Type 2 diabetes and risk of post-herpetic neuralgia: A Mendelian randomization study

Type 2 diabetes and risk of post-herpetic neuralgia: A Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Type 2 diabetes and risk of post-herpetic neuralgia: A Mendelian randomization study Yuanqi ZHANG, Guohong XIANG, Ling QIU This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4312613/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective A two-sample Mendelian randomization method was used to study the causal relationship between Type 2 diabetes and post-herpetic neuralgia (PHN). Method Genome-wide association statistics of type 2 diabetes with PHN were obtained, and single nucleotide polymorphisms (SNPs) strongly associated with type 2 diabetes were used as instrumental variables(IVS).TSMR method with inverse variance weighting (IVW) as the primary analytical approach to evaluate the causal association between type 2 diabetes and PHN. Sensitivity analysis was also conducted to evaluate the strength and reliability of the findings. Results 39 SNPs strongly associated with type 2 diabetes were included in the analysis, which showed that type 2 diabetes was significantly associated with PHN(IVW: OR=1.508,95%CI=1.003-2.267), P=0.04). Sensitivity analyses demonstrated the strength and reliability of the causal relationship. Conclusion There was a correlation between type 2 diabetes and PHN, and type 2 diabetes was linked to a higher risk of PHN. Biological sciences/Genetics Health sciences/Endocrinology Health sciences/Neurology Type 2 diabetes Post-herpetic neuralgia Mendelian randomization Causality Figures Figure 1 Introduction Herpes zoster (HZ) is a viral disease that occurs when the varicella-zoster virus (VZV) becomes active and multiplies in nerve cells. PHN is chronic, intractable nerve pain left after herpes healing [ 1 ] , and persistent severe pain seriously impacts the well-being and standard of living of patients significantly [ 2 ] .PHN is among the most prevalent and significant clinical consequences of HZ [ 3 ] , and clinical statistics show that there are approximately 1 million HZ patients in the US each year, and the occurrence of subsequent PHN reaches 5% ~ 20% [ 4 ] . The prevalence of both HZ and PHN tends to increase gradually with aging [ 5 ] . Relevant studies have suggested that the occurrence of PHN is linked to a variety of risk factors, including advanced age; pain (prodromal pain, high pain level in the acute phase, and abnormal pain); rash (large rash size, involvement of special areas such as perineum and brachial plexus, and the appearance of gangrenous, maculopapular, and hemorrhagic special lesions); underlying diseases and long-term drug history (diabetes mellitus, malignant neoplasm, tuberculosis, recent traumatic injuries, and long-term use of immunosuppressants or glucocorticoids, etc.); anxiety and depression, etc [ 6 , 7 ] . Due to the complexity of PHN pain mechanisms, these risk factors currently remain to be proven by further research. Some studies have found that diabetes mellitus (diabetes mellitus) may be one of the risk factors for PHN [ 8 , 9 ] . Literature shows that the increasing prevalence of diabetes poses a serious threat to human health on a worldwide scale [ 10 ] . According to data released by the IDF, there are almost 537 million individuals worldwide who have diabetes, and by 2040, the number of people living with diabetes is projected to reach 642 million. Most cases of diabetes are type 2, which comprises around 90–95% of all cases [ 11 ] .In addition, the incidence of HZ and PHN in diabetic patients is gradually increasing [ 12 – 14 ] . Studies have shown that diabetes mellitus patients often have decreased cellular immune function and impaired macrophage phagocytosis, which may increase the risk of VZV infection [ 15 ] . Clinical observations have revealed that a large percentage of diabetic patients develop PHN and have a higher coefficient of difficulty in treatment [ 13 , 16 ] , which may be related to the molecular biological mechanisms of diabetic peripheral neuropathy [ 17 – 20 ] . A national cohort study showed that type 2 diabetes patients who used metformin had a lower incidence of HZ and PHN than non-users and that the dose used was positively associated with the risk of developing the disease [ 21 ] . However, these observations are limited by the design and sample, making it difficult to make strong causal inferences and susceptible to confounding factors. Genetic variants are used as IVS in Mendelian randomization to evaluate exposure-outcome relationships [ 22 ] , and because The assignment of genetic variations occurs during conception through randomization [ 23 ] , mendelian randomization is generally more resistant to confounding and reverse causality than conventional epidemiology designs [ 24 ] . In this study, MR analysis was conducted to assess the impact of type 2 diabetes on PHN and to provide evidence to explore the potential correlation between type 2 diabetes and PHN, by exploring the mechanism of diabetes mellitus on PHN, we can provide targeted treatment or prevention for patients with HZ combined with diabetes mellitus, thus decreasing the likelihood of PHN in people with diabetes mellitus. Materials and Methods Study Design In this study, type 2 diabetes was used as an exposure factor, SNPs closely associated with type 2 diabetes were selected as IVS, and PHN was used as an outcome variable. IVW was mainly used to analyze the causal effect of type 2 diabetes on PHN. To select appropriate IVs in a two-sample MR study, three basic criteria had to be fulfilled. Correlation assumption (hypothesis 1): The chosen IV must have a strong correlation with exposure. Independence assumption (hypothesis 2): In terms of exposure-outcome confounds, the SNPS does not appear to be involved. Exclusivity assumption (hypothesis 3): the outcome is affected only through exposure and not related to other pathways. ( Fig. 1 ) Data Sources The study was primarily taken from the Open GWAS website summary data sample library(https: //gwas.mrcieu.ac.uk/). Genetic association data for type 2 diabetes were obtained from the MRC Integrative Epidemiology Unit, a database with a sample size of 149,821 individuals, including 127,904 single nucleotide polymorphisms (SNPs). The genetic association data of PHN were obtained from the FinnGen database. All of the above data were obtained from public databases and did not require additional ethical approval (Supplementary Table S1 ). SNP Selection SNPs significantly associated with type 2 diabetes (P < 5×10 − 8 , R 2 10 suggesting that the presence of a weak instrumental variable was less likely. Sensitivity Analysis The TSMR method with IVW was used as the main analytical method to analyze the causal effect of type 2 diabetes on PHN. The MR-PRESSO global test and Cochran Q statistic were also utilized to detect the presence of heterogeneity or directed pleiotropy. In addition, scatter plots, and leave-one-out were used to assess the MR "no horizontal pleiotropy" hypothesis. Results 39 genome-wide significantly associated (P < 5×10 − 8 ,R 2 10 (Supplementary Table S2).Our MR study supported a causal relationship between type 2 diabetes and PHN risk (IVW: OR = 1.508,95%CI = 1.003–2.267), P = 0.04) (Supplementary Fig. S1 a,b and Supplementary Table S3 ), Other models did not show a meaningful connection. No heterogeneity was found among estimates of individual SNPs. (P = 0.853, P > 0.05), nor was horizontal pleiotropy detected (P = 0.873, P > 0.05). The leave-one-out method of analysis was shown to be result robust(Supplementary Fig. S2) . Discussion We utilized a genetic method to investigate the cause-and-effect link between type 2 diabetes and PHN. The MR findings support an association between type 2 diabetes and PHN (IVW: OR = 1.508,95%CI = 1.003–2.267), P = 0.04). Early detection and intervention should be performed for this high-risk group to improve the prognosis through timely diagnosis and development of therapeutic strategies. As most patients with HZ combined with diabetes mellitus are associated with microcirculatory disorders and peripheral neuropathy [ 25 ] , resulting in severe and extensive skin lesions, not only the recovery time is long and there is severe neuralgia, but also the lesion site is easy to be infected, which worsens the wound and further affects the quality of patient's survival, and even threatens their lives [ 26 ] . The main reasons analyzed include: higher blood glucose concentration in diabetic patients provides favorable conditions for viral growth, reproduction, and proliferation. Moreover, sustained high blood glucose can trigger the activation of polyol bypass in the body [ 27 ] , and eventually VZV infection occurs. It has also been suggested that impaired diabetes mellitus microcirculation causes a stress response in neurons, triggering reactivation of VZV [ 28 ] , which leads to an increased risk of HZ and PHN. Together with the fact that diabetes mellitus patients are often associated with reduced immune function [ 29 , 30 ] (due to metabolic disorders, the body's natural and acquired immunity is impaired in a variety of defense functions, including phagocytosis, cellular bactericidal effects, serum conditioners, and cellular immunity), this may also increase the risk of infection. Although the pathogenesis of PHN is still uncertain, studies have been conducted in an attempt to elucidate how PHN is linked to type 2 diabetes. First, some microorganisms can adhere better to high glucose host environments and, therefore, are more likely to have a poor prognosis for PHN in diabetes mellitus patients. Secondly, due to vascular lesions that reduce the blood supply to the surrounding tissues and the lack of nutrient factors for the damaged nerves, thus making nerve regeneration slower than normal, the pain is longer and more severe than that of the average patient with HZ and is, therefore, prone to be followed by PHN [ 31 ] . Prolonged pain might result in the onset of chronic inflammation, which in turn again increases the risk of developing PHN [ 32 ] . It has been found that fasting blood glucose, glycosylated hemoglobin level, and the occurrence of VZV infection interact with each other [ 33 ] , and glycemic control is an important factor affecting the recovery process of patients with type 2 diabetes combined with VZV infection, so glucose-lowering treatment is very important. Compared with non-pharmacological hypoglycemia, Glucose-lowering (insulin or dimethylbicarb) combined with conventional therapy of HZ can better shorten the length of hospitalization and reduce neuropathic pain symptoms [ 21 ] . Meanwhile, localized skin conditions should be closely monitored clinically to prevent secondary infections and complications [ 34 , 35 ] . However, not all glucose-lowering drugs have the same positive effects, and one report [ 36 ] in an Asian diabetic population suggests that dipeptidyl peptidase (DPP)-4 inhibitors may be involved in the regulation of immune function through CD 26, which in turn increases the risk of HZ.In addition, type 2 diabetes combined with HZ has a complex pathomechanism, acute condition, rapid evolution, prominent sequela, difficult treatment, and great pain for patients; therefore, we recommend that type 2 diabetic patients be vaccinated with HZ vaccine at an earlier stage so as to minimize the risk of HZ and PHN in diabetes mellitus patients.Finally, it is worth noting that although diabetic painful neuropathy (PDN) is a common sensory peripheral neuropathy in diabetic patients [ 37 ] .If patients present with abnormal local skin sensation and obvious pain, but do not have the typical features of PDN, clinicians should be alerted to HZ and closely observe and give antiviral treatment as early as possible to decrease the frequency of PHN and enhance the standard of living for those with diabetes. Compared with traditional observational studies, MR studies have a lower chance of being impacted by factors that can confuse the results and the reverse causality bias. However, our study also has some limitations. 1st, we restricted our analysis to participants from European populations, which may limit the transfer of our findings to other racial and ethnic groups.2nd, because our data were derived from GWAS, detailed clinical information was lacking, and subgroup analyses of specific factors.3rd, hypotheses may be violated due to horizontal pleiotropy, in which genetic variation affecting the results through pathways different from the exposure studied may introduce biased estimates; however, we performed several sensitivity analyses, including MR-PRESSO, heterogeneity tests, and omission analyses, which consistently supported our results. Conclusions Our findings suggest that type 2 diabetes increases PHN risk, emphasizing the importance of preventive and targeted treatment for diabetes mellitus patients who may be prone to PHN, as well as the importance for clinicians to focus on the differential diagnosis and treatment of patients with type 2 diabetes who develop HZ and PDN. It also provides important clues for further investigation of the association mechanism between diabetes mellitus and PHN. Declarations Conflict of interest The authors declare no conflict of interest in this article. Funding Construction Project of Qiu Ling Sichuan Famous Traditional Chinese Medicine Practitioner Inheritance Workshop, Administration of Traditional Chinese Medicine of Sichuan Province (Letter of Sichuan Office of Traditional Chinese Medicine [2022] No. 36); Author Contribution Z.Y.Q: research design, analyzing data, writing and revising the paper,Submission of papers; X.G.H: Participation in data analysis and interpretation of results, revision of key methodological elements in the paper; Q.L: Proposing research ideas, general checking and finalizing papers, providing research funding. Acknowledgments GWAS summary data for type 2 diabetes, PHN were obtained from https://gwas.mrcieu.ac.uk/ . Thanks to the researchers of the GWAS catalog database. Data Availability The datasets generated and/or analysed during the current study are available in the GWAS catalog database repository, https://gwas.mrcieu.ac.uk/ References Gross GE, Eisert L, Doerr HW, et al. S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia[J]. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology: JDDG, 2020, 18(1): 55–78. Harifi G, Amine M, Ait Ouazar M, et al. Prevalence of chronic pain with neuropathic characteristics in the Moroccan general population: a national survey[J]. Pain Medicine (Malden, Mass.), 2013, 14(2): 287–292. Keating GM. Shingles (Herpes Zoster) Vaccine (Zostavax(®)): A Review in the Prevention of Herpes Zoster and Postherpetic Neuralgia[J]. BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy, 2016, 30(3): 243–254. Mallick-Searle T, Snodgrass B, Brant JM. Postherpetic neuralgia: epidemiology, pathophysiology, and pain management pharmacology[J]. Journal of Multidisciplinary Healthcare, 2016, 9: 447–454. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective[J]. BMJ open, 2014, 4(6): e004833. Forbes HJ, Thomas SL, Smeeth L, 等. A systematic review and meta-analysis of risk factors for postherpetic neuralgia[J]. Pain, 2016, 157(1): 30–54. 曹婷. 带状疱疹病例分析及带状疱疹后遗神经痛危险因素研究[D]. 北京中医药大学, 2019. 秦夏莲. 带状疱疹患者发生后遗神经痛的相关因素研究[J]. 现代医学与健康研究电子杂志, 2022, 6(14): 116–118. Wen SY, Ou-Yang C, Chang C, et al. Impact of Type 1 Versus Type 2 Diabetes on Developing Herpes Zoster and Post-herpetic Neuralgia: A Population-based Cohort Study[J]. Acta Dermato-Venereologica, 2023, 103: adv9400. Fralick M, Jenkins AJ, Khunti K, et al. Global accessibility of therapeutics for diabetes mellitus[J]. Nature Reviews. Endocrinology, 2022, 18(4): 199–204. Srivastava SP. Editorial: Current understanding of complications associated with diabetes[J]. Frontiers in Clinical Diabetes and Healthcare, 2023, 4. Poirrier JE, Meyers JL, Nagar SP, et al. Herpes Zoster Incidence and Burden in Adults With Type 2 Diabetes in the U.S.: A Retrospective Database Analysis[J]. Diabetes Care, 2022, 45(11): 2585–2593. Saadatian-Elahi M, Bauduceau B, Del-Signore C, et al. Diabetes as a risk factor for herpes zoster in adults: A synthetic literature review[J]. Diabetes Research and Clinical Practice, 2020, 159: 107983. Suaya JA, Chen SY, Li Q, et al. Incidence of herpes zoster and persistent post-zoster pain in adults with or without diabetes in the United States[J]. Open Forum Infectious Diseases, 2014, 1(2): ofu049. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM)[J]. FEMS immunology and medical microbiology, 1999, 26(3–4): 259–265. 杨婧, 刘荣国, 冯淑秀, 等. 糖尿病对高电压脉冲射频治疗带状疱疹后神经痛的影响分析[J]. 中国疼痛医学杂志, 2021, 27(7): 505–509. Shin J, Yin Y, Park H, et al. p38 siRNA-encapsulated PLGA nanoparticles alleviate neuropathic pain behavior in rats by inhibiting microglia activation[J]. Nanomedicine (London, England), 2018, 13(13): 1607–1621. Verschoor CP, Lelic A, Parsons R, et al. Serum C-Reactive Protein and Congestive Heart Failure as Significant Predictors of Herpes Zoster Vaccine Response in Elderly Nursing Home Residents[J]. The Journal of Infectious Diseases, 2017, 216(2): 191–197. Mu ZP, Wang YG, Li CQ, et al. Association Between Tumor Necrosis Factor-α and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes: a Meta-Analysis[J]. Molecular Neurobiology, 2017, 54(2): 983–996. Vincent AM, McLean LL, Backus C, et al. Short-term hyperglycemia produces oxidative damage and apoptosis in neurons[J]. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 2005, 19(6): 638–640. Yen FS, Wei JCC, Yip HT, et al. Metformin use and the risks of herpes zoster and postherpetic neuralgia in patients with type 2 diabetes[J]. Journal of Medical Virology, 2023, 95(1): e28278. Smith GD, Ebrahim S. “Mendelian randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease?[J]. International Journal of Epidemiology, 2003, 32(1): 1–22. Sekula P, Del Greco M F, Pattaro C, et al. Mendelian Randomization as an Approach to Assess Causality Using Observational Data[J]. Journal of the American Society of Nephrology: JASN, 2016, 27(11): 3253–3265. Lawlor DA, Harbord RM, Sterne JAC, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology[J]. Statistics in Medicine, 2008, 27(8): 1133–1163. Hsu CY, Ke DS, Lin CL, et al. Risk of Herpes Zoster in Patients with Adhesive Capsulitis of the Shoulder[J]. International Journal of Environmental Research and Public Health, 2020, 17(10): 3592. Lin CF, Hong CT, Lee WH, et al. Disseminated cutaneous herpes zoster and multiple cerebral infarcts in an adult with diabetes mellitus[J]. Journal of Neurovirology, 2020, 26(1): 130–132. Katsuda Y, Sasase T, Tadaki H, et al. Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin[J]. Experimental Animals, 2015, 64(2): 161–169. Kaiserman I, Kaiserman N, Nakar S, et al. Herpetic eye disease in diabetic patients[J]. Ophthalmology, 2005, 112(12): 2184–2188. Okamoto S, Hata A, Sadaoka K, et al. Comparison of varicella-zoster virus-specific immunity of patients with diabetes mellitus and healthy individuals[J]. The Journal of Infectious Diseases, 2009, 200(10): 1606–1610. 李玉秋, 王琛, 韦兰, 等. 带状疱疹急性期患者血清前炎性细胞因子、免疫球蛋白和T淋巴细胞亚群水平与后遗神经痛的相关性分析[J]. 河北医药, 2020(6): 805–809. Muñoz-Quiles C, López-Lacort M, Orrico-Sánchez A, et al. Impact of postherpetic neuralgia: A six year population-based analysis on people aged 50 years or older[J]. The Journal of Infection, 2018, 77(2): 131–136. Head H, Campbell AW, Kennedy PG. The pathology of Herpes Zoster and its bearing on sensory localisation[J]. Reviews in Medical Virology, 1997, 7(3): 131–143. Tang J, Zhang Z, Yao M. Predictive Value of Blood Glucose Coefficient of Variation for Prognoses in Patients with Diabetes Mellitus-Associated Herpes Zoster[J]. Pain Physician, 2024, 27(1): 51–58. Forbes HJ, Bhaskaran K, Thomas SL, et al. Quantification of risk factors for postherpetic neuralgia in herpes zoster patients: A cohort study[J]. Neurology, 2016, 87(1): 94–102. 丁伟民, 吴玮, 郑旺福, 等. 带状疱疹后遗神经痛患者继发感染病原菌特点及相关影响因素分析[J]. 中华医院感染学杂志, 2017(22): 5137–5140. Chen HH, Lin CL, Yeh SY, et al. Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes[J]. QJM: monthly journal of the Association of Physicians, 2016, 109(2): 91–95. Daousi C, MacFarlane IA, Woodward A, et al. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes[J]. Diabetic Medicine: A Journal of the British Diabetic Association, 2004, 21(9): 976–982. 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PHN is chronic, intractable nerve pain left after herpes healing \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e, and persistent severe pain seriously impacts the well-being and standard of living of patients significantly \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.PHN is among the most prevalent and significant clinical consequences of HZ \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, and clinical statistics show that there are approximately 1\u0026nbsp;million HZ patients in the US each year, and the occurrence of subsequent PHN reaches 5% ~ 20% \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The prevalence of both HZ and PHN tends to increase gradually with aging\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Relevant studies have suggested that the occurrence of PHN is linked to a variety of risk factors, including advanced age; pain (prodromal pain, high pain level in the acute phase, and abnormal pain); rash (large rash size, involvement of special areas such as perineum and brachial plexus, and the appearance of gangrenous, maculopapular, and hemorrhagic special lesions); underlying diseases and long-term drug history (diabetes mellitus, malignant neoplasm, tuberculosis, recent traumatic injuries, and long-term use of immunosuppressants or glucocorticoids, etc.); anxiety and depression, etc \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Due to the complexity of PHN pain mechanisms, these risk factors currently remain to be proven by further research.\u003c/p\u003e \u003cp\u003eSome studies have found that diabetes mellitus (diabetes mellitus) may be one of the risk factors for PHN \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Literature shows that the increasing prevalence of diabetes poses a serious threat to human health on a worldwide scale \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. According to data released by the IDF, there are almost 537\u0026nbsp;million individuals worldwide who have diabetes, and by 2040, the number of people living with diabetes is projected to reach 642\u0026nbsp;million. Most cases of diabetes are type 2, which comprises around 90\u0026ndash;95% of all cases \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.In addition, the incidence of HZ and PHN in diabetic patients is gradually increasing\u003csup\u003e[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Studies have shown that diabetes mellitus patients often have decreased cellular immune function and impaired macrophage phagocytosis, which may increase the risk of VZV infection\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Clinical observations have revealed that a large percentage of diabetic patients develop PHN and have a higher coefficient of difficulty in treatment \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e, which may be related to the molecular biological mechanisms of diabetic peripheral neuropathy \u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. A national cohort study showed that type 2 diabetes patients who used metformin had a lower incidence of HZ and PHN than non-users and that the dose used was positively associated with the risk of developing the disease \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. However, these observations are limited by the design and sample, making it difficult to make strong causal inferences and susceptible to confounding factors.\u003c/p\u003e \u003cp\u003eGenetic variants are used as IVS in Mendelian randomization to evaluate exposure-outcome relationships\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, and because The assignment of genetic variations occurs during conception through randomization\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, mendelian randomization is generally more resistant to confounding and reverse causality than conventional epidemiology designs\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, MR analysis was conducted to assess the impact of type 2 diabetes on PHN and to provide evidence to explore the potential correlation between type 2 diabetes and PHN, by exploring the mechanism of diabetes mellitus on PHN, we can provide targeted treatment or prevention for patients with HZ combined with diabetes mellitus, thus decreasing the likelihood of PHN in people with diabetes mellitus.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eIn this study, type 2 diabetes was used as an exposure factor, SNPs closely associated with type 2 diabetes were selected as IVS, and PHN was used as an outcome variable. IVW was mainly used to analyze the causal effect of type 2 diabetes on PHN. To select appropriate IVs in a two-sample MR study, three basic criteria had to be fulfilled. Correlation assumption (hypothesis 1): The chosen IV must have a strong correlation with exposure. Independence assumption (hypothesis 2): In terms of exposure-outcome confounds, the SNPS does not appear to be involved. Exclusivity assumption (hypothesis 3): the outcome is affected only through exposure and not related to other pathways. ( Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData Sources\u003c/h2\u003e \u003cp\u003eThe study was primarily taken from the Open GWAS website summary data sample library(https: //gwas.mrcieu.ac.uk/). Genetic association data for type 2 diabetes were obtained from the MRC Integrative Epidemiology Unit, a database with a sample size of 149,821 individuals, including 127,904 single nucleotide polymorphisms (SNPs). The genetic association data of PHN were obtained from the FinnGen database. All of the above data were obtained from public databases and did not require additional ethical approval (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSNP Selection\u003c/h2\u003e \u003cp\u003eSNPs significantly associated with type 2 diabetes (P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e, R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, KB\u0026thinsp;=\u0026thinsp;10,000) were included, ensuring that each selected SNP was independent and not chained for imbalance. The F statistic was calculated for each SNP, with an F value\u0026thinsp;\u0026gt;\u0026thinsp;10 suggesting that the presence of a weak instrumental variable was less likely.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity Analysis\u003c/h2\u003e \u003cp\u003eThe TSMR method with IVW was used as the main analytical method to analyze the causal effect of type 2 diabetes on PHN. The MR-PRESSO global test and Cochran Q statistic were also utilized to detect the presence of heterogeneity or directed pleiotropy. In addition, scatter plots, and leave-one-out were used to assess the MR \"no horizontal pleiotropy\" hypothesis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e39 genome-wide significantly associated (P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e,R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, KB\u0026thinsp;=\u0026thinsp;10,000) index SNPs were included. f-value for each SNP was \u0026gt;\u0026thinsp;10 (Supplementary Table S2).Our MR study supported a causal relationship between type 2 diabetes and PHN risk (IVW: OR\u0026thinsp;=\u0026thinsp;1.508,95%CI\u0026thinsp;=\u0026thinsp;1.003\u0026ndash;2.267), P\u0026thinsp;=\u0026thinsp;0.04) (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ea,b and Supplementary Table S3 ), Other models did not show a meaningful connection.\u003c/p\u003e \u003cp\u003eNo heterogeneity was found among estimates of individual SNPs. (P\u0026thinsp;=\u0026thinsp;0.853, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), nor was horizontal pleiotropy detected (P\u0026thinsp;=\u0026thinsp;0.873, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The leave-one-out method of analysis was shown to be result robust(Supplementary Fig. S2) .\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe utilized a genetic method to investigate the cause-and-effect link between type 2 diabetes and PHN. The MR findings support an association between type 2 diabetes and PHN (IVW: OR\u0026thinsp;=\u0026thinsp;1.508,95%CI\u0026thinsp;=\u0026thinsp;1.003\u0026ndash;2.267), P\u0026thinsp;=\u0026thinsp;0.04). Early detection and intervention should be performed for this high-risk group to improve the prognosis through timely diagnosis and development of therapeutic strategies.\u003c/p\u003e \u003cp\u003eAs most patients with HZ combined with diabetes mellitus are associated with microcirculatory disorders and peripheral neuropathy \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, resulting in severe and extensive skin lesions, not only the recovery time is long and there is severe neuralgia, but also the lesion site is easy to be infected, which worsens the wound and further affects the quality of patient's survival, and even threatens their lives \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. The main reasons analyzed include: higher blood glucose concentration in diabetic patients provides favorable conditions for viral growth, reproduction, and proliferation. Moreover, sustained high blood glucose can trigger the activation of polyol bypass in the body \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e, and eventually VZV infection occurs. It has also been suggested that impaired diabetes mellitus microcirculation causes a stress response in neurons, triggering reactivation of VZV\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, which leads to an increased risk of HZ and PHN. Together with the fact that diabetes mellitus patients are often associated with reduced immune function \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e(due to metabolic disorders, the body's natural and acquired immunity is impaired in a variety of defense functions, including phagocytosis, cellular bactericidal effects, serum conditioners, and cellular immunity), this may also increase the risk of infection.\u003c/p\u003e \u003cp\u003eAlthough the pathogenesis of PHN is still uncertain, studies have been conducted in an attempt to elucidate how PHN is linked to type 2 diabetes. First, some microorganisms can adhere better to high glucose host environments and, therefore, are more likely to have a poor prognosis for PHN in diabetes mellitus patients. Secondly, due to vascular lesions that reduce the blood supply to the surrounding tissues and the lack of nutrient factors for the damaged nerves, thus making nerve regeneration slower than normal, the pain is longer and more severe than that of the average patient with HZ and is, therefore, prone to be followed by PHN\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Prolonged pain might result in the onset of chronic inflammation, which in turn again increases the risk of developing PHN \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt has been found that fasting blood glucose, glycosylated hemoglobin level, and the occurrence of VZV infection interact with each other \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e, and glycemic control is an important factor affecting the recovery process of patients with type 2 diabetes combined with VZV infection, so glucose-lowering treatment is very important. Compared with non-pharmacological hypoglycemia, Glucose-lowering (insulin or dimethylbicarb) combined with conventional therapy of HZ can better shorten the length of hospitalization and reduce neuropathic pain symptoms \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Meanwhile, localized skin conditions should be closely monitored clinically to prevent secondary infections and complications \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. However, not all glucose-lowering drugs have the same positive effects, and one report \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e in an Asian diabetic population suggests that dipeptidyl peptidase (DPP)-4 inhibitors may be involved in the regulation of immune function through CD 26, which in turn increases the risk of HZ.In addition, type 2 diabetes combined with HZ has a complex pathomechanism, acute condition, rapid evolution, prominent sequela, difficult treatment, and great pain for patients; therefore, we recommend that type 2 diabetic patients be vaccinated with HZ vaccine at an earlier stage so as to minimize the risk of HZ and PHN in diabetes mellitus patients.Finally, it is worth noting that although diabetic painful neuropathy (PDN) is a common sensory peripheral neuropathy in diabetic patients \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.If patients present with abnormal local skin sensation and obvious pain, but do not have the typical features of PDN, clinicians should be alerted to HZ and closely observe and give antiviral treatment as early as possible to decrease the frequency of PHN and enhance the standard of living for those with diabetes.\u003c/p\u003e \u003cp\u003eCompared with traditional observational studies, MR studies have a lower chance of being impacted by factors that can confuse the results and the reverse causality bias. However, our study also has some limitations. 1st, we restricted our analysis to participants from European populations, which may limit the transfer of our findings to other racial and ethnic groups.2nd, because our data were derived from GWAS, detailed clinical information was lacking, and subgroup analyses of specific factors.3rd, hypotheses may be violated due to horizontal pleiotropy, in which genetic variation affecting the results through pathways different from the exposure studied may introduce biased estimates; however, we performed several sensitivity analyses, including MR-PRESSO, heterogeneity tests, and omission analyses, which consistently supported our results.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur findings suggest that type 2 diabetes increases PHN risk, emphasizing the importance of preventive and targeted treatment for diabetes mellitus patients who may be prone to PHN, as well as the importance for clinicians to focus on the differential diagnosis and treatment of patients with type 2 diabetes who develop HZ and PDN. It also provides important clues for further investigation of the association mechanism between diabetes mellitus and PHN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest in this article.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eConstruction Project of Qiu Ling Sichuan Famous Traditional Chinese Medicine Practitioner Inheritance Workshop, Administration of Traditional Chinese Medicine of Sichuan Province (Letter of Sichuan Office of Traditional Chinese Medicine [2022] No. 36);\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eZ.Y.Q: research design, analyzing data, writing and revising the paper,Submission of papers; X.G.H: Participation in data analysis and interpretation of results, revision of key methodological elements in the paper; Q.L: Proposing research ideas, general checking and finalizing papers, providing research funding.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eGWAS summary data for type 2 diabetes, PHN were obtained from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Thanks to the researchers of the GWAS catalog database.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analysed during the current study are available in the\u0026nbsp;GWAS catalog database\u0026nbsp;repository,\u0026nbsp;https://gwas.mrcieu.ac.uk/\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGross GE, Eisert L, Doerr HW, et al. S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia[J]. Journal der Deutschen Dermatologischen Gesellschaft\u0026thinsp;=\u0026thinsp;Journal of the German Society of Dermatology: JDDG, 2020, 18(1): 55\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarifi G, Amine M, Ait Ouazar M, et al. Prevalence of chronic pain with neuropathic characteristics in the Moroccan general population: a national survey[J]. Pain Medicine (Malden, Mass.), 2013, 14(2): 287\u0026ndash;292.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeating GM. Shingles (Herpes Zoster) Vaccine (Zostavax(\u0026reg;)): A Review in the Prevention of Herpes Zoster and Postherpetic Neuralgia[J]. BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy, 2016, 30(3): 243\u0026ndash;254.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMallick-Searle T, Snodgrass B, Brant JM. Postherpetic neuralgia: epidemiology, pathophysiology, and pain management pharmacology[J]. Journal of Multidisciplinary Healthcare, 2016, 9: 447\u0026ndash;454.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective[J]. BMJ open, 2014, 4(6): e004833.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForbes HJ, Thomas SL, Smeeth L, 等. A systematic review and meta-analysis of risk factors for postherpetic neuralgia[J]. Pain, 2016, 157(1): 30\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e曹婷. 带状疱疹病例分析及带状疱疹后遗神经痛危险因素研究[D]. 北京中医药大学, 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e秦夏莲. 带状疱疹患者发生后遗神经痛的相关因素研究[J]. 现代医学与健康研究电子杂志, 2022, 6(14): 116\u0026ndash;118.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWen SY, Ou-Yang C, Chang C, et al. Impact of Type 1 Versus Type 2 Diabetes on Developing Herpes Zoster and Post-herpetic Neuralgia: A Population-based Cohort Study[J]. Acta Dermato-Venereologica, 2023, 103: adv9400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFralick M, Jenkins AJ, Khunti K, et al. Global accessibility of therapeutics for diabetes mellitus[J]. Nature Reviews. Endocrinology, 2022, 18(4): 199\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSrivastava SP. Editorial: Current understanding of complications associated with diabetes[J]. Frontiers in Clinical Diabetes and Healthcare, 2023, 4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoirrier JE, Meyers JL, Nagar SP, et al. Herpes Zoster Incidence and Burden in Adults With Type 2 Diabetes in the U.S.: A Retrospective Database Analysis[J]. Diabetes Care, 2022, 45(11): 2585\u0026ndash;2593.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaadatian-Elahi M, Bauduceau B, Del-Signore C, et al. Diabetes as a risk factor for herpes zoster in adults: A synthetic literature review[J]. Diabetes Research and Clinical Practice, 2020, 159: 107983.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuaya JA, Chen SY, Li Q, et al. Incidence of herpes zoster and persistent post-zoster pain in adults with or without diabetes in the United States[J]. Open Forum Infectious Diseases, 2014, 1(2): ofu049.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM)[J]. FEMS immunology and medical microbiology, 1999, 26(3\u0026ndash;4): 259\u0026ndash;265.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e杨婧, 刘荣国, 冯淑秀, 等. 糖尿病对高电压脉冲射频治疗带状疱疹后神经痛的影响分析[J]. 中国疼痛医学杂志, 2021, 27(7): 505\u0026ndash;509.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShin J, Yin Y, Park H, et al. p38 siRNA-encapsulated PLGA nanoparticles alleviate neuropathic pain behavior in rats by inhibiting microglia activation[J]. Nanomedicine (London, England), 2018, 13(13): 1607\u0026ndash;1621.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerschoor CP, Lelic A, Parsons R, et al. Serum C-Reactive Protein and Congestive Heart Failure as Significant Predictors of Herpes Zoster Vaccine Response in Elderly Nursing Home Residents[J]. The Journal of Infectious Diseases, 2017, 216(2): 191\u0026ndash;197.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu ZP, Wang YG, Li CQ, et al. Association Between Tumor Necrosis Factor-α and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes: a Meta-Analysis[J]. Molecular Neurobiology, 2017, 54(2): 983\u0026ndash;996.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVincent AM, McLean LL, Backus C, et al. Short-term hyperglycemia produces oxidative damage and apoptosis in neurons[J]. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 2005, 19(6): 638\u0026ndash;640.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYen FS, Wei JCC, Yip HT, et al. Metformin use and the risks of herpes zoster and postherpetic neuralgia in patients with type 2 diabetes[J]. Journal of Medical Virology, 2023, 95(1): e28278.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith GD, Ebrahim S. \u0026ldquo;Mendelian randomization\u0026rdquo;: can genetic epidemiology contribute to understanding environmental determinants of disease?[J]. International Journal of Epidemiology, 2003, 32(1): 1\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSekula P, Del Greco M F, Pattaro C, et al. Mendelian Randomization as an Approach to Assess Causality Using Observational Data[J]. Journal of the American Society of Nephrology: JASN, 2016, 27(11): 3253\u0026ndash;3265.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLawlor DA, Harbord RM, Sterne JAC, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology[J]. Statistics in Medicine, 2008, 27(8): 1133\u0026ndash;1163.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu CY, Ke DS, Lin CL, et al. Risk of Herpes Zoster in Patients with Adhesive Capsulitis of the Shoulder[J]. International Journal of Environmental Research and Public Health, 2020, 17(10): 3592.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin CF, Hong CT, Lee WH, et al. Disseminated cutaneous herpes zoster and multiple cerebral infarcts in an adult with diabetes mellitus[J]. Journal of Neurovirology, 2020, 26(1): 130\u0026ndash;132.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatsuda Y, Sasase T, Tadaki H, et al. Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin[J]. Experimental Animals, 2015, 64(2): 161\u0026ndash;169.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaiserman I, Kaiserman N, Nakar S, et al. Herpetic eye disease in diabetic patients[J]. Ophthalmology, 2005, 112(12): 2184\u0026ndash;2188.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkamoto S, Hata A, Sadaoka K, et al. Comparison of varicella-zoster virus-specific immunity of patients with diabetes mellitus and healthy individuals[J]. The Journal of Infectious Diseases, 2009, 200(10): 1606\u0026ndash;1610.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e李玉秋, 王琛, 韦兰, 等. 带状疱疹急性期患者血清前炎性细胞因子、免疫球蛋白和T淋巴细胞亚群水平与后遗神经痛的相关性分析[J]. 河北医药, 2020(6): 805\u0026ndash;809.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu\u0026ntilde;oz-Quiles C, L\u0026oacute;pez-Lacort M, Orrico-S\u0026aacute;nchez A, et al. Impact of postherpetic neuralgia: A six year population-based analysis on people aged 50 years or older[J]. The Journal of Infection, 2018, 77(2): 131\u0026ndash;136.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHead H, Campbell AW, Kennedy PG. The pathology of Herpes Zoster and its bearing on sensory localisation[J]. Reviews in Medical Virology, 1997, 7(3): 131\u0026ndash;143.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang J, Zhang Z, Yao M. Predictive Value of Blood Glucose Coefficient of Variation for Prognoses in Patients with Diabetes Mellitus-Associated Herpes Zoster[J]. Pain Physician, 2024, 27(1): 51\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForbes HJ, Bhaskaran K, Thomas SL, et al. Quantification of risk factors for postherpetic neuralgia in herpes zoster patients: A cohort study[J]. Neurology, 2016, 87(1): 94\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e丁伟民, 吴玮, 郑旺福, 等. 带状疱疹后遗神经痛患者继发感染病原菌特点及相关影响因素分析[J]. 中华医院感染学杂志, 2017(22): 5137\u0026ndash;5140.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen HH, Lin CL, Yeh SY, et al. Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes[J]. QJM: monthly journal of the Association of Physicians, 2016, 109(2): 91\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaousi C, MacFarlane IA, Woodward A, et al. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes[J]. Diabetic Medicine: A Journal of the British Diabetic Association, 2004, 21(9): 976\u0026ndash;982.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Type 2 diabetes, Post-herpetic neuralgia, Mendelian randomization, Causality","lastPublishedDoi":"10.21203/rs.3.rs-4312613/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4312613/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e A two-sample Mendelian randomization method was used to study the causal relationship between Type 2 diabetes and post-herpetic neuralgia (PHN).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e Genome-wide association statistics of type 2 diabetes with PHN were obtained, and single nucleotide polymorphisms (SNPs) strongly associated with type 2 diabetes were used as instrumental variables(IVS).TSMR method with inverse variance weighting (IVW) as the primary analytical approach to evaluate the causal association between type 2 diabetes and PHN. Sensitivity analysis was also conducted to evaluate the strength and reliability of the findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e 39 SNPs strongly associated with type 2 diabetes were included in the analysis, which showed that type 2 diabetes was significantly associated with PHN(IVW: OR=1.508,95%CI=1.003-2.267), P=0.04). Sensitivity analyses demonstrated the strength and reliability of the causal relationship.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e There was a correlation between type 2 diabetes and PHN, and type 2 diabetes was linked to a higher risk of PHN.\u003c/p\u003e","manuscriptTitle":"Type 2 diabetes and risk of post-herpetic neuralgia: A Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-07 18:58:47","doi":"10.21203/rs.3.rs-4312613/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"294f3283-4e74-47f1-adcb-501006ceee9c","owner":[],"postedDate":"May 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31579285,"name":"Biological sciences/Genetics"},{"id":31579286,"name":"Health sciences/Endocrinology"},{"id":31579287,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2024-09-06T06:08:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-07 18:58:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4312613","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4312613","identity":"rs-4312613","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}