A Genetic Risk Approach to Differential Diagnosis of Type 1 Diabetes and Risk Stratification in the Spanish Population.

IF 6.7 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

European Journal of Endocrinology Pub Date : 2026-10-15 DOI:10.1093/ejendo/lvag188

Laura Saso-Jiménez, Inés Urrutia, Maitane González-Arceo, Hector Diez, Josu Aurrekoetxea-Oribe, Begona Calvo, Jose Ramón Bilbao, Itxaso Rica, Nuria Valdés, Alicia Huerta-Chagoya, Silvia Bonàs-Guarch, Josep María Mercader, Jorge Ferrer, Luis Castano, Rosa Martínez

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引用次数: 0

Abstract

Context: Accurate type 1 diabetes (T1D) risk assessment can improve diagnosis and preventive care, reducing misdiagnosis and enabling preclinical interventions. Genetic Risk Scores (GRS) offer a promising tool, but population-specific validation is required.Objective. To assess the performance of established vs. a novel Spanish-specific GRS for T1D differential diagnosis and risk stratification.

Methods: From 2,338 genotyped individuals, 2,215 Spanish participants of European ancestry passed quality control: 816 T1D, 469 type 2 diabetes (T2D), 457 monogenic diabetes (MD), and 473 controls. A novel Spanish-specific GRS (T1D-SP-GRS) was developed and compared with HLA-DRB1 and two European-derived models (T1D-GRS and T1D-GRS2). The best-performing score was evaluated for T1D discrimination vs. T2D and MD, and for association with T1D-onset age.

Results: T1D-GRS2 outperformed T1D-SP-GRS for T1D vs. controls (AUC-ROC: 0.888 [95% CI: 0.867-0.908] vs. 0.837 [0.797-0.877], p=0.001), retaining high discrimination vs. T2D and MD (0.886 [0.865-0.907]). In the combined pediatric-onset T1D and control cohort, the P50 cutoff yielded a sensitivity of 0.80 (95% CI: 0.76-0.84) and specificity of 0.81 (0.77-0.84); P25 prioritized sensitivity (0.97 [0.95-0.99]) while P75 specificity (0.96 [0.93-0.97]). A P90 threshold conferred 26-fold higher T1D odds vs. controls, and 18- and 17-fold vs. T2D and MD (p <0.001). Higher T1D-GRS2 in childhood- vs. adulthood-onset T1D revealed an age-dependent risk profile primarily driven by HLA.

Conclusions: T1D-GRS2 discriminates T1D from other diabetes etiologies, providing a complementary tool to support diagnostic accuracy. The higher genetic risk associated with a younger age at onset provides key insights for early-stage T1D screening and intervention strategies.

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西班牙人群1型糖尿病鉴别诊断和风险分层的遗传风险方法。

背景：准确的1型糖尿病（T1D）风险评估可以改善诊断和预防保健，减少误诊并使临床前干预成为可能。遗传风险评分（GRS）提供了一个很有前途的工具，但需要特定人群的验证。评估已建立的与新的西班牙特异性GRS在T1D鉴别诊断和风险分层中的表现。方法：从2338个基因分型个体中，2215名欧洲血统的西班牙参与者通过了质量控制：816名T1D， 469名2型糖尿病（T2D）， 457名单基因糖尿病（MD）和473名对照。开发了一种新的西班牙特异性GRS (T1D-SP-GRS)，并与HLA-DRB1和两种欧洲衍生模型（T1D-GRS和T1D-GRS2）进行了比较。评估T1D与T2D和MD的区别，以及与T1D发病年龄的关系。结果：T1D- grs2治疗T1D优于对照组（AUC-ROC: 0.888 [95% CI: 0.867-0.908]比0.837 [0.797-0.877],p=0.001），与T2D和MD（0.886[0.865-0.907]）保持较高的鉴别性。在儿科发病的T1D和对照组合并队列中，P50临界值的敏感性为0.80 (95% CI: 0.76-0.84)，特异性为0.81 (0.77-0.84)；P25优先敏感性为0.97 [0.95-0.99]，P75优先特异性为0.96[0.93-0.97]。P90阈值使T1D的几率比对照组高26倍，比T2D和MD高18倍和17倍(p)。结论：T1D- grs2可将T1D与其他糖尿病病因区分开来，为支持诊断准确性提供了补充工具。较高的遗传风险与较年轻的发病年龄相关，这为早期T1D筛查和干预策略提供了关键的见解。

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来源期刊

European Journal of Endocrinology 医学-内分泌学与代谢

CiteScore

9.80

自引率

3.40%

发文量

354

审稿时长

1 months

期刊介绍： European Journal of Endocrinology is the official journal of the European Society of Endocrinology. Its predecessor journal is Acta Endocrinologica. The journal publishes high-quality original clinical and translational research papers and reviews in paediatric and adult endocrinology, as well as clinical practice guidelines, position statements and debates. Case reports will only be considered if they represent exceptional insights or advances in clinical endocrinology. Topics covered include, but are not limited to, Adrenal and Steroid, Bone and Mineral Metabolism, Hormones and Cancer, Pituitary and Hypothalamus, Thyroid and Reproduction. In the field of Diabetes, Obesity and Metabolism we welcome manuscripts addressing endocrine mechanisms of disease and its complications, management of obesity/diabetes in the context of other endocrine conditions, or aspects of complex disease management. Reports may encompass natural history studies, mechanistic studies, or clinical trials. Equal consideration is given to all manuscripts in English from any country.