Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary.
Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary.
Int J Mol Sci. 2024 Feb 2;25(3):1815. doi: 10.3390/ijms25031815.
Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22-49-fold) risk of neuropathy (rs2032930 and rs2032931 of (, rs604349 of ( and with reduced (0.07-0.08-fold) risk (rs917778 of and rs2234753 of (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus ( = 0.042 and = 0.003, respectively) and at 5 Hz for n. peroneus ( = 0.037), as well as the deep breath test ( = 0.022) and the NTSS ( = 0.023). The rs2032931 was associated with current perception thresholds ( = 0.003 and = 0.037, respectively), deep breath test ( = 0.022), and NTSS ( = 0.023). The rs604349 correlated with values measured at 2000 ( = 0.049), 250 ( = 0.018), and 5 Hz ( = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device ( = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus ( = 0.020), deep breath test ( = 0.040), and NTSS ( = 0.003). There was a significant relationship between rs91778 and cold perception threshold ( = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.
神经病变是 2 型糖尿病（T2DM）的一种严重且常见的并发症。本研究通过全外显子组测序寻找与糖尿病神经病变发展相关的遗传因素。为此，对 24 例长期患有神经病变的 2 型糖尿病患者和 24 例无神经病变的患者进行了详细的神经学评估和全外显子组测序。心血管自主神经功能通过心血管反射试验评估。心率变异性通过三角指数测量。感觉神经功能由 Neurometer 和 Medoc 设备估计。通过神经病变总症状评分（NTSS）来描述神经病变症状。全外显子组测序（WES）在 Thermo Ion GeneStudio S5 系统上进行，该系统确定了大约 32000 个基因的编码序列，包含 5000 万个碱基对。使用 Ion Reporter 软件检测变体，并使用 ANNOVAR 进行注释，整合来自 dbSNP、ClinVar、gnomAD 和 OMIM 的数据库信息。使用集成基因组浏览器（IGV）可视化映射的读数。我们已经确定了与神经病变风险增加（22-49 倍）（和 （的 rs2032930 和 rs2032931）显著相关的遗传变异，以及与风险降低（0.07-0.08 倍）（和 （的 rs604349）显著相关的遗传变异。rs2032930 与正中神经的 5 Hz 和 250 Hz （=0.042 和 =0.003）以及腓肠神经的 5 Hz （=0.037）的当前感知阈值呈显著相关性，以及深呼吸试验（=0.022）和 NTSS（=0.023）。rs2032931 与当前感知阈值（=0.003 和 =0.037）、深呼吸试验（=0.022）和 NTSS（=0.023）相关。rs604349 与正中神经的 2000 Hz（=0.049）、250 Hz（=0.018）和 5 Hz（=0.005）以及 Medoc 设备测量的温暖感知阈值呈相关性（=0.042）。rs2234753 与正中神经的 2000 Hz （=0.020）、深呼吸试验（=0.040）和 NTSS（=0.003）的当前感知阈值呈相关性。rs91778 与冷觉阈值呈显著相关（=0.013）。在我们的研究中，已经确定了一些遗传变异，这些变异可能会影响 2 型糖尿病患者神经病变的发生风险。这些结果可能为早期预防措施开辟新的机会，并为未来的新药开发提供目标。
