Background & Aims
Neuropathic pain (NP) is a highly debilitating condition, affecting around 7% of the general population1. A common aetiology of NP is diabetes, manifesting as painful diabetic peripheral neuropathy (pDPN) . Diabetes can also increase the risk of other NP aetiologies, such as carpal tunnel syndrome2. However, there is large interindividual variation in the onset of NP and understanding the mechanisms that contribute to its development is vital for informing its prevention and treatment3. We recently conducted a systematic review to identify genetic risk factors for NP4, but no studies have attempted to comprehensively collate this data specifically in people with diabetes .
Therefore, the aim of this study was to conduct a systematic review to identify genetic risk factors for NP in adults with diabetes mellitus and to summarise the results through narrative synthesis.
Methods
The protocol for this systematic review has been registered on PROSPERO (Registration: CRD42022335554). A comprehensive literature search was conducted using the online databases Cochrane, Embase, PubMed, Web of Science and Scopus, for studies published up to June 2023. We included all studies published in English investigating genetic risk factors for any NP condition in adults (18 years or over) with any type of diabetes. Animal studies, studies conducted in vitro, literature reviews without a meta-analysis and conference abstracts were excluded.
Results
We retrieved 21,311 articles of which eight5–12 met the study criteria, including molecular genetic studies (MGS; n=4)8 10–12, genome-wide association studies (GWAS; n=3)5–7, and a candidate gene study (n=1)9. Seven studies were conducted wholly (n=4)5–7 9 or partially in type 2 diabetes (n=3)8 10 11, with one study providing incomplete information12. Five studies investigated pDPN8–12 and three studies investigated general NP in diabetics5–7. Genetic associations were reported for variants near GFRA2, HMGB1P46 and TLR12P (immune response), OPRM1 (neurotransmission) and ZSCAN20 (ion channel activity). Additionally, MGS identified rare potentially pathogenic variants in the voltage-gated sodium channel genes SCN3A, SCN7A-SCN11A and SCN1B-SCN3B, as well as the ion channel genes ANO3, HCN1, KCNK18, TRPA1, TRPM8, TRPV4, ANO1, KCNK18, KCNQ3 and TRPA1 in either painful or painless DPN. Meta-analysis was not conducted due to insufficient replication of genetic markers.
Conclusions
These findings demonstrate a potential role for genetic factors in the development of NP in people with diabetes. However, the evidence is currently limited and non-genetic factors can also contribute, which is being studied in another systematic review. The studies in the current review were hindered by small sample size impacting statistical power (<1000 cases in any study) and differences in case definition making successful replication less likely. Further studies are required, particularly GWAS, with larger sample sizes, a consistent case definition and in specific NP types other than pDPN, to properly elucidate the genetic mechanisms underpinning NP in diabetes.
References
1. Van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain 2014; 155: 654–62
2. Wiberg A, Smillie RW, Dupré S, Schmid AB, Bennett DL, Furniss D. Replication of epidemiological associations of carpal tunnel syndrome in a UK population-based cohort of over 400,000 people. J Plast Reconstr Aesthet Surg 2022; 75: 1034–40
3. Hébert HL, Veluchamy A, Torrance N, Smith BH. Risk factors for neuropathic pain in diabetes mellitus. Pain 2017; 158: 560–8
4. Veluchamy A, Hébert HL, Meng W, Palmer CNA, Smith BH. Systematic review and meta-analysis of genetic risk factors for neuropathic pain. Pain 2018; 159: 825–48
5. Meng W, Deshmukh HA, Van Zuydam NR, et al. A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain. Eur J Pain 2015; 19: 392–9
6. Meng W, Deshmukh HA, Donnelly LA, et al. A Genome-wide Association Study Provides Evidence of Sex-specific Involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) With Diabetic Neuropathic Pain. EBioMedicine 2015; 2: 1386–93
7. Veluchamy A, Hébert HL, Van Zuydam NR, et al. Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility. JAMA Netw Open 2021; 4: e2136560
8. Blesneac I, Themistocleous AC, Fratter C, et al. Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy. Pain 2018; 159: 469–80
9. Cheng KI, Lin SR, Chang LL, Wang JY, Lai CS. Association of the functional A118G polymorphism of OPRM1 in diabetic patients with foot ulcer pain. J Diabetes Complications 2010; 24: 102–8
10. ?l?czkowska M, Almomani R, Marchi M, et al. Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy. Int J Mol Sci Switzerland; 2022; 23: 7190
11. Almomani R, Sopacua M, Marchi M, et al. Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies. Int J Mol Sci 2023; 24: 8278
12. Wadhawan S, Pant S, Golhar R, et al. Na(V) channel variants in patients with painful and nonpainful peripheral neuropathy. Neurol Genet 2017; 3: e207
Presenting Author
Harry L Hebert
Poster Authors
Harry Hebert
PhD
University of Dundee
Lead Author
Imran Jallaldeen
MPH
University of Dundee
Lead Author
Fatima Farida
MPH
University of Dunde
Lead Author
BHUSHAN THAKKAR
University of Dundee
Lead Author
Abirami Veluchamy
PhD
University of Dundee
Lead Author
Lesley Colvin
University of Dundee
Lead Author
Blair H. Smith
University of Dundee
Lead Author
Topics
- Epidemiology