Systematic review and meta-analysis of genetic risk factors for neuropathic pain

Abstract

Neuropathic pain (NP) is an increasingly common chronic pain state and a major health burden, affecting approximately 7% to 10% of the general population. Emerging evidence suggests that genetic factors could partially explain individual susceptibility to NP and the estimated heritability in twins is 37%. The aim of this study was to systematically review and summarize the studies in humans that have investigated the influence of genetic factors associated with NP. We conducted a comprehensive literature search and performed meta-analyses of all the potential genetic variants associated with NP. We reviewed 29 full-text articles and identified 28 genes that were significantly associated with NP, mainly involved in neurotransmission, immune response, and metabolism. Genetic variants in HLA genes, COMT, OPRM1, TNFA, IL6, and GCH1, were found to have an association with NP in more than one study. In the meta-analysis, polymorphisms in HLA-DRB1*13 (odds ratio [OR], 2.96; confidence interval [CI], 1.93-4.56), HLA-DRB1*04 (OR, 1.40; CI, 1.02-1.93), HLA-DQB1*03 (OR, 2.86; CI, 1.57-5.21), HLA-A*33 (OR, 2.32; CI, 1.42-3.80), and HLA-B*44 (OR, 3.17; CI, 2.22-4.55) were associated with significantly increased risk of developing NP, whereas HLA-A*02 (OR, 0.64; CI, 0.47-0.87) conferred reduced risk and neither rs1799971 in OPRM1 (OR, 0.55; CI, 0.27-1.11) nor rs4680 in COMT (OR, 0.95; CI, 0.81-1.13) were significantly associated with NP. These findings demonstrate an important and specific contribution of genetic factors to the risk of developing NP. However, large-scale replication studies are required to validate these candidate genes. Our review also highlights the need for genome-wide association studies with consistent case definition to elucidate the genetic architecture underpinning NP.

New Perspective in Diabetic Neuropathy: From the Periphery to the Brain, a Call for Early Detection, and Precision Medicine

“…The increased efficiency and availability in gene sequencing technology has led to the exploration of potential genetic factors predisposing to a number of chronic diseases. A meta-analysis found that variants in several genes, e.g., HLA, COMT, OPRM1, TNFA, IL-6, and GCH1, were associated to neuropathic pain in at least one study (139). Moreover, genetic variants have been associated with DPN and neuropathic pain in diabetes (12).…”

Association of rs3783641 single‐nucleotide polymorphism in GTP cyclohydrolase 1 gene with post‐herpetic neuralgia

“…NP affects approximately 10–20% of individuals following herpes zoster . Emerging evidence has suggested that genetic factors could partially explain individual susceptibility to NP and a recent twins study reported an estimated heritability of 37% . A growing body of research suggests that a number of genes play a critical role in determining pain sensitivity or susceptibility to neuropathic pain, such as COMT , ADRB2 , OPRM1 , MC1R , GCH1 , HTR2A , and TNFA .…”

“…4,6 Emerging evidence has suggested that genetic factors could partially explain individual susceptibility to NP and a recent twins study reported an estimated heritability of 37%. 7,8 A growing body of research suggests that a number of genes play a critical role in determining pain sensitivity or susceptibility to neuropathic pain, such as COMT, ADRB2, OPRM1, MC1R, GCH1, HTR2A, and TNFA. 7,9 One of the most studied genes is the GCH1 gene which is the coding for the enzyme GTP cyclohydrolase 1, the rate-limiting enzyme in the tetrahydrobiopterin biosynthetic pathway that regulates monoamine, epinephrine, and nitric oxide biosynthesis.…”

Identification of potential mechanism and hub genes for neuropathic pain by expression‐based genome‐wide association study

“…1 A number of mechanisms are involved in NP, such as nerve injury 2 and anatomical remodeling. 1 A number of mechanisms are involved in NP, such as nerve injury 2 and anatomical remodeling.…”