Page 656 - fbkCardioDiabetes_2017

632 Susceptible and Prognostic Genetic Factors Associated
with Diabetic Peripheral Neuropathy: A Literature Review

gation has shifted to the use of molecular genetic derangements and cardiovascular risk factors [16].
markers for understanding the genetic aetiology of The mechanisms underlying the pathogenesis of
T2D [6,7]. The common susceptible genetic variants DPN are different between types 1 and type 2 diabe-
are known to have a prominent effect on the risk of tes mellitus [17]. Recent literature has reported that
T2D across the world in multiple ethnic groups [8,9]. there are different groups of susceptible genetic loci
Some variants appear to exert more pronounced ge- which are clearly involved in the development of DPN.
netic effects in specific ethnic groups. Most loci asso- Different studies reported that some patients with
ciated with T2D map to regulatory or intronic regions pre-diabetes develop neuropathic complications,
of the genome [9]. whereas others reported little evidence of neuropa-
thy even after long-standing diabetes. This observa-
Diabetic peripheral neuropathy (DPN) is one of the tion confirms the involvement of genetic aetiological
debilitating complications of diabetes that presents factors associated with the development of DPN [18].
in approximately 50% of patients. It is the primary These data from different studies suggest that T2D
cause of diabetes-related hospital admissions and and its complications may have shared genetic risk
non-traumatic foot amputations [4,5,10]. The molecu- factors [12,18].
lar mechanisms involved in the development of DPN
is a complex process that includes activation of the
polyol pathway, exaggerated oxidative stress, over GENETIC AETIOLOGY AND PATHOGENESIS
activity of protein kinase C and increased formation OF DPN
of advanced glycation end-products in the presence The pathogenesis of DPN is a complex process and
of hyperglycemia. In addition, there is increasing is involved with hyperglycaemia induced oxidative
evidence that genetic factors could also contribute stress and altered polyol metabolism that changes
to the development of DPN [10,11]. The consequenc- the nerve microvasculature, growth factor support
es of diabetic neuropathy include neurogenic pain, and lipid metabolism [19]. It is important to identi-
numbness, lack of coordination of voluntary move- fy these factors alone or in combination to arrange
ments and a susceptible to foot ulceration that lead effective DPN treatment, as better understanding of
to infection and toe or foot amputations. The rate of the mechanisms underlying the onset and progres-
toe or foot amputations is 15 times greater in dia- sion of DPN is of prime importance in the process
betic patients compared with individuals without di- of management [20]. Different groups of cell types
abetes. To date, approximately 80 T2D susceptibility in diabetic complication prone tissues are targets of
genetic loci have been reported in different ethnic damage due to uncontrolled hyperglycemia. Schwann
groups worldwide [12-14]. The majority of studies on cells are the prime target of hyperglycaemia which re-
the prevalence and associated aetiological factors of sults in cell damage leading to altered axon integrity
DPN have been conducted in Western countries. Few and defective growth factor signaling [21,22]. Defec-
data are available for Asian populations [15]. tive inflammatory pathways including advanced gly-
cation end products/receptor (AGE/RAGE) signaling
The objective of this paper is to provide an up-to-
date review of the susceptible and prognostic genet- in axons and Schwann cells have been reported in
ic factors associated with DPN. The genetic variants experimental animals with diabetic neuropathy which
associated with DPN were identified by an exten- contributed to nerve damage [23].
sive search of scientific literature using the criteria Lu et al., 2017, in China, studied single nucleotide
described below. The most recent and relevant pa- variants (SNVs) from previously identified ten ge-
pers published in the15 years from January 2002 to netic loci and analyzed the association of these loci
December 2016 were searched in PubMed using the with peripheral nerve function in patients with T2D.
search terms ‘Diabetic peripheral neuropathy/genet- They found that rs5219 of KCNJ11 gene polymorphism
ics’, ‘genome-wide association study’. Only the full (E23K, G>A) was associated with peripheral nerve
text articles published in English were included for function. The results obtained from nerve conduc-
this review. tion studies (NCS), showed that the allele ‘A’ had a
protective effect on peripheral nerve function. They
DIABETIC PERIPHERAL NEUROPATHY also found that SNVs rs7756992 of CDKAL1 and
According to the Toronto Consensus Panel on Dia- rs7903146 of TCF7L2 were associated with DPN in
betic Neuropathy, diabetic peripheral neuropathy is this Chinese T2D population [24].
defined as a symmetrical, length dependent sen- Yigit et al., 2013, identified 230 unrelated patients with
sorimotor polyneuropathy that develops on a back DPN at the outpatient clinics of the Physical Thera-
ground of longstanding hyperglycemia, associated py and Rehabilitation Department of Gaziosmanpa-

GCDC 2017