Soremekun Chisom, Ojewunmi Oyesola, Nwagbata Amarachukwu, Bazireh Homa, Sharma Sapna, Jjingo Daudi, Kateete David Patrick, Nash Oyekanmi, Grallert Harald, Batini Chiara, Peters Annette, Fatumo Segun
NCD Genomics & The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.
Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
PLoS One. 2025 May 30;20(5):e0324269. doi: 10.1371/journal.pone.0324269. eCollection 2025.
Glycated hemoglobin (HbA1c) measures the average blood sugar level over the past three months. As a vital biomarker of blood glucose levels, it is used to diagnose Type-2 diabetes mellitus (T2D) and monitor glycemic control. A heritability estimate of 47% to 59% suggests that about half of the variation in HbA1c levels can be attributed to genetic factors. Despite African populations being the most genetically diverse and unique for fine-mapping, there is a paucity of data on the genetic drivers of HbA1c in African individuals. In this study, we performed functional annotation and a Phenome-Wide Association Study (PheWAS) of HbA1c-associated variants in two African populations.
In this study, we utilized summary statistics of the HbA1c GWAS meta-analysis of 7,526 individuals from South Africa and Uganda to conduct a PheWAS using GWASATLAS. We also performed a functional analysis using the functional mapping and annotation (FUMA) tool. Single nucleotide polymorphisms (SNPs) were prioritized using the SNP2GENE function, while the gene expression patterns and shared molecular functions were explored in the GENE2FUNC.
Three genome-wide significant loci were identified with the lead SNPs: rs6724428, rs148228241, and rs8045544 - mapped to GULP1, HBA1, and ITFG3 genes, respectively. The minor allele frequencies of rs148228241 (0.07) and rs8045544 (0.19) are rare or non-existent in non-African populations. Both rs8045544 and rs148228241 are significantly associated with the mean corpuscular hemoglobin concentration (MCHC). A lower MCHC is associated with alpha thalassaemia, resulting from deletions in HBA1 and HBA2 genes. Such deletions are prevalent in malaria-endemic regions of Africa due to their selective survival advantage. The rs6724428 variant is associated with skeletal functions, reflecting the link between glucose metabolism and bone mineral density.
Our findings highlight the interplay between glucose metabolism, erythropoiesis, and skeletal health. The significant associations of HbA1c-variants with both skeletal function and MCHC underscore the potential of these variants to impact broader physiological processes. A large-scale study of African individuals will be essential to unravel genetic variants influencing HbA1c.
糖化血红蛋白（HbA1c）可测量过去三个月的平均血糖水平。作为血糖水平的重要生物标志物，它用于诊断2型糖尿病（T2D）并监测血糖控制情况。47%至59%的遗传度估计表明，HbA1c水平约一半的变异可归因于遗传因素。尽管非洲人群在基因上最为多样化且是精细定位的独特群体，但关于非洲个体中HbA1c的遗传驱动因素的数据却很匮乏。在本研究中，我们对两个非洲人群中与HbA1c相关的变异进行了功能注释和全表型组关联研究（PheWAS）。
在本研究中，我们利用来自南非和乌干达的7526名个体的HbA1c全基因组关联研究（GWAS）荟萃分析的汇总统计数据，使用GWASATLAS进行PheWAS。我们还使用功能映射和注释（FUMA）工具进行了功能分析。使用SNP2GENE功能对单核苷酸多态性（SNP）进行优先级排序，同时在GENE2FUNC中探索基因表达模式和共享分子功能。
通过主要单核苷酸多态性（SNP）鉴定出三个全基因组显著位点：rs6724428、rs148228241和rs8045544，分别映射到GULP1、HBA1和ITFG3基因。rs148228241（0.07）和rs8045544（0.19）的次要等位基因频率在非非洲人群中罕见或不存在。rs8045544和rs148228241均与平均红细胞血红蛋白浓度（MCHC）显著相关。较低的MCHC与α地中海贫血相关，这是由HBA1和HBA2基因的缺失导致的。由于其选择性生存优势，此类缺失在非洲疟疾流行地区很普遍。rs6724428变异与骨骼功能相关，反映了葡萄糖代谢与骨矿物质密度之间的联系。
我们的研究结果突出了葡萄糖代谢、红细胞生成和骨骼健康之间的相互作用。HbA1c变异与骨骼功能和MCHC的显著关联强调了这些变异影响更广泛生理过程的潜力。对非洲个体进行大规模研究对于揭示影响HbA'c的基因变异至关重要。
