Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 disruption using CRISPR-Cas9

Glaucoma is a common cause of blindness, yet current therapeutic options are imperfect. Clinical trials have invariably shown that reduction in intraocular pressure (IOP) regardless of disease subtype prevents visual loss. Reducing ciliary body aqueous humor production can lower IOP, and the adeno-associated virus ShH10 serotype was identified as able to transduce mouse ciliary body epithelium following intravitreal injection. Using ShH10 to deliver a single vector CRISPR-Cas9 system disrupting Aquaporin 1 resulted in reduced IOP in treated eyes (10.4 ± 2.4 mm Hg) compared with control (13.2 ± 2.0 mm Hg) or non-injected eyes (13.1 ± 2.8 mm Hg; p < 0.001; n = 12). Editing in the aquaporin 1 gene could be detected in ciliary body, and no off-target increases in corneal or retinal thickness were identified. In experimental mouse models of corticosteroid and microbead-induced ocular hypertension, IOP could be reduced to prevent ganglion cell loss (32 ± 4 /mm2) compared with untreated eyes (25 ± 5/mm2; p < 0.01). ShH10 could transduce human ciliary body from post-mortem donor eyes in ex vivo culture with indel formation detectable in the Aquaporin 1 locus. Clinical translation of this approach to patients with glaucoma may permit long-term reduction of IOP following a single injection

Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies

&lt;p&gt;Background: Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.&lt;/p&gt; &lt;p&gt;Methods and Findings: We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.&lt;/p&gt; &lt;p&gt;Conclusions: Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.&lt;/p&gt

Incorporating multiple sets of eQTL weights into gene-by-environment interaction analysis identifies novel susceptibility loci for pancreatic cancer.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.We thank the two anonymous reviewers for their constructive comments. This research was supported by the National Institutes of Health (NIH) grant R01CA169122; P.W. was supported by NIH grants R01HL116720 and R21HL126032. S.H.O. was supported by NIH grant P30CA008748. R.E.N. and the Queensland Pancreatic Cancer Study were funded by the Australian National Health and Medical Research Council. The authors thank Ms. Jessica Swann and the National Institute of Statistical Sciences writing workshop for editorial assistance and suggestions. The authors acknowledge the Texas Advanced Computing Center at The University of Texas at Austin for providing computing resources. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. The authors declare that there is no conflict of interest

An efficacy trial of brief lifestyle intervention delivered by generalist community nurses (CN SNAP trial)

<p>Abstract</p> <p>Background</p> <p>Lifestyle risk factors, in particular smoking, nutrition, alcohol consumption and physical inactivity (SNAP) are the main behavioural risk factors for chronic disease. Primary health care (PHC) has been shown to be an effective setting to address lifestyle risk factors at the individual level. However much of the focus of research to date has been in general practice. Relatively little attention has been paid to the role of nurses working in the PHC setting. Community health nurses are well placed to provide lifestyle intervention as they often see clients in their own homes over an extended period of time, providing the opportunity to offer intervention and enhance motivation through repeated contacts. The overall aim of this study is to evaluate the impact of a brief lifestyle intervention delivered by community nurses in routine practice on changes in clients' SNAP risk factors.</p> <p>Methods/Design</p> <p>The trial uses a quasi-experimental design involving four generalist community nursing services in NSW Australia. Services have been randomly allocated to an 'early intervention' group or 'late intervention' (comparison) group. 'Early intervention' sites are provided with training and support for nurses in identifying and offering brief lifestyle intervention for clients during routine consultations. 'Late intervention site' provide usual care and will be offered the study intervention following the final data collection point. A total of 720 generalist community nursing clients will be recruited at the time of referral from participating sites. Data collection consists of 1) telephone surveys with clients at baseline, three months and six months to examine change in SNAP risk factors and readiness to change 2) nurse survey at baseline, six and 12 months to examine changes in nurse confidence, attitudes and practices in the assessment and management of SNAP risk factors 3) semi-structured interviews/focus with nurses, managers and clients in 'early intervention' sites to explore the feasibility, acceptability and sustainability of the intervention.</p> <p>Discussion</p> <p>The study will provide evidence about the effectiveness and feasibility of brief lifestyle interventions delivered by generalist community nurses as part of routine practice. This will inform future community nursing practice and PHC policy.</p> <p>Trial Registration</p> <p>ACTRN12609001081202</p

Association between urinary biomarkers of total sugars intake and measures of obesity in a cross-sectional study

Obesity is an important modifiable risk factor for chronic diseases. While there is increasing focus on the role of dietary sugars, there remains a paucity of data establishing the association between sugar intake and obesity in the general public. The objective of this study was to investigate associations of estimated sugar intake with odds for obesity in a representative sample of English adults. We used data from 434 participants of the 2005 Health Survey of England. Biomarkers for total sugar intake were measured in 24 h urine samples and used to estimate intake. Linear and logistic regression analyses were used to investigate associations between biomarker-based estimated intake and measures of obesity (body mass intake (BMI), waist circumference and waist-to-hip ratio) and obesity risk, respectively. Estimated sugar intake was significantly associated with BMI, waist circumference and waist-to-hip ratio; these associations remained significant after adjustment for estimated protein intake as a marker of non-sugar energy intake. Estimated sugar intake was also associated with increased odds for obesity based on BMI (OR 1.02; 95%CI 1.00-1.04 per 10g), waist-circumference (1.03; 1.01-1.05) and waist-to-hip ratio (1.04; 1.02-1.06); all OR estimates remained significant after adjusting for estimated protein intake. Our results strongly support positive associations between total sugar intake, measures of obesity and likelihood of being obese. It is the first time that such an association has been shown in a nationally-representative sample of the general population using a validated biomarker. This biomarker could be used to monitor the efficacy of public health interventions to reduce sugar intake

Alcohol intake and risk of colorectal cancer: results from the UK Dietary Cohort Consortium.

BACKGROUND: Epidemiological studies have suggested that excessive alcohol intake increases colorectal cancer (CRC) risk. However, findings regarding tumour subsites and sex differences have been inconsistent. METHODS: We investigated the prospective associations between alcohol intake on overall and site- and sex-specific CRC risk. Analyses were conducted on 579 CRC cases and 1996 matched controls nested within the UK Dietary Cohort Consortium using standardised data obtained from food diaries as a main nutritional method and repeated using data from food frequency questionnaire (FFQ). RESULTS: Compared with individuals in the lightest category of drinkers (>0-or=45 g per day. No clear associations were observed between site-specific CRC risk and alcohol intake in either sex. Analyses using FFQ showed similar results. CONCLUSION: We found no significantly increased risk of CRC up to 30 g per day of alcohol intake within the UK Dietary Cohort Consortium

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.The EPIC Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). NJW, NGF, and FI were supported by the Medical Research Council Epidemiology Unit core funding [MC_UU_12015/1 and MC_UU_12015/5]. NJW and NGF acknowledge support from the National Institute for Health Research Cambridge Biomedical Research Centre [IS-BRC-1215-20014] and NJW is an NIHR Senior Investigator

Omega-6 Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of Individual-Level Data for 39 740 Adults from 20 Prospective Cohort Studies

Background: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. Methods: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. Findings: Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m(2), who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72,

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention