Abirami Veluchamy

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2–1.4), P=1.0 × 10−8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01–1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01–1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15–1.32), P=1.9 × 10−9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

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

Abstract 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.

Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS)

Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) Harry L Hébert, Bridget Shepherd, Keith Milburn, Abirami Veluchamy, Weihua Meng, Fiona Carr, Louise A Donnelly, Roger Tavendale, Graham Leese, Helen M Colhoun, Ellie Dow, Andrew D Morris, Alexander S Doney, Chim C Lang, Ewan R Pearson, Blair H Smith and Colin NA Palmer* Division of Population Health Sciences, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Health Informatics Centre Services, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK, Institute of Genetics & Molecular Medicine and Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Risk factors for neuropathic pain in diabetes mellitus

According to the International Diabetes Federation, diabetes mellitus (DM) is estimated to affect around 415 million adults worldwide, roughly 8.8% of the adult population, with the figure projected to rise to over 600 million by 2040. Regional prevalence varies from 3.2% in Africa to 12.9% in North America. Diabetesmellitus is associatedwith a number of chronic sequelae and around 50% of people with DM go on to develop polyneuropathy. This condition has a variety of clinical manifestations, which are grouped into positive symptoms including dysesthesia (abnormal sense of touch), tingling and itching, and negative symptoms including numbness, muscle weakness, and trouble with balance. Up to 25% of people with diabetic neuropathy (DN) also develop neuropathic pain (NP). Neuropathic pain is defined by the International Association for The Study of Pain as “pain directly caused by a lesion or disease affecting the somatosensory system.” Symptoms of painful diabetic neuropathy (PDN) include those described above for nonpainful DN with additional “burning,” “electric shocks,” “stabbing,” and “pins and needles” symptoms all being described. Painful diabetic neuropathy is associated with increased distress and poor quality of life compared with nonpainful DN, DM, and the general population including depression, anxiety, and sleep disturbance. In addition, an association has been described with reduced productivity and employability at work compared with nonpainful DN. The combination of these factors places a large economic burden on patients and health care services, a situation likely to grow steadily worse with the aforementioned projected rise in DM prevalence. This situation is further exacerbated by the fact that 13% of patients with PDN do not report their symptoms to primary care, and 39% of patients with PDN have never received treatment. Even for those patients whodo attend primary and secondary care for their diabetes, pain is not a symptom that is always included in clinical assessments. Furthermore, not all patients with DN develop PDN, and the reasons for this are unclear. Understanding the risk factors for PDN will go some way to resolving this and will also help to inform management and prevention of this painful condition by health care services. Any factor that increases the risk of DM or DN is likely to be a risk factor for PDN. However, it is the specific nature and magnitude of the risk that remains unclear and is the focus of this topical review.

CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With MyalgiaCLINICAL PERSPECTIVE

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

Abstract 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.

A genome-wide association study suggested that the mitogen-activated protein kinase 14 gene (MAPK14) is associated with diabetic foot ulcer

Diabetic foot ulcers (DFUs) are a devastating complication of diabetes.

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.

Novel Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk Of Coronary Artery Disease

Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. We report a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (n=1736) and ORCADES (n=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity, and one at 13q34 (COL4A2) for retinal arteriolar tortuosity; these two loci were subsequently confirmed in three independent cohorts. In the combined analysis, the lead SNP at each locus was rs1808382 in ACTN4/CAPN12 (P=2.39×10−13) and rs7991229 in COL4A2 (P=4.66×10−12). Notably, the ACTN4/CAPN12 locus associated with retinal venular tortuosity traits is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal vascular traits, and provide new insights into vascular diseases.

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<5×10–8) in the meta-analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), &ggr;-aminobutyric acid receptor subunit &ggr;-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=6.2×10–9]. Conclusion These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.