Neuropathic pain is defined as pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system and it affects around 1 in 4 diabetic patients in the UK. The purpose ...of this genome-wide association study (GWAS) was to identify genetic contributors to this disorder. Cases of neuropathic pain were defined as diabetic patients with a multiple prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain. Controls were diabetic individuals who were not prescribed any of these drugs, nor amitriptyline, carbamazepine, or nortriptyline. Overall, 961 diabetic neuropathic pain cases and 3260 diabetic controls in the Genetics of Diabetes Audit and Research Tayside (GoDARTS) cohort were identified. We found a cluster in the Chr1p35.1 (ZSCAN20-TLR12P) with a lowest P value of 2.74×10−7 at rs71647933 in females and a cluster in the Chr8p23.1, next to HMGB1P46 with a lowest P value of 8.02×10−7 at rs6986153 in males. Sex-specific narrow sense heritability was higher in males (30.0%) than in females (14.7%). This GWAS on diabetic neuropathic pain provides evidence for the sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with the disorder, indicating the need for further research.
•The case definition of diabetic neuropathic pain in this study is matched with those used in epidemiological studies.•We confirmed that diabetic neuropathic pain is a heritable trait.•We provided new genetic evidence of sex-specific involvement of two chromosome loci with diabetic neuropathic pain.
Using a pragmatic case definition, we identified two new genetic areas that may be involved in diabetic neuropathic pain, a common and debilitating complication of diabetes. One of these is more significant in males, the other in females. Furthermore, we calculated that the contribution of genes to developing neuropathic pain in diabetic men is about twice that in diabetic women. These findings help to explain why some people are more vulnerable to this complication, and help to elucidate the biological mechanisms of neuropathic pain. They will inform personalised (gender-specific) approaches to treatment, and the development of new drugs.
Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response ...might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method.
In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture.
5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1–68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect.
Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.
Wellcome Trust.
Abstract
Context
Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development ...of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity.
Objective
To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies.
Design
We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models.
Results
Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10−9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10−9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity.
Conclusion
We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.
Despite a lack of evidence for survival benefit, the American College of Obstetrics and Gynecology has recommendations for referral to gynecologic oncologists for the treatment of endometrial cancer. ...Therefore, we propose to determine the influence of gynecologic oncologists on the treatment and survival of patients with endometrial cancer.
Data were obtained from Medicare and Surveillance, Epidemiology, and End Results (SEER) databases from 1988 to 2005. Kaplan-Meier and Cox proportional hazard methods were used for analyses.
Of 18,338 women, 21.4% received care from gynecologic oncologists (group A) while 78.6% were treated by others (group B). Women in group A were older (age > 71 years: 49.6% v 44%; P < .001), had more lymph nodes (> 16) removed (22% v 17%; P < .001), presented with more advanced (stages III to IV) cancers (21.9% v 14.6%; P < .001), had higher-grade tumors (P < .001), and were more likely to receive chemotherapy for advanced disease (22.6% v 12.4%; P < .001). In those with stages II to IV disease, the 5-year disease-specific survival (DSS) of group A was 79% versus 73% in group B (P = .001). Moreover, in advanced-stage (III to IV) disease, group A had 5-year DSS of 72% versus 64% in group B (P < .001). However, no association with DSS was identified in stage I cancers. On multivariable analysis, younger age, early stage, lower grade, and treatment by gynecologic oncologists were independent prognostic factors for improved survival.
Patients with endometrial cancer treated by gynecologic oncologists were more likely to undergo staging surgery and receive adjuvant chemotherapy for advanced disease. Care provided by gynecologic oncologists improved the survival of those with high-risk cancers.
Abstract Background Traumatic abdominal wall injuries (AWIs) are being increasingly recognized after blunt force injury. Methods All available abdominal/pelvic computed axial tomography (CAT) scans ...of blunt trauma patients evaluated at our level I trauma center from January 2005 to August 2006 were reviewed for the presence of AWI. AWI was graded using a severity-based numeric system. AWI grade was then compared with variables from a prospectively maintained trauma registry. Results Of 1549 reviewed CAT scans, 9% showed AWI (grade I = 53%, grade II = 28%, grade III = 9%, grade IV = 8%, and grade V = 2%). There was no association between AWI and seatbelt use, Injury Severity Score, weight, or need for abdominal surgery. Conclusions AWI occurs in 9% of blunt trauma patients undergoing abdominal/pelvic CAT scans. The incidence of herniation on CAT at presentation after blunt trauma is .2%, and the incidence of patients at risk of future hernia formation is 1.5%. AWI can be effectively cataloged using a straightforward numeric grading system.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney ...transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adrenal infarction is a rare cause of abdominal pain during pregnancy, and if missed, it can result in devastating clinical consequences for the mother and the child. The authors report a case of a ...young female who presented with severe abdominal pain and nausea. The biochemistry showed raised inflammatory markers and significant lactic acidosis. As the cause of the symptoms was not clear and the patient continued to deteriorate, a contrast‐enhanced CT abdomen and pelvis was done which was suggestive of an acute left adrenal infarction. Subsequently, the patient was confirmed to have biochemical hypoadrenalism and required replacement doses of hydrocortisone until recovery of the adrenal glucocorticoid reserve and anticoagulation for the duration of pregnancy. We discuss the workup including diagnostic imaging, follow‐up, and considerations for future pregnancies in this case.
Pregnancy predisposes to Adrenal infarction (AI) as it is a hypercoagulable state, however, its occurrence remains rare. Abdominal pain is a frequent symptom but delineating its cause during gestation is challenging, and therefore, clinicians must suspect AI especially when the symptoms are sudden, severe, and associated with nausea/vomiting or fever.
Type 2 diabetes mellitus is an independent risk factor for heart failure development, but the relationship between incident heart failure and antecedent glycemia has not been evaluated.
The Genetics ...of Diabetes Audit and Research in Tayside Study study holds data for 8683 individuals with type 2 diabetes mellitus. Dispensed prescribing, hospital admission data, and echocardiography reports were linked to extract incident heart failure cases from December 1998 to August 2011. All available HbA1c measures until heart failure development or end of study were used to model HbA1c time-dependently. Individuals were observed from study enrolment until heart failure development or end of study. Proportional hazard regression calculated heart failure development risk associated with specific HbA1c ranges accounting for comorbidities associated with heart failure, including blood pressure, body mass index, and coronary artery disease. Seven hundred and one individuals with type 2 diabetes mellitus (8%) developed heart failure during follow up (mean 5.5 years, ±2.8 years). Time-updated analysis with longitudinal HbA1c showed that both HbA1c <6% (hazard ratio =1.60; 95% confidence interval, 1.38-1.86; P value <0.0001) and HbA1c >10% (hazard ratio =1.80; 95% confidence interval, 1.60-2.16; P value <0.0001) were independently associated with the risk of heart failure.
Both high and low HbA1c predicted heart failure development in our cohort, forming a U-shaped relationship.
Recent studies have identified several common genes associated with multiple autoimmune diseases that support the hypothesis of the presence of shared or general autoimmunity genes. However, most of ...this work has been performed in populations of white origin. The main objectives of this study are to replicate the genotype-phenotype correlation between 19 such variants and rheumatoid arthritis (RA), and to evaluate gene-gene interactions between these genes in individuals from an ethnically homogenous nonwhite Colombian population.
Nineteen single-nucleotide polymorphisms (SNP) from 16 genes/loci were genotyped in 353 RA cases and 368 controls. For each SNP, allelic and genotype-based association tests were applied to evaluate genotype-phenotype correlation. Permutation-based tests were used to validate the statistical significance. Gene-gene interactions were assessed by logistic regression.
We replicated the genetic association with rs13277113 (p = 0.0009, OR 1.46) and rs2736340 (p = 0.0001, OR 1.63) from C8orf13-BLK (8p23.1, associated with RA and systemic lupus erythematosus), and rs763361 (p = 0.03) from CD226 (18q22.3, associated with multiple sclerosis and type 1 diabetes) in the Colombian population. The population-attributable risks were estimated as 27%, 34%, and 16% for rs13277113, rs2736340, and rs763361, respectively. We also detected evidence for gene-gene interaction between SNP in MMEL1 (rs3890745) and C80rf13-BLK (rs13277113; p = 0.0002).
Our results demonstrate that the IL2/IL21 region, C8orf13-BLK, and CD226 influence RA in Colombians, and RA shares some of the pathogenic mechanisms associated with other autoimmune diseases.
Abstract Background We have recently shown that the C-reactive protein (CRP) response to statin therapy is highly variable, with 45% of people on atorvastatin having no decrease in CRP. Whether there ...is any genetic component to this variability is unclear. We sought to identify genetic determinants and quantify the single nucleotide polymorphism based heritability of CRP response to statins. Methods In a meta-analysis of genome-wide association studies, we included datasets from both randomised controlled trials and observational studies. There were about 10 000 statin-treated individuals overall, grouped into a first discovery stage (from the CARDS trial and PROSPER, PARC, and FSH studies) and a second replication stage (from the JUPITER trial). CRP response was modelled as log(CRP follow-up/CRP baseline) adjusted for baseline CRP and other covariates. Genome-complex trait analysis (GCTA) was used to identify the narrow-sense heritability of CRP response. Findings The study consisted of about 5300 statin users in the discovery cohort and 4000 statin users as replication cohort. On the GCTA analysis narrow-sense heritability ( h2 ) for CRP response was 0·19 (SE 0·24) and was higher than that reported for LDL cholesterol response to statin therapy 0·05 (SE 0·14). Preliminary results of the genome-wide association meta-analysis identified three loci that achieved genome-wide statistical significance: APOE , rs429358 (p=7·91E–10); RP11-458D21.5 , rs184819447 (p=2·32E–9); MYT1L , rs79020661 (p=3·21E–8). Other than APOE none of these was associated with LDL response to statin therapy or baseline CRP. Interpretation These data are consistent with statin-induced change in CRP having a mechanism distinct from LDL cholesterol change. We identified several loci associated with CRP-response to statin therapy and they need to be investigated further by additional replication analysis. Funding HD is funded by a National Institute for Health Research Clinical Academic Fellowship.
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