<p>Participant demographics.</p>

G6PD deficiency (G6PD-D) variants are associated with lower hemoglobin A1c (HbA1c) concentrations, raising concerns about the diagnostic efficacy of HbA1c for abnormal glucose tolerance (Abnl-GT) in Africans, in whom risk of G6PD-D and Abnl-GT is high. G6PD-D is assessed using genotyping or an enzymatic assay, but because G6PD-D is X-linked, the enzymatic assay is necessary for determining status for women heterozygous for deficiency variants. We assessed: 1) ability of HbA1c to detect Abnl-GT by G6PD-D; 2) concordance of genotyping and enzymatic assay for G6PD-D in sub-Saharan Africans living in the US. 534 participants of the Africans in America study were included, with HbA1c ranging from 3.1–11.3%. Abnl-GT determined by HbA1c (≥5.7%) was compared to the diagnostic standard, the oral glucose tolerance test (fasting glucose≥100 mg/dL and/or 2h glucose≥140 mg/dL). G6PD-D status was determined by genotype (n = 263), enzymatic assay (n = 83), or both (n = 188). G6PD-D could not be determined for 13 women heterozygotes with only genotype data. In the remaining participants, HbA1c was 0.9% lower among those with G6PD-D (4.6 ± 0.5; range 3.1–5.6) compared to those with normal G6PD activity (5.5 ± 0.6; range 4.2–11.3; P < 0.001). Glucose concentrations did not differ between groups. HbA1c sensitivity and specificity for Abnl-GT were 0% (0/17) and 100% (37/37) among those with G6PD-D, and 50% (98/195) and 80% (217/272) among those with normal activity. After excluding women heterozygotes, concordance for G6PD-D detection by genotype and the enzymatic assay was 100%. G6PD-D was associated with ~0.9% lower HbA1c in this study, leading to a failure of HbA1c to identify Abnl-GT in these participants. Such a dramatic difference in a screening tool could have consequences in practice, including late diagnosis, undertreatment, and increased complications among those with G6PD-D. Additionally, the results for the enzymatic assay were perfectly concordant with the genotype results for G6PD-D. However, as genotype alone cannot predict G6PD-D in heterozygous women, the enzymatic assay was more informative.葡萄糖-6-磷酸脱氢酶缺乏症（G6PD deficiency, G6PD-D）与更低的糖化血红蛋白（hemoglobin A1c, HbA1c）水平相关，这引发了学界对HbA1c用于非洲人群糖耐量异常（abnormal glucose tolerance, Abnl-GT）诊断效能的担忧——该人群中G6PD-D和Abnl-GT的患病风险均较高。G6PD-D可通过基因分型或酶学检测进行评估，但由于G6PD-D属于X连锁遗传病，对于携带缺乏症致病变异的杂合女性，酶学检测是确定其G6PD-D状态的必要手段。本研究评估了两项内容：1）HbA1c检测G6PD-D相关Abnl-GT的效能；2）居住在美国的撒哈拉以南非洲裔人群中，G6PD-D的基因分型与酶学检测结果的一致性。 本研究纳入「非洲裔美国人研究」的534名参与者，其HbA1c水平范围为3.1%~11.3%。以HbA1c≥5.7%定义的Abnl-GT，与金标准诊断方法——口服葡萄糖耐量试验（空腹血糖≥100 mg/dL和/或2小时血糖≥140 mg/dL）的结果进行对比。G6PD-D状态的确定方式包括基因分型（n=263）、酶学检测（n=83）或两者联合检测（n=188）。13名仅持有基因型检测数据的杂合女性无法明确其G6PD-D状态。 在剩余参与者中，G6PD-D阳性者的HbA1c水平较G6PD活性正常者低0.9%（4.6±0.5，范围3.1~5.6 vs 5.5±0.6，范围4.2~11.3；P<0.001），两组的血糖水平无显著差异。在G6PD-D阳性人群中，HbA1c检测Abnl-GT的灵敏度为0%（0/17）、特异度为100%（37/37）；而在G6PD活性正常人群中，该指标的灵敏度为50%（98/195）、特异度为80%（217/272）。排除杂合女性参与者后，基因分型与酶学检测的G6PD-D检测结果一致性达100%。 本研究显示，G6PD-D与HbA1c水平降低约0.9%相关，导致HbA1c无法识别该人群中的Abnl-GT。这种筛查工具的性能差异可能带来实际临床后果，包括G6PD-D携带者的诊断延迟、治疗不足及并发症风险升高。此外，本研究中酶学检测结果与G6PD-D的基因分型结果完全一致。但由于单一基因分型无法预测杂合女性的G6PD-D状态，因此酶学检测能提供更全面的诊断信息。