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 recQ-mediated genome instability protein 2 (RMI2) gene),
rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07-0.08-fold)
risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic
acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation
with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p
= 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well
as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated
with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath
test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured
at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well
as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed
correlations with a current perception threshold measured at 2000 Hz for n. medianus
(p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant
relationship between rs91778 and cold perception threshold (p = 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.
