Samantha J. Fahy

A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25

Myopia and hyperopia are at opposite ends of the continuum of refraction, the measure of the eye′s ability to focus light, which is an important cause of visual impairment (when aberrant) and is a highly heritable trait. We conducted a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort. We identified SNPs on 15q25 associated with refractive error (rs8027411, P = 7.91 × 10−8). We replicated this association in six adult cohorts of European ancestry with a combined 13,414 individuals (combined P = 2.07 × 10−9). This locus overlaps the transcription initiation site of RASGRF1, which is highly expressed in neurons and retina and has previously been implicated in retinal function and memory consolidation. Rasgrf1−/− mice show a heavier average crystalline lens (P = 0.001). The identification of a susceptibility locus for refractive error on 15q25 will be important in characterizing the molecular mechanism responsible for the most common cause of visual impairment.

Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10−8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%–3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10−25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10−16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10−13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10−16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

Provision of smoking cessation support for pregnant women in England: results from an online survey of NHS stop smoking services for pregnant women

BackgroundSmoking during pregnancy is a major public health concern and an NHS priority. In 2010, 26% of UK women smoked immediately before or during their pregnancy and 12% smoked continuously. Smoking cessation support is provided through free at the point of use Stop Smoking Services for Pregnant women (SSSP). However, to date, little is known of how these services provide support across England. The aim of this study was to describe the key elements of support provided through English SSSP.MethodsSSSP managers were invited to participate in this survey by email. Data were then collected via an online questionnaire; one survey was completed for each SSSP. Up to four reminder emails were sent over a two month period.Results86% (121 of 141) of services completed the survey. Responding services were, on average, larger than non-responding services in terms of the number of pregnant women setting quit dates and successfully quitting (p < 0.01). In line with the 2010 NICE guidelines, Stop Smoking in Pregnancy and following Childbirth, one in five SSSP identified pregnant smokers using carbon monoxide (CO) testing and refer via an opt-out pathway. All services offered nicotine replacement therapy (NRT) to pregnant women and 87% of services also offered dual therapy NRT, i.e. combination of a patch and short acting NRT product.. The 2010 NICE guidelines note that services should be flexible and client-centred. Consistent with this, SSSP offer pregnant women a range of support types (median 4) including couple/family, group (open or closed) or one-to-one. These are available in a number of locations (median 5), including in community venues, clinics and women’s homes.ConclusionsEnglish Stop Smoking Services offer behavioural support and pharmacotherapy to pregnant women motivated to quit smoking. Interventions provided are generally evidence-based and delivered in a variety of both social and health care settings.

The Relationship between Retinal Arteriolar and Venular Calibers Is Genetically Mediated, and Each Is Associated with Risk of Cardiovascular Disease

PURPOSE Retinal arteriolar and venular calibers are highly heritable and associated with cardiovascular disease. This study was designed to investigate the relative influence of genetic and environmental factors on the high phenotypic correlation (r = 0.59) between these two traits and to assess the shared and specific influence of established and novel cardiovascular disease risk factors on them. METHODS A total of 1463 Caucasian female twins (706 monozygotic and 757 dizygotic), between 24 and 79 years of age, underwent retinal photography from which retinal arteriolar (mean, 153.75 ± 22.1 μm, SD) and venular (mean, 232.1 ± 36.6 μm) calibers were measured with semiautomated software. A bivariate heritability model was used to assess the genetic and environmental influences underlying both specific trait variance and the covariance between the vessel traits. The investigation was an assessment of phenotypic associations between retinal arteriolar and venular calibers and cardiovascular disease risk factors. RESULTS Additive genetic factors accounted for approximately three fourths of the covariance between retinal arteriolar and venular calibers within the cohort. This finding was replicated in a sample of 1981 twins from the Australian Twins Eye Study. The partial correlation showed that known risk factors accounted for only 5% of the covariance between arteriolar and venular calibers. Novel associations were found between venular caliber and β-cell function (P = 0.011) and insulin sensitivity (P = 0.002). CONCLUSIONS These results suggest that future gene-mapping studies may identify pleiotropic genetic variants influencing both retinal arteriolar and venular calibers. Genetic variants associated with retinal caliber and (risk factors for) cardiovascular disease should provide new etiologic insights into this complex disease.

‘Opt-out’ referrals after identifying pregnant smokers using exhaled air carbon monoxide: impact on engagement with smoking cessation support

Background In the UK, free smoking cessation support is available to pregnant women; only a minority accesses this. ‘Opt-out’ referrals to stop smoking services (SSS) are recommended by UK guidelines. These involve identifying pregnant smokers using exhaled carbon monoxide (CO) and referring them for support unless they object. Methods To assess the impact of ‘opt-out’ referrals for pregnant smokers on SSS uptake and effectiveness, we conducted a ‘before–after’ service development evaluation. In the 6-month ‘before’ period, there was a routine ‘opt-in’ referral system for self-reported smokers at antenatal ‘booking’ appointments. In the 6-month ‘after’ period, additional ‘opt-out’ referrals were introduced at the 12-week ultrasound appointments; women with CO≥4 ppm were referred to, and outcome data were collected from, local SSS. Results Approximately 2300 women attended antenatal care in each period. Before the implementation, 536 (23.4%) women reported smoking at ‘booking’ and 290 (12.7%) were referred to SSS. After the implementation, 524 (22.9%) women reported smoking at ‘booking’, an additional 156 smokers (6.8%) were identified via the ‘opt-out’ referrals and, in total, 421 (18.4%) were referred to SSS. Over twice as many women set a quit date with the SSS after ‘opt-out’ referrals were implemented (121 (5.3%, 95% CI 4.4% to 6.3%) compared to 57 (2.5%, 95% CI 1.9% to 3.2%) before implementation) and reported being abstinent 4 weeks later (93 (4.1%, 95% CI 3.3% to 4.9%) compared to 46 (2.0%, 1.5% to 2.7%) before implementation). Conclusions In a hospital with an ‘opt-in’ referral system, adding CO screening with ‘opt-out’ referrals as women attended ultrasound examinations doubled the numbers of pregnant smokers setting quit dates and reporting smoking cessation.

Optic Disc Planimetry, Corneal Hysteresis, Central Corneal Thickness, and Intraocular Pressure as Risk Factors for Glaucoma

PURPOSE To determine whether corneal hysteresis and central corneal thickness are independent risk factors for glaucoma. DESIGN A cross-sectional population-based cohort study. METHODS Associations were tested between corneal hysteresis, measured in 1754 population-based subjects from the TwinsUK cohort, and glaucoma-related endophenotypes, including intraocular pressure (IOP), vertical cup-to-disc ratio, optic disc area, and optic disc cup area. Corneal hysteresis, IOP, and central corneal thickness (CCT) were measured; optic disc photographs were analyzed; and multivariable linear regression analysis was performed. RESULTS Data were available on 1645 individuals. Multiple regression analysis showed corneal hysteresis to be significantly negatively associated with age (beta coefficient = -0.03, P < .00005) and IOP (beta coefficient = -0.06, P < .00005). Corneal hysteresis was also found to be associated with CCT (beta coefficient = 0.02, P < .0005). There was no significant association between corneal hysteresis and optic disc area (P = .6), cup area (P = .77), vertical cup-to-disc ratio (P = .51), or spherical equivalent (P = .08). CCT was also found to be significantly associated with IOP (beta coefficient = 3.3, P < .0005) and corneal hysteresis (beta coefficient = 9.4, P < .0005), but not with age (P = .59) or spherical equivalent (P = .16). CONCLUSION In this large cohort of healthy British twins, we found no relationship between corneal hysteresis or CCT and quantitative measures of optic disc cupping, suggesting that corneal hysteresis and CCT are not independent risk factors for glaucoma.