊心脏研究的总共3677名非裔美国参与者（包括1071名患有SCT的参与者）的全血Illumina EPIC阵列数据进行了全表观基因组关联（EWAS）荟萃分析。我们鉴定出103个差异甲基化的CpG和119个与SCT相关的差异甲基化区域。最强的信号是11号染色体上β-珠蛋白基因簇内或附近预测调控元件内的高甲基化顺式位点。除了珠蛋白基因座外，与SCT相关的差异甲基化位点在参与氧化还原调节和氧化应激的基因中富集。我们还证明了SCT与生物学年龄和表观遗传年龄加速的差异有关，尽管根据所使用的表观遗传时钟，关联的模式和强度有所不同。具体而言，与非裔美国对照相比，纳入与不良健康结局相关的临床表型或实验室生物标志物的更新的表观遗传时钟与SCT个体的衰老加速有关。我们的结果为未来研究DNAm在SCT个体的生物衰老和相关健康结局中的作用奠定了基础。
