Genetic determinants of telomere length and cancer risk

The relationship of telomere length with cancer risk has been the source of much debate within epidemiological studies, which have produced inconsistent finding both between and within different cancer types. Over recent years, genome-wide association studies of increasing size have identified variants that determine human telomere length. These variants have subsequently been utilised as instrumental variables in Mendelian randomisation based studies, allowing the investigation of potential causal relationships between telomere length and cancer. Here we discuss recent advances in both genomic discovery, studies that give increasing evidence towards a causal role for telomere length in cancer risk and considerations for future studies

Large-Scale Analysis of the Association between Air Pollutants and Leucocyte Telomere Length in the UK Biobank

Shorter telomere length (TL) and air pollution are both associated with higher risk of aging-related diseases.1,2 Oxidative stress may mediate the adverse effects of air pollution and also accelerate telomere attrition. Therefore, some of the adverse effects of air pollution could be mediated through an effect on TL. A few small studies, summarized in a recent systematic review and meta-analysis,3 suggested a possible association of exposure to particulate matter (PM) with an aerodynamic diameter of less than or equal to 2.5 micrometers≤2.5μm≤2.5μm (particulate matter begin subscript 2.5 end subscriptPM2.5PM2.5) with shorter leukocyte TL (LTL), but overall findings were inconclusive.4 Here, we have leveraged our recent measurement of LTL in over 474,000 participants in the UK Biobank (UKB)5 and available individual-level estimates of exposures to particulates [particulate matter begin subscript 2.5 end subscriptPM2.5PM2.5; particulate matter begin subscript 2.5 to 10 end subscriptPM2.5–10PM2.5–10, PM with an aerodynamic diameter range of from 2.5 to 10 micrometers10μm10μm (referred to as particulate matter begin subscript coarse end subscriptPMcoarsePMcoarse); particulate matter begin subscript 10 end subscriptPM10PM10, PM with an aerodynamic diameter of less than or equal to 10 micrometers≤10μm≤10μm; particulate matter begin subscript 2.5 absorbance end subscriptPM2.5absorbancePM2.5absorbance, a proxy for elemental carbon] and gaseous [nitrogen oxides (nitrogen oxidesNOxNOx) and nitrogen dioxide (nitrogen dioxideNO2NO2)] air pollutants in UKB participants4 to undertake a large-scale study of the associations of air pollutants with LTL. </p

Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors

BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken. METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank. RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25×10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 T allele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism. CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety

Addenbrooke's Cognitive Examination III (ACE-III) and mini-ACE for the detection of dementia and mild cognitive impairment

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To assess the diagnostic test accuracy of the Addenbrooke's Cognitive Examination-III (ACE-III) and the mini-ACE, for the screening of all-cause dementia, dementia subtypes (Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia), and mild cognitive impairment, across all healthcare settings at all prespecified thresholds

Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis

BACKGROUND: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. METHODS: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. RESULTS: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 × 10-10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02). CONCLUSIONS: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS

Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

Background: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies. Objectives: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death. Methods: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients. Results: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro–B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients. Conclusions: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin

Elucidation of the genetic causes of bicuspid aortic valve disease

Aims The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10−08) and was replicated in an independent case–control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10−16), GATA4 (P = 1.61 × 10−09), and TEX41 (P = 7.68 × 10−04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.</p

Genetic analysis for a shared biological basis between migraine and coronary artery disease.

OBJECTIVE: To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD). METHODS: Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci. RESULTS: We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP). CONCLUSIONS: The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies