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Volume 15
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10.3390/metabo15120772
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Zinc-Related Proteasome Variants in Type 1 Diabetes: An in Silico-Guided Case-Control Study

by
Raif Gregorio Nasre-Nasser
1,2,
Anna Carolina Meireles Vieira
2,
Felipe Mateus Pellenz
2,3,
Luciane Moretto
1,2,
Eliandra Girardi
2,
Taís Silveira Assmann
1,
Chih-Hao Lu
4,
Luís Henrique Canani
1,2,
Cristine Dieter
1,2,5 and
Daisy Crispim
1,2,*
1
Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-000, Rio Grande do Sul, Brazil
2
Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
3
Escola da Saúde, Universidade do Vale do Rio dos Sinos—UNISINOS, São Leopoldo 93022-154, Rio Grande do Sul, Brazil
4
Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
5
Programa de Pós-Graduação em Saúde e Desenvolvimento Humano, Universidade La Salle, Canoas 92010-000, Rio Grande do Sul, Brazil
*
Author to whom correspondence should be addressed.
Metabolites 2025, 15(12), 772; https://doi.org/10.3390/metabo15120772 (registering DOI)
Submission received: 6 November 2025 / Revised: 25 November 2025 / Accepted: 26 November 2025 / Published: 28 November 2025
(This article belongs to the Special Issue The Multifaceted Roles of Biomarkers in Metabolic Disorders: From Diagnosis and Monitoring to Prediction, Management, and Treatment, 2nd Edition)
Versions Notes

Abstract

Introduction: The proteasome is a multicatalytic complex responsible for protein degradation and regulation of immune responses, and has been implicated in type 1 diabetes mellitus (T1DM) pathogenesis. Zinc (Zn2+) is essential for insulin granule biogenesis and modulates proteasomal activity. This study investigated associations between single-nucleotide polymorphisms (SNPs) in proteasomal subunits predicted to bind Zn2+ and T1DM susceptibility or related traits. Methods: This case–control study included 654 patients with T1DM and 573 subjects without DM from Southern Brazil. SNPs were selected through in silico analysis using MIB docking platform to identify Zn2+-interacting residues in proteasomal subunits. Five SNPs in proteasomal subunit genes—PSMA6 (rs1048990), PSMB6 (rs2304975), PSMB9 (rs17587), PSMC6 (rs2295825), and PSMD3 (rs3087852)—were genotyped using TaqMan assays. Results: The PSMC6 rs2295825C allele was associated with lower T1DM (OR = 0.77, 95% CI 0.61–0.97; p = 0.028) and diabetic retinopathy (DR; OR = 0.65; 95% CI 0.42–0.99; p = 0.048) risk, and a more favorable lipid profile (higher HDL-C, lower triglycerides) compared to the G/G genotype. The PSMB9 rs17587A/A genotype was linked to higher total cholesterol and HbA1c levels. The PSMA6 rs1048990G allele was linked to increased prevalence of diabetic kidney disease (DKD; OR = 1.75, 95% CI 1.02–2.99; p = 0.042), and the PSMD3 rs3087852A allele was associated with lower urinary albumin excretion. No significant associations were observed for the PSMB6 rs2304975 SNP. Conclusions: The PSMC6 rs2295825 SNP may confer protection against T1DM. The PSMC6 rs2295825, PSMB9 rs17587, PSMA6 rs1048990, and PSMD3 rs3087852 SNPs appear to influence lipid metabolism and diabetic microvascular complications.
Keywords: T1DM; proteasome; single nucleotide polymorphism; zinc; PSMC6; PSMB9; PSMA6; PSMD3; kidney disease; retinopathy T1DM; proteasome; single nucleotide polymorphism; zinc; PSMC6; PSMB9; PSMA6; PSMD3; kidney disease; retinopathy

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MDPI and ACS Style

Nasre-Nasser, R.G.; Meireles Vieira, A.C.; Pellenz, F.M.; Moretto, L.; Girardi, E.; Assmann, T.S.; Lu, C.-H.; Canani, L.H.; Dieter, C.; Crispim, D. Zinc-Related Proteasome Variants in Type 1 Diabetes: An in Silico-Guided Case-Control Study. Metabolites 2025, 15, 772. https://doi.org/10.3390/metabo15120772

AMA Style

Nasre-Nasser RG, Meireles Vieira AC, Pellenz FM, Moretto L, Girardi E, Assmann TS, Lu C-H, Canani LH, Dieter C, Crispim D. Zinc-Related Proteasome Variants in Type 1 Diabetes: An in Silico-Guided Case-Control Study. Metabolites. 2025; 15(12):772. https://doi.org/10.3390/metabo15120772

Chicago/Turabian Style

Nasre-Nasser, Raif Gregorio, Anna Carolina Meireles Vieira, Felipe Mateus Pellenz, Luciane Moretto, Eliandra Girardi, Taís Silveira Assmann, Chih-Hao Lu, Luís Henrique Canani, Cristine Dieter, and Daisy Crispim. 2025. "Zinc-Related Proteasome Variants in Type 1 Diabetes: An in Silico-Guided Case-Control Study" Metabolites 15, no. 12: 772. https://doi.org/10.3390/metabo15120772

APA Style

Nasre-Nasser, R. G., Meireles Vieira, A. C., Pellenz, F. M., Moretto, L., Girardi, E., Assmann, T. S., Lu, C.-H., Canani, L. H., Dieter, C., & Crispim, D. (2025). Zinc-Related Proteasome Variants in Type 1 Diabetes: An in Silico-Guided Case-Control Study. Metabolites, 15(12), 772. https://doi.org/10.3390/metabo15120772

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