Faculty Bibliography
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219
PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
BACKGROUND:Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS:, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS:, -0·09 to 0·30). INTERPRETATION:PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING:British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
PMID: 27908689
ISSN: 2213-8595
CID: 5478542
Identifying gene-gene interactions that are highly associated with four quantitative lipid traits across multiple cohorts
Genetic loci explain only 25-30 % of the heritability observed in plasma lipid traits. Epistasis, or gene-gene interactions may contribute to a portion of this missing heritability. Using the genetic data from five NHLBI cohorts of 24,837 individuals, we combined the use of the quantitative multifactor dimensionality reduction (QMDR) algorithm with two SNP-filtering methods to exhaustively search for SNP-SNP interactions that are associated with HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG). SNPs were filtered either on the strength of their independent effects (main effect filter) or the prior knowledge supporting a given interaction (Biofilter). After the main effect filter, QMDR identified 20 SNP-SNP models associated with HDL-C, 6 associated with LDL-C, 3 associated with TC, and 10 associated with TG (permutation P value <0.05). With the use of Biofilter, we identified 2 SNP-SNP models associated with HDL-C, 3 associated with LDL-C, 1 associated with TC and 8 associated with TG (permutation P value <0.05). In an independent dataset of 7502 individuals from the eMERGE network, we replicated 14 of the interactions identified after main effect filtering: 11 for HDL-C, 1 for LDL-C and 2 for TG. We also replicated 23 of the interactions found to be associated with TG after applying Biofilter. Prior knowledge supports the possible role of these interactions in the genetic etiology of lipid traits. This study also presents a computationally efficient pipeline for analyzing data from large genotyping arrays and detecting SNP-SNP interactions that are not primarily driven by strong main effects.
PMID: 27848076
ISSN: 1432-1203
CID: 5478532
Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia
OBJECTIVE:To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein. METHODS:Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. RESULTS:The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82-0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99). CONCLUSION/CONCLUSIONS:Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.
PMCID:5538572
PMID: 27657194
ISSN: 1525-6065
CID: 5478522
An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection
UNLABELLED:The ability to noninvasively diagnose acute cellular rejection (ACR) with high specificity and sensitivity would significantly advance personalized liver transplant recipient care and management of immunosuppression. We performed microRNA (miRNA) profiling in 318 serum samples from 69 liver transplant recipients enrolled in the Immune Tolerance Network immunosuppression withdrawal (ITN030ST) and Clinical Trials in Organ Transplantation (CTOT-03) studies. We quantified serum miRNA at clinically indicated and/or protocol biopsy events (n = 130). The trajectory of ACR diagnostic miRNAs during immunosuppression withdrawal were also evaluated in sera taken at predetermined intervals during immunosuppression minimization before and at clinically indicated liver biopsy (n = 119). Levels of 31 miRNAs were significantly associated with ACR diagnosis with two miRNAs differentiating ACR from non-ACR (area under the receiver operating characteristic curve = 90%, 95% confidence interval = 82%-96%) and predicted ACR events up to 40 days before biopsy-proven rejection. The most differentially expressed miRNAs were low or absent in the blood of healthy individuals but highly expressed in liver tissue, indicating an ectopic origin from the liver allograft. Pathway analyses of rejection-associated miRNAs and their target messenger RNAs (mRNAs) showed induction of proinflammatory and cell death-related pathways. Integration of differentially expressed serum miRNA with concordant liver biopsy mRNA demonstrates interaction between molecules with a known role in transplant rejection. CONCLUSION:Distinct miRNA levels profiled from sera at the time of clinical allograft dysfunction can be used to noninvasively diagnose ACR. Predictive trajectories of the same profile during supervised immunosuppression minimization diagnosed rejection up to 40 days prior to clinical expression. The rejection-associated miRNAs in sera appear to be ectopically expressed liver and specific immune cell miRNAs that are biologically related, and the consequences of immune-mediated damage to the allograft. (Hepatology 2017;65:269-280).
PMID: 27533743
ISSN: 1527-3350
CID: 5478492
Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder
Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear- and mitochondrial-encoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis. Whole exome sequencing uncovered compound heterozygous mutations in NADH dehydrogenase (ubiquinone) flavoprotein 1 gene (NDUFV1), c.1162+4A>C (NM_007103.3), resulting in skipping of exon 8, and c.640G>A, causing the amino acid substitution p.Glu214Lys, both of which have previously been reported in a patient with complex I deficiency. Patient fibroblasts showed a significant reduction in NDUFV1 protein expression, decreased complex CI and complex IV assembly and consequential reductions in the enzymatic activities of both complexes by 38% and 67%, respectively. The pathogenic effect of these variations was further confirmed by immunoblot analysis of subunits for MRC enzyme complexes in patient muscle, liver and fibroblast where we observed 90%, 60% and 95% reduction in complex CI, respectively. Together these studies highlight the importance of a comprehensive, multipronged approach to the laboratory evaluation of patients with suspected Leigh syndrome.
PMCID:5362551
PMID: 27344648
ISSN: 2192-8304
CID: 5478472
Utility of next-generation sequencing technologies for the efficient genetic resolution of haematological disorders
Next-generation sequencing (NGS) has now evolved to be a relatively affordable and efficient means of detecting genetic mutations. Whole genome sequencing (WGS) or whole exome sequencing (WES) offers the opportunity for rapid diagnosis in many paediatric haematological conditions, where phenotypes are variable and either a large number of genes are involved, or the genes are large making sanger sequencing expensive and labour-intensive. NGS offers the potential for gene discovery in patients who do not have mutations in currently known genes. This report shows how WES was used in the diagnosis of six paediatric haematology cases. In four cases (Diamond-Blackfan anaemia, congenital neutropenia (n = 2), and Fanconi anaemia), the diagnosis was suspected based on classical phenotype, and NGS confirmed those suspicions. Mutations in RPS19, ELANE and FANCD2 were found. The final two cases (MYH9 associated macrothrombocytopenia associated with multiple congenital anomalies; atypical juvenile myelomonocytic leukaemia associated with a KRAS mutation) highlight the utility of NGS where the diagnosis is less certain, or where there is an unusual phenotype. We discuss the advantages and limitations of NGS in the setting of these cases, and in haematological conditions more broadly, and discuss where NGS is most efficiently used.
PMID: 25703294
ISSN: 1399-0004
CID: 5479452
Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network
Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.
PMCID:5010878
PMID: 26857349
ISSN: 1532-6535
CID: 5479292
Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles
We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.
PMCID:4733408
PMID: 26485092
ISSN: 1600-6143
CID: 5479272
Machine Learning Derived Disease Risk Prediction of Anorexia Nervosa [Meeting Abstract]
ISI:000392559600010
ISSN: 0001-5652
CID: 5479112
Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array
Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15,241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~ 53,000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P = 5.88 × 10(-7), ß = -0.146) and TTC39B rs686030:C>A (P = 6.95 x 10(-7), ß = 0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), ß = 0.734), ABCG8 rs4299376:G(>)T (P = 2.40 × 10(-18), ß = 0.278), ABCG5 rs6544718:T>C (P = 2.08 × 10(-14), ß = 0.044) and ABCG5 rs6720173:G>C (P = 3.81 × 10(-12), ß(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.
PMCID:4681116
PMID: 25920552
ISSN: 1476-5438
CID: 5478312
