1.
Genetics and postsurgical neuropathic pain: An ancillary study of a multicentre survey.
Blanc, P, Génin, E, Jesson, B, Dubray, C, Dualé, C, ,
European journal of anaesthesiology. 2019;(5):342-350
Abstract
BACKGROUND Neuropathic pain following surgery could be a useful model for the study of the genetic mechanisms of peripheral neuropathic pain. OBJECTIVE The aim of this study was to identify genetic predictors of persistent postsurgical neuropathic pain. DESIGN An ancillary study from a prospective cohort. SETTING Eighteen French university hospitals. PATIENTS Five hundred and sixty-one patients at risk of persistent postoperative pain who underwent scheduled surgery were classified as 159 cases and 402 controls. INTERVENTION Pre-operative blood sampling for DNA analysis and questionnaires sent at the third and sixth month after surgery. MAIN OUTCOME MEASURES The phenotype was the report of pain at the site of surgery with a positive response in the DN4 questionnaire within 6 months after surgery. Out of a list of 126 candidate genes involved in the initial processes of peripheral neuropathic pain, a set of 4599 single nucleotide polymorphisms was tested on an Illumina chip. We carried out the association tests, based on an additive model, on 4422 single nucleotide polymorphisms. RESULTS After correcting for type-I error inflation, only one suggestive association was reached for one single nucleotide polymorphism, the rs2286614, which we had selected to tag KCNK4. This gene encodes for TRAAK, a two-pore domain background K channel involved in the modulation of the primary thermoreceptors of the transient receptor potential channels family. CONCLUSION This is the first genetic association study specifically investigating the occurrence of persistent postsurgical neuropathic pain. Its results help target future research to better understand the mechanisms of peripheral neuropathic pain. TRIAL REGISTRATION ClinicalTrials.gov (ref. NCT00812734).
2.
Obstructive Sleep Apnea and Circulating Potassium Channel Levels.
Jiang, N, Zhou, A, Prasad, B, Zhou, L, Doumit, J, Shi, G, Imran, H, Kaseer, B, Millman, R, Dudley, SC
Journal of the American Heart Association. 2016;(8)
Abstract
BACKGROUND Cardiac arrhythmias and sudden cardiac death are more frequent in patients with obstructive sleep apnea (OSA). OSA is associated with QT prolongation, and QT prolongation is an independent risk factor for sudden cardiac death. Because QT prolongation can be mediated by potassium channel loss of function, we tested whether OSA or continuous positive airway pressure therapy altered mRNA expression of circulating white blood cell potassium channels. METHODS AND RESULTS In total, 28 patients with OSA newly diagnosed by polysomnogram and 6 participants without OSA were enrolled. Potassium channel levels in white blood cells at baseline and at a 4-week follow-up visit were compared. There was a significant inverse correlation between the severity of the OSA stratified by apnea-hypopnea index and mRNA expression of the main potassium channels assessed: KCNQ1 (r=-0.486, P=0.007), KCNH2 (r=-0.437, P=0.016), KCNE1 (r=-0.567, P=0.001), KCNJ2 (r=-0.442, P=0.015), and KCNA5 (r=-0.468, P=0.009). In addition, KCNQ1, KCNH2, and KCNE1 inversely correlated with the oxygen desaturation index 4. After 4 weeks of continuous positive airway pressure therapy, circulating KCNQ1 and KCNJ2 were increased 1.4±0.4-fold (P=0.040) and 2.1±1.4-fold (P=0.046) in the moderate OSA group. Compared with patients with mild or moderate OSA, patients with severe OSA had a persistently higher apnea-hypopnea index (mild 2.0±1.8, moderate 1.0±0.9, severe 5.8±5.6; P=0.015), perhaps explaining why the potassium channel changes were not seen in the severe OSA group. CONCLUSIONS The mRNA expression of most potassium channels inversely correlates with the severity of OSA and hypoxemia. Continuous positive airway pressure therapy improves circulating KCNQ1 and KCNJ2 in patients with moderate OSA.
3.
Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.
Florez, JC, Jablonski, KA, Kahn, SE, Franks, PW, Dabelea, D, Hamman, RF, Knowler, WC, Nathan, DM, Altshuler, D
Diabetes. 2007;(2):531-6
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Abstract
The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over approximately 3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.
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Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53).
Gloyn, AL, Hashim, Y, Ashcroft, SJ, Ashfield, R, Wiltshire, S, Turner, RC, ,
Diabetic medicine : a journal of the British Diabetic Association. 2001;(3):206-12
Abstract
AIMS: The beta-cell ATP-sensitive potassium channel consists of two subunits, SUR1 and Kir6.2. Population association studies have shown that three variants in SUR1 and one in Kir6.2 are associated with Type 2 diabetes. These polymorphisms do not result in a functional change or affect splicing, suggesting that they could be in linkage disequilibrium with a pathogenic mutation. The present study aimed firstly to screen the promoter regions of SUR1 and Kir6.2 to determine whether mutations in linkage disequilibrium with the silent variants lie in regulatory regions, which might lead to changes in gene expression. Secondly, novel and previously described variants associated with Type 2 diabetes (SUR1 exon 16-3t, exon 18 T, and Kir6.2 E23K) were investigated in the UKPDS cohort. METHODS The promoter sequences of both genes were screened by single-stranded conformational polymorphism analysis for variants associated with Type 2 diabetes. The previously reported variants were evaluated in 364 Type 2 diabetic and 328 normoglycaemic control subjects. RESULTS Two variants were detected in the SUR1 promoter, a three base insertion (caa) at -522 bp and a single base substitution at - 679 bp (c-->g). Neither of the variants were associated with diabetes, nor were they in a sequence consensus region for transcription factors. No association with diabetes was observed for either SUR1 variant. However, in contrast, analysis of the Kir6.2 E23K variant showed that the KK homozygosity was more frequent in Type 2 diabetic than control subjects. Variants were not associated with clinical characteristics nor did they affect response to sulphonylurea therapy CONCLUSION There is no support at present for mutations in either Kir6.2 or SUR1 promoter sequences contributing to Type 2 diabetes. However, the minimal promoter region of SUR1 has yet to be investigated. The E23K variant of Kir6.2 is associated with Type 2 diabetes mellitus in the UKPDS cohort.