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 7-10% 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 (OR,2.96; CI,1.93-4.56), HLADRB1*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

Loss-of-function variants of the filaggrin gene are associated with atopic eczema and associated phenotypes in Swedish families

Recent studies have identified 2 loss-of-function variants, R501X and 2282del4, in the filaggrin gene as predisposing factors in the development of eczema. In this study, representing the first analysis of the variants in a Swedish population, we analysed transmission in 406 multiplex eczema families with mainly adult patients. In accordance with previous studies we found association between the filaggrin gene variants and atopic eczema (p=9.5x10(-8)). The highest odds ratio for the combined alllele, 4.73 (1.98-11.29), p=3.6x10(-8), was found for the subgroup with a severe eczema phenotype, and association was also found with raised allergen-specific IgE, allergic asthma and allergic rhinoconjunctivitis occurring in the context of eczema. Our results support an important role for the filaggrin gene variants R501 X and 2282del4 in the development and severity of atopic eczema and indicate a possible role for the subsequent progression into eczema-associated phenotypes.</p

Tailored second line therapy in asthmatic children with the arginine-16 genotype

The arginine-16 beta-2 receptor genotype confers increased susceptibility to exacerbations in asthmatic children taking regular long acting beta-2 agonists. We therefore evaluated using montelukast as an alternative to salmeterol as tailored second line asthma controller therapy in children expressing this susceptible genotype. 62 persistent asthmatic children with the homozygous arginine-16 genotype were randomized to receive salmeterol 50ug bid or montelukast 5/10mg od as add on to inhaled fluticasone for 1 year. School absences (the primary outcome) were reduced with montelukast arm compared to salmeterol: difference in score = 0.40 (95%CI 0.07-0.87) p=0.005. Albuterol use was also reduced with montelukast compared with salmeterol: difference in score = 0.47 (95%CI 0.16-0.79) p<0.0001. Greater improvements occurred in both symptom and quality of life scores with montelukast vs salmeterol, while there was no difference in FEV1. Montelukast may be suitable as tailored second line controller therapy instead of salmeterol in asthmatic children expressing the susceptible arginine-16 genotype - moving towards a personalised medicine approach to management

Interaction between variants in the <i>CYP2C9</i> and <i>POR</i> genes and the risk of sulfonylurea-induced hypoglycaemia:A GoDARTS Study

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)-induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes, on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1,770 patients were included in the analysis of SU efficacy assessed as the combined outcome of the HbA1c reduction and prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR=2.81, 95%CI 1.30-6.09, P=0.009) and better response to SU treatment (β = -0.218, SE=0.074, P=0.003) only in patients carrying POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.</p

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records

Clopidogrel efficacy is influenced by genetic variation of CYP2C19, however few studies have considered stroke patients. We used electronic medical records (EMR) linked to a bioresource to examine real-world implications of clopidogrel pharmacogenetics in stroke. Patients hospitalized for any arterial thrombo-occlusive event (ATO) who subsequently redeemed clopidogrel prescriptions in the community were entered into the study (n=651). During 24 months follow-up the primary endpoint of recurrent ATO or death occurred in 299 (46%) patients. CYP2C19*2 loss-of-function allele carriers had an increased risk, hazard ratio (HR) 1.29 (95% confidence interval 1.04-1.59, P=0.019). In the ischemic stroke subgroup (n=94) the estimate of risk was greater (HR 2.23, 95% confidence interval 1.17-4.24, P=0.015) further supported by a meta-analysis of available studies. In conclusion, we have demonstrated the clinical impact of CYP2C19*2 on clopidogrel efficacy using a purely EMR approach. This suggests that the risk in the ischemic stroke population may be particularly high.</p

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

Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits:a Genetics of Diabetes Audit and Research Tayside study

Objective: Replication of associations in genome-wide association studies is desirable to ensure that such signals are potentially clinically meaningful. This study aimed to replicate associations of selected single-nucleotide polymorphisms (SNPs) with hypothyroidism and serum thyroid-stimulating hormone (TSH) using electronic medical records (EMRs).Patients and Methods: A cross-sectional study was carried out among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside recruited in Tayside (Scotland, UK). EMRs (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with hypothyroidism and their controls as well as average serum TSH concentration, and linked to genetic biobank data. Genetic tests of association were performed using logistic and linear regression models.Results: We analysed 1703 cases of hypothyroidism and 9457 controls. All four SNPs located on chromosome 9 at FOXE1 were associated with hypothyroidism with similar effect estimates (odds ratio=0.75-0.76, P&lt;5e-08). Also, loci on chromosomes 1 (PTPN22), six (HLA-E/HLA-C) and 12 (SH2B3) were replicated. For serum TSH, we confirmed 12 SNPs previously reported at PDE8B, CAPZB, PDE10A, LOC105371356, NR3C2, VEGFA, IGFBP5, INSR, PRDM11, NFIA, ITPK1 and ABO. Overall, these SNPs accounted for 6.8% of the serum TSH variation (P&lt;1e-04).Conclusion: EMRs linked to genomic data in large populations enable validation of genome-wide association studies discoveries without additional genotyping costs. Our replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation.</p

Age-dependent elastin degradation is enhanced in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is primarily a lung condition characterised by the presence of persistent airflow limitation resulting from inflammation, remodelling of small airways, and emphysema. It is well-recognised that the impacts of COPD extend beyond the lung with many patients suffering systemic manifestations such as cardiovascular diseases that affect morbidity and mortality [1]. “Accelerated ageing” has been proposed as a mechanism that underlies many of the pulmonary and extrapulmonary consequences of COPD [2, 3]. It is thought that a decline in organ function is a feature of ageing in response to the accumulation of cell and molecular damage, and in the case of COPD, noxious inhalants such as tobacco smoke increase this damage, thus accelerating the ageing process, leading to the development of COPD. With the exception of lung function decline, however, evidence indicating that tobacco smoking or COPD accelerates age-associated deterioration remains scarce

Genetic correlations between pain phenotypes and depression and neuroticism

Correlations between pain phenotypes and psychiatric traits such as depression and the personality trait of neuroticism are not fully understood. In this study, we estimated the genetic correlations of eight pain phenotypes (defined by the UK Biobank, n = 151,922–226,683) with depressive symptoms, major depressive disorders and neuroticism using the the cross-trait linkage disequilibrium score regression (LDSC) method integrated in the LD Hub. We also used the LDSC software to calculate the genetic correlations among pain phenotypes. All pain phenotypes, except hip pain and knee pain, had significant and positive genetic correlations with depressive symptoms, major depressive disorders and neuroticism. All pain phenotypes were heritable, with pain all over the body showing the highest heritability (h 2 = 0.31, standard error = 0.072). Many pain phenotypes had positive and significant genetic correlations with each other indicating shared genetic mechanisms. Our results suggest that pain, neuroticism and depression share partially overlapping genetic risk factors. </p