Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Young-onset diabetes in Asian Indians is associated with lower measured and genetically determined beta cell function.

AIMS/HYPOTHESIS: South Asians in general, and Asian Indians in particular, have higher risk of type 2 diabetes compared with white Europeans, and a younger age of onset. The reasons for the younger age of onset in relation to obesity, beta cell function and insulin sensitivity are under-explored. METHODS: Two cohorts of Asian Indians, the ICMR-INDIAB cohort (Indian Council of Medical Research-India Diabetes Study) and the DMDSC cohort (Dr Mohan's Diabetes Specialties Centre), and one of white Europeans, the ESDC (East Scotland Diabetes Cohort), were used. Using a cross-sectional design, we examined the comparative prevalence of healthy, overweight and obese participants with young-onset diabetes, classified according to their BMI. We explored the role of clinically measured beta cell function in diabetes onset in Asian Indians. Finally, the comparative distribution of a partitioned polygenic score (pPS) for risk of diabetes due to poor beta cell function was examined. Replication of the genetic findings was sought using data from the UK Biobank. RESULTS: The prevalence of young-onset diabetes with normal BMI was 9.3% amongst white Europeans and 24-39% amongst Asian Indians. In Asian Indians with young-onset diabetes, after adjustment for family history of type 2 diabetes, sex, insulin sensitivity and HDL-cholesterol, stimulated C-peptide was 492 pmol/ml (IQR 353-616, p<0.0001) lower in lean compared with obese individuals. Asian Indians in our study, and South Asians from the UK Biobank, had a higher number of risk alleles than white Europeans. After weighting the pPS for beta cell function, Asian Indians have lower genetically determined beta cell function than white Europeans (p<0.0001). The pPS was associated with age of diagnosis in Asian Indians but not in white Europeans. The pPS explained 2% of the variation in clinically measured beta cell function, and 1.2%, 0.97%, and 0.36% of variance in age of diabetes amongst Asian Indians with normal BMI, or classified as overweight and obese BMI, respectively. CONCLUSIONS/INTERPRETATION: The prevalence of lean BMI in young-onset diabetes is over two times higher in Asian Indians compared with white Europeans. This phenotype of lean, young-onset diabetes appears driven in part by lower beta cell function. We demonstrate that Asian Indians with diabetes also have lower genetically determined beta cell function.

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease.

OBJECTIVE: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (ßs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (ßs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation. CONCLUSIONS: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.

Trends in gabapentinoid prescribing, co-prescribing of opioids and benzodiazepines, and associated deaths in Scotland.

BACKGROUND: Gabapentinoid drugs (gabapentin and pregabalin) are effective in neuropathic pain, which has a prevalence of ∼7%. Concerns about increased prescribing have implications for patient safety, misuse, and diversion. Drug-related deaths (DRDs) have increased and toxicology often implicates gabapentinoids. We studied national and regional prescribing rates (2006-2016) and identified associated sociodemographic factors, co-prescriptions and mortality, including DRDs. METHODS: National data from the Information Service Division, NHS Scotland were analysed for prescribing, sociodemographic, and mortality data from the Health Informatics Centre, University of Dundee. DRDs in which gabapentinoids were implicated were identified from National Records of Scotland and Tayside Drug Death Databases. RESULTS: From 2006 to 2016, the number of gabapentin prescriptions in Scotland increased 4-fold (164 630 to 694 293), and pregabalin 16-fold (27 094 to 435 490). In 2016 'recurrent users' (three or more prescriptions) had mean age 58.1 yr, were mostly females (62.5%), and were more likely to live in deprived areas. Of these, 60% were co-prescribed an opioid, benzodiazepine, or both (opioid 49.9%, benzodiazepine 26.8%, both 17.1%). The age-standardised death rate in those prescribed gabapentinoids was double that in the Scottish population (relative risk 2.16, 95% confidence interval 2.08-2.25). Increases in gabapentinoids contributing to cause of DRDs were reported regionally and nationally (gabapentin 23% vs 15%; pregabalin 21% vs 7%). In Tayside, gabapentinoids were implicated in 22 (39%) of DRDs, 17 (77%) of whom had not received a prescription. CONCLUSIONS: Gabapentinoid prescribing has increased dramatically since 2006, as have dangerous co-prescribing and death (including DRDs). Older people, women, and those living in deprived areas were particularly likely to receive prescriptions. Their contribution to DRDs may be more related to illegal use with diversion of prescribed medication.

A common missense variant of LILRB5 is associated with statin intolerance and myalgia.

Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34-2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07-1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05-2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10-1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16-1.54). Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors.

OBJECTIVES: To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. METHODS: Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. RESULTS: A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P<5×10) in the meta-analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), γ-aminobutyric acid receptor subunit γ-2, sarcoma (Src) homology 2 (SH2) B adaptor protein 1 and membrane bound O-acyltransferase domain containing 1]. The strongest associated SNP was located in an intron of RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), which contains an RNA binding protein [rs2061538: minor allele frequency=0.16, odds ratio=1.52 (95% confidence interval: 1.32-1.76), P=6.2×10]. CONCLUSION: These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.

Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort.

ABSTRACT: We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10-8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the "irritable" nociceptor profile to those with a "nonirritable" nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 × 10-8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.

Development and external validation of multivariable risk models to predict incident and resolved neuropathic pain: a DOLORisk Dundee study.

Neuropathic pain is difficult to treat, and an understanding of the risk factors for its onset and resolution is warranted. This study aimed to develop and externally validate two clinical risk models to predict onset and resolution of chronic neuropathic pain. Participants of Generation Scotland: Scottish Family Health Study (GS; general Scottish population; n = 20,221) and Genetic of Diabetes Audit and Research in Tayside Scotland (GoDARTS; n = 5236) were sent a questionnaire on neuropathic pain and followed- -up 18 months later. Chronic neuropathic pain was defined using DN4 scores (≥ 3/7) and pain for 3 months or more. The models were developed in GS using logistic regression with backward elimination based on the Akaike information criterion. External validation was conducted in GoDARTS and assessed model discrimination (ROC and Precision-Recall curves), calibration and clinical utility (decision curve analysis [DCA]). Analysis revealed incidences of neuropathic pain onset (6.0% in GS [236/3903] and 10.7% in GoDARTS [61/571]) and resolution (42.6% in GS [230/540] and 23.7% in GoDARTS [56/236]). Psychosocial and lifestyle factors were included in both onset and resolved prediction models. In GoDARTS, these models showed adequate discrimination (ROC = 0.636 and 0.699), but there was evidence of miscalibration (Intercept = - 0.511 and - 0.424; slope = 0.623 and 0.999). The DCA indicated that the models would provide clinical benefit over a range of possible risk thresholds. To our knowledge, these are the first externally validated risk models for neuropathic pain. The findings are of interest to patients and clinicians in the community, who may take preventative or remedial measures.

Characteristics of non-fatal overdoses and associated risk factors in patients attending a specialist community-based substance misuse service.

Introduction: There are concerns about rising drug-related deaths and the potential contribution of prescription analgesics. There is limited understanding regarding the role of prescription analgesics in non-fatal overdoses (NFODs), nor is there a good understanding of what factors are associated with more severe overdose. Objectives: To explore risk factors and characteristics of NFODs among people attending a specialist community-based substance misuse service. Methods: After Caldicott approval, data on NFODs, in people attending the Tayside Substance Misuse Service (TSMS), were extracted from the Scottish Ambulance Service database, along with opioid replacement therapy (ORT) prescribing data. Statistical analysis was performed using R studio and Microsoft Excel. Results: 557 people (78% [434/556] male, mean age ± standard deviation 38.4 ± 7.95) had an NFOD. Repeat NFODs were more likely in males compared to females (p < .0065). Males were more likely to be administered naloxone (OR = 1.94, 95% CI = 1.10-3.40, p < .02). NFODs at home were more likely to be moderate to severe (categorized by Glasgow Comma Scale [p < .02, OR = 4.95, 95% CI = 1.24-24.38]). Methadone (321/557, 57.63%), benzodiazepines (281/557, 50.45%) and heroin (244/557, 43.81%) were the commonest substances: prescribed methadone overdose was more likely than buprenorphine (p < .00001). Opioids and benzodiazepines were often taken together (275/557, 49.40%), with almost all gabapentinoid NFODs also involving opioids (60/61, 98.40%). Conclusions: Polysubstance use with opioids prescribed for ORT, such as methadone, is highly likely to be implicated in NFOD, with males being at the highest risk of severe and repeat NFOD. Future work should focus on strategies to further reduce NFODs.

Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility.

Importance: Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP. Objective: To identify genetic variants associated with NP susceptibility. Design, Setting, and Participants: This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019. Exposures: Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants. Main Outcomes and Measures: GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication. Results: This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated. Conclusions and Relevance: To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.

Cohort profile: DOLORisk Dundee: a longitudinal study of chronic neuropathic pain.

PURPOSE: Neuropathic pain is a common disorder of the somatosensory system that affects 7%-10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset. PARTICIPANTS: DOLORisk Dundee has been constructed by rephenotyping two pre-existing Scottish population cohorts for neuropathic pain using a standardised 'core' study protocol: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) (n=5236) consisting of predominantly type 2 diabetics from the Tayside region, and Generation Scotland: Scottish Family Health Study (GS:SFHS; n=20 221). Rephenotyping was conducted in two phases: a baseline postal survey and a combined postal and online follow-up survey. DOLORisk Dundee consists of 9155 participants (GoDARTS=1915; GS:SFHS=7240) who responded to the baseline survey, of which 6338 (69.2%; GoDARTS=1046; GS:SFHS=5292) also responded to the follow-up survey (18 months later). FINDINGS TO DATE: At baseline, the proportion of those with chronic neuropathic pain (Douleur Neuropathique en 4 Questions questionnaire score ≥3, duration ≥3 months) was 30.5% in GoDARTS and 14.2% in Generation Scotland. Electronic record linkage enables large scale genetic association studies to be conducted and risk models have been constructed for neuropathic pain. FUTURE PLANS: The cohort is being maintained by an access committee, through which collaborations are encouraged. Details of how to do this will be available on the study website (http://dolorisk.eu/). Further follow-up surveys of the cohort are planned and funding applications are being prepared to this effect. This will be conducted in harmony with similar pain rephenotyping of UK Biobank.

Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10-3 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.

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

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.

CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia.

BACKGROUND: To test the association of a recently reported variant in the creatine kinase (CK) muscle gene, CKM Glu83Gly (rs11559024) with constitutive creatine phosphokinase (CK) levels, CK variation, and inducibility. Given the diagnostic importance of CK in determining muscle damage, we tested the association of the variant with myalgia. METHODS AND RESULTS: Meta-analysis between longitudinal cohort GoDARTS (Genetics of Diabetes Audit and Research, Tayside Scotland), minor allele frequency (=0.02), and randomized clinical trial (JUPITER [Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin], minor allele frequency=0.018) was used to replicate the association with baseline CK measures. GoDARTS was used to study the relationship with CK variability. Myalgia was studied in JUPITER trial participants. Baseline and SDs of CK were on average 18% (P value=6×10-63) and 24% (P value=2×10-5) lower for carriers of the variant, respectively. The variant was not associated with myalgia (odds ratio, 0.84; 95% confidence interval, 0.52-1.38). CONCLUSIONS: This study highlights that a genetic factor known to be associated with constitutive CK levels is also associated with CK variability and inducibility. This is discussed in the context of evidence to suggest that the variant has an impact on inducibility of CK by trauma through a previously reported case of a homozygous carrier. However, the lack of association between the variant and myalgia suggests that it cannot reliably be used as a biomarker for muscle symptoms.

A Genome-Wide Association Study Provides New Evidence That CACNA1C Gene is Associated With Diabetic Cataract.

PURPOSE: Diabetic cataract is one of the major eye complications of diabetes. It was reported that cataract occurs two to five times more frequently in patients with diabetes compared with those with no diabetes. The purpose of this study was to identify genetic contributors of diabetic cataract based on a genome-wide association approach using a well-defined Scottish diabetic cohort. METHODS: We adapted linked e-health records to define diabetic cataract. A diabetic cataract case in this study was defined as a type 2 diabetic patient who has ever been recorded in the linked e-health records to have cataracts in both eyes or who had previous cataract extraction surgeries in at least one eye. A control in this study was defined as a type 2 diabetic individual who has never been diagnosed as cataract in the linked e-health records and had no history of cataract surgeries. A standard genome-wide association approach was applied. RESULTS: Overall, we have 2341 diabetic cataract cases and 2878 controls in the genetics of diabetes audit and research in Tayside Scotland (GoDARTS) dataset. We found that the P value of rs2283290 in the CACNA1C gene was 8.81 × 10(-10), which has reached genome-wide significance. We also identified that the blood calcium level was statistically different between diabetic cataract cases and controls. CONCLUSIONS: We identified supporting evidence that CACNA1C gene is associated with diabetic cataract. The role of calcium in the cataractogenesis needs to be reevaluated in future studies.