Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort

Hajdú, Noémi; Ludvig, Zsófia; Rácz, Ramóna; Istenes, Ildikó; Békeffy, Magdolna; Vági, Orsolya Erzsébet; Körei, Anna Erzsébet; Horváth, Eszter; Tóbiás, Bálint; Illés, Anett; Pikó, Henriett; Kósa, János P.; Árvai, Kristóf; Posta, Máté; Lakatos, Péter András; Kempler, Péter; Putz, Zsuzsanna; Tordai, Dóra Zsuzsanna

doi:10.3390/ijms27125487

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Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort

by

Noémi Hajdú

^1,*,†,

Zsófia Ludvig

^1,†,

Ramóna Rácz

¹,

Ildikó Istenes

¹,

Magdolna Békeffy

¹,

Orsolya Erzsébet Vági

¹,

Anna Erzsébet Körei

¹,

Eszter Horváth

¹,

Bálint Tóbiás

^1,2,

Anett Illés

^1,2

,

Henriett Pikó

^1,2,

János P. Kósa

^1,2

,

Kristóf Árvai

^2,3,

Máté Posta

^4,5,

Péter András Lakatos

^1,2,

Péter Kempler

¹,

Zsuzsanna Putz

¹ and

Dóra Zsuzsanna Tordai

¹

Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary

²

Hungarian Research Network HUN-REN-ENDOMOLPAT, 1085 Budapest, Hungary

³

Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary

⁴

Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary

⁵

Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(12), 5487; https://doi.org/10.3390/ijms27125487

Submission received: 19 May 2026 / Revised: 14 June 2026 / Accepted: 15 June 2026 / Published: 17 June 2026

(This article belongs to the Special Issue Genetic Variations in Human Diseases: 3rd Edition)

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Abstract

Diabetic neuropathy is a common and multifactorial complication of type 2 diabetes, in which genetic susceptibility is increasingly recognized as a contributing factor. This study (cross-sectional case–control) aimed to investigate the associations between previously identified genetic variants and clinically relevant neurophysiological and symptomatic parameters. A total of 48 individuals with type 2 diabetes (24 with neuropathy and 24 without) were included. Neuropathy was assessed using standardized neurological, sensory, and cardiovascular autonomic function tests. Genetic variants were selected in a prior discovery analysis of this same cohort and re-tested here, precluding independent validation. Associations between genetic variants and clinical parameters were assessed through group-based comparisons using Mann–Whitney U tests and Fisher’s exact test, correlation analysis using Spearman’s rank correlation, permutation-based testing to improve robustness, and multivariable linear regression adjusted for age and sex to account for potential demographic confounding (q < 0.1). Mann–Whitney U test analysis identified several associations between genetic variants and neuropathy-related clinical parameters. In the Mann–Whitney U test analysis, only the rs6682221 variant remained significantly associated with heat detection threshold in the left hand after false discovery rate correction (p = 0.000150; q = 0.02736), although this association did not remain significant in the complementary permutation analysis based on median differences. Spearman’s rank correlation analysis identified a significant positive association between rs6682221 allele burden and heat detection threshold in the left hand, which remained significant after permutation correction (r = 0.552, p = 0.000086, q = 0.016). Multivariable regression adjusted for age and sex revealed several independent associations between selected variants and sensory neuropathy-related parameters. These findings should be considered exploratory, as all analyses were performed within the original discovery cohort and no independent validation cohort was available. Independent replication and functional studies are required before any clinical relevance can be inferred.

Keywords: type 2 diabetes; diabetic neuropathy; cardiovascular autonomic neuropathy; sensory neuropathy; whole-exome sequencing; single-nucleotide polymorphisms; case–control; clinical associations with genetic variants

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MDPI and ACS Style

Hajdú, N.; Ludvig, Z.; Rácz, R.; Istenes, I.; Békeffy, M.; Vági, O.E.; Körei, A.E.; Horváth, E.; Tóbiás, B.; Illés, A.; et al. Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort. Int. J. Mol. Sci. 2026, 27, 5487. https://doi.org/10.3390/ijms27125487

AMA Style

Hajdú N, Ludvig Z, Rácz R, Istenes I, Békeffy M, Vági OE, Körei AE, Horváth E, Tóbiás B, Illés A, et al. Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort. International Journal of Molecular Sciences. 2026; 27(12):5487. https://doi.org/10.3390/ijms27125487

Chicago/Turabian Style

Hajdú, Noémi, Zsófia Ludvig, Ramóna Rácz, Ildikó Istenes, Magdolna Békeffy, Orsolya Erzsébet Vági, Anna Erzsébet Körei, Eszter Horváth, Bálint Tóbiás, Anett Illés, and et al. 2026. "Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort" International Journal of Molecular Sciences 27, no. 12: 5487. https://doi.org/10.3390/ijms27125487

APA Style

Hajdú, N., Ludvig, Z., Rácz, R., Istenes, I., Békeffy, M., Vági, O. E., Körei, A. E., Horváth, E., Tóbiás, B., Illés, A., Pikó, H., Kósa, J. P., Árvai, K., Posta, M., Lakatos, P. A., Kempler, P., Putz, Z., & Tordai, D. Z. (2026). Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort. International Journal of Molecular Sciences, 27(12), 5487. https://doi.org/10.3390/ijms27125487

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Associations Between Previously Identified Genetic Variants and Clinical Phenotypes of Diabetic Neuropathy in Type 2 Diabetes: An Exploratory Analysis of the Discovery Cohort

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