Variation in _PNPLA3_ is associated with outcomes in alcoholic liver disease

Two recent genome-wide association studies have described associations of SNP variants in _PNPLA3_ with nonalcoholic fatty liver and plasma liver enzyme levels in population based cohorts. We investigated the contributions of these variants to clinical outcomes in Mestizo subjects with a history of excessive alcohol consumption. We show that non-synonymous variant rs738409[G] (I148M) in _PNPLA3_ is strongly associated with alcoholic liver disease and progression to alcoholic cirrhosis (unadjusted OR = 2.25, P = 1.7x10^-10^; ancestry-adjusted OR = 1.79, P = 1.9x10^-5^)

Clinical validity assessment of a breast cancer risk model combining genetic and clinical information

_Background:_ The extent to which common genetic variation can assist in breast cancer (BCa) risk assessment is unclear. We assessed the addition of risk information from a panel of BCa-associated single nucleotide polymorphisms (SNPs) on risk stratification offered by the Gail Model.

_Methods:_ We selected 7 validated SNPs from the literature and genotyped them among white women in a nested case-control study within the Women’s Health Initiative Clinical Trial. To model SNP risk, previously published odds ratios were combined multiplicatively. To produce a combined clinical/genetic risk, Gail Model risk estimates were multiplied by combined SNP odds ratios. We assessed classification performance using reclassification tables and receiver operating characteristic (ROC) curves. 

_Results:_ The SNP risk score was well calibrated and nearly independent of Gail risk, and the combined predictor was more predictive than either Gail risk or SNP risk alone. In ROC curve analysis, the combined score had an area under the curve (AUC) of 0.594 compared to 0.557 for Gail risk alone. For reclassification with 5-year risk thresholds at 1.5% and 2%, the net reclassification index (NRI) was 0.085 (Z = 4.3, P = 1.0×10^-5^). Focusing on women with Gail 5-year risk of 1.5-2% results in an NRI of 0.195 (Z = 3.8, P = 8.6×10^−5^).

_Conclusions:_ Combining clinical risk factors and validated common genetic risk factors results in improvement in classification of BCa risks in white, postmenopausal women. This may have implications for informing primary prevention and/or screening strategies. Future research should assess the clinical utility of such strategies.
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Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (43,360 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 19 significant associations (p < 5e-8), two of which are replications of earlier associations with refractive error. These 19 associations in total explain 2.7% of the variance in myopia age of onset, and point towards a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point towards multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans

Identification and characterisation of the high-risk surgical population in the United Kingdom

INTRODUCTION: Little is known about mortality rates following general surgical procedures in the United Kingdom. Deaths are most common in the 'high-risk' surgical population consisting mainly of older patients, with coexisting medical disease, who undergo major surgery. Only limited data are presently available to describe this population. The aim of the present study was to estimate the size of the high-risk general surgical population and to describe the outcome and intensive care unit (ICU) resource use. METHODS: Data on inpatient general surgical procedures and ICU admissions in 94 National Health Service hospitals between January 1999 and October 2004 were extracted from the Intensive Care National Audit & Research Centre database and the CHKS database. High-risk surgical procedures were defined prospectively as those for which the mortality rate was 5% or greater. RESULTS: There were 4,117,727 surgical procedures; 2,893,432 were elective (12,704 deaths; 0.44%) and 1,224,295 were emergencies (65,674 deaths; 5.4%). A high-risk population of 513,924 patients was identified (63,340 deaths; 12.3%), which accounted for 83.8% of deaths but for only 12.5% of procedures. This population had a prolonged hospital stay (median, 16 days; interquartile range, 9–29 days). There were 59,424 ICU admissions (11,398 deaths; 19%). Among admissions directly to the ICU following surgery, there were 31,633 elective admissions with 3,199 deaths (10.1%) and 24,764 emergency admissions with 7,084 deaths (28.6%). The ICU stays were short (median, 1.6 days; interquartile range, 0.8–3.7 days) but hospital admissions for those admitted to the ICU were prolonged (median, 16 days; interquartile range, 10–30 days). Among the ICU population, 40.8% of deaths occurred after the initial discharge from the ICU. The highest mortality rate (39%) occurred in the population admitted to the ICU following initial postoperative care on a standard ward. CONCLUSION: A large high-risk surgical population accounts for 12.5% of surgical procedures but for more than 80% of deaths. Despite high mortality rates, fewer than 15% of these patients are admitted to the ICU

Assessment of the genetic basis of rosacea by genome-wide association study.

Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea

Chiral discrimination in optical trapping and manipulation

When circularly polarized light interacts with chiral molecules or nanoscale particles powerful symmetry principles determine the possibility of achieving chiral discrimination, and the detailed form of electrodynamic mechanisms dictate the types of interaction that can be involved. The optical trapping of molecules and nanoscale particles can be described in terms of a forward-Rayleigh scattering mechanism, with trapping forces being dependent on the positioning within the commonly non-uniform intensity beam profile. In such a scheme, nanoparticles are commonly attracted to local potential energy minima, ordinarily towards the centre of the beam. For achiral particles the pertinent material response property usually entails an electronic polarizability involving transition electric dipole moments. However, in the case of chiral molecules, additional effects arise through the engagement of magnetic counterpart transition dipoles. It emerges that, when circularly polarized light is used for the trapping, a discriminatory response can be identified between left- and right-handed polarizations. Developing a quantum framework to accurately describe this phenomenon, with a tensor formulation to correctly represent the relevant molecular properties, the theory leads to exact analytical expressions for the associated energy landscape contributions. Specific results are identified for liquids and solutions, both for isotropic media and also where partial alignment arises due to a static electric field. The paper concludes with a pragmatic analysis of the scope for achieving enantiomer separation by such methods