Summary Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Purpose To quantify retinal capillary density and morphology in uveitis using SD-OCTA. Design Cross-sectional, observational study Methods Healthy and uveitic subjects were recruited from two tertiary care eye centers. Prototype SD-OCTA devices (Cirrus, Carl Zeiss Meditec, Inc., Dublin, CA) were used to generate 3×3 mm2 OCTA images centered on the fovea. Subjects were placed into 3 groups based on the type of optical microangiography (OMAG) algorithm used for image processing (intensity-and/or phase) and type of retinal segmentation (automatic or manual). A semi-automated method was used to calculate skeleton density (SD), vessel density (VD), fractal dimension (FD), and vessel diameter index (VDI). Retinal vasculature was assessed in the superficial retinal layer (SRL), deep retinal layer (DRL), and non-segmented retinal layer (NS-RL). A generalized estimating equations model was used to analyze associations between the OCTA measures and disease status within each retinal layer. A P value < 0.05 was accepted as significant. Reproducibility and repeatability were assessed using the Intraclass Correlation Coefficient (ICC). Results The SD, VD, and FD of the parafoveal capillaries were lower in uveitic eyes compared to healthy eyes in all retinal segments. In addition, SD and VD were significantly lower in the DRL of subjects with uveitic macular edema. There was no correlation in any capillary parameters and anatomic classification of uveitis. Conclusions Quantitative analysis of parafoveal capillary density and morphology in uveitis demonstrates significantly lower capillary density and complexity. SD-OCTA algorithms are robust enough to detect these changes and can provide a novel diagnostic index of disease for uveitis subjects.

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We have recently proposed that lipid peroxidation may be a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. During this exercise, we noted a risk factor swap between breast and kidney cancer (oophorectomy and increased parity, detrimental for kidney, beneficial for breast; high blood pressure, detrimental for kidney, beneficial for breast when it occurs during pregnancy; alcohol, beneficial for kidney, detrimental for breast, and so on). We have subsequently proposed the hypothesis that lipid peroxidation represents a protective mechanism in breast cancer, and reviewed the evidence of the role of lipid peroxidation on established hormonal and non-hormonal factors for breast cancer. Here, we review the evidence in support of lipid peroxidation playing a role in the relationships between dietary factors and breast cancer. Available evidence implicates increased lipid peroxidation products in the anti-carcinogenic effect of suspected protective factors for breast cancer, including soy, marine n-3 fatty acids, green tea, isothiocyanates, and vitamin D and calcium. We also review the epidemiological evidence supporting a modifying effect of oxidative stress genes in dietary factor-breast cancer relationships. IntroductionLipid peroxidation is a natural metabolic process under normal conditions. It can be divided into three stages: initiation, propagation and termination [1]. The initiation phase includes activation of oxygen and is rate limiting. Polyunsaturated fatty acids (the main component of membrane lipids) are susceptible to peroxidation. Lipid peroxidation is one of the most investigated consequences of reactive oxygen species' (ROS) actions on membrane structure and function. The idea of lipid peroxidation as a solely destructive process has changed during the past decade. It has been shown that lipid hydroperoxides and oxygenated products of lipid peroxidation degradation as well as lipid peroxidation initiators (that is, ROS) can participate in the signal transduction cascade [2,3], the control of cell proliferation, and the induction of differentiation, maturation, and apoptosis [4][5][6]. It has been shown that lipid peroxidation and ROS are triggers and essential mediators of apoptosis, which eliminates precancerous and cancerous, virus-infected and otherwise damaged cells that threaten our health [7][8][9][10]. In addition, although the essential n-6 fatty acid linoleic acid has been shown to increase breast cancer in experimental studies, other n-6 fatty acids (such as conjugated linoleic acid, and gamma linolenic acid) and n-3 fatty acids (such as eicosapentaenoic acid, docosahexaenoic acid (DHA), and alpha-linolenic acid) have been shown to inhibit the growth of breast cancer in vivo and in vitro and this inhibition is correlated with the extent of lipid peroxidation generated in tumor cells [11]. This suppression of cancer growth is enhanced by pro-oxidants and eliminated by antioxidants, and this elimination is proportional to the inhib...

Purpose To estimate the prevalence of refractive errors in adult Chinese Americans, and evaluate factors associated with myopia and high myopia. Design A population-based, cross-sectional study. Methods Chinese Americans 50 years and older residing in Monterey Park, California, were recruited. Noncycloplegic automated refraction with supplemental subjective refraction was performed. Myopia, high myopia, hyperopia, and high hyperopia were defined as a spherical equivalent of < −0.5 diopter (D), < −5.0D, > +0.5D, and ≥ +3.0D, respectively. Astigmatism and high astigmatism were defined as a cylinder of > 0.5D and > 2.25D, respectively. Risk factor assessment was guided by a conceptual model. Results Data from 4144 participants were analyzed. The overall prevalence of myopia, high myopia, hyperopia, high hyperopia, astigmatism, and high astigmatism was 35.1% (95% confidence interval, 33.6%–36.6%), 7.4% (6.6%–8.3%), 40.2% (38.7%–41.8%), 2.7% (2.2%–3.3%), 45.6% (44.1%–47.2%), and 3.7% (3.1%–4.3%), respectively. The prevalence of myopia and high myopia was lower among older individuals (Ps < 0.05). Reversed age trends were observed for the other refractive errors (Ps < 0.05). There was no sex difference in the prevalence of refractive errors, except for a higher prevalence of hyperopia among females (P = 0.010). Age, acculturation, education, income, marital status, birth country, history of ocular disease, non-ocular comorbidities, and recent eye exam were associated with prevalence of myopia. All of these factors, except for acculturation, were also associated with high myopia. Conclusions Our data present the first population-based estimates of the prevalence of refractive errors among adult Chinese Americans. Compared with whites, Hispanics, and blacks, Chinese Americans have a higher burden of myopia, high myopia, and astigmatism.

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There is little information regarding associations between suspected bladder cancer risk factors and tumor subtypes at diagnosis. Some, but not all, studies have found that bladder cancer among smokers is often more invasive than it is among nonsmokers. This population-based case-control study was conducted in Los Angeles, California, involving 1,586 bladder cancer patients and their individually matched controls. Logistic regression was used to conduct separate analyses according to tumor subtypes defined by stage and grade. Cigarette smoking increased risk of both superficial and invasive bladder cancer, but the more advanced the stage, the stronger the effect. The odds ratios associated with regular smokers were 2.2 (95% confidence intervals, 1.8-2.8), 2.7 (2.1-3.6) and 3.7 (2.5-5.5) for low-grade superficial, high-grade superficial and invasive tumors respectively. This pattern was consistently observed regardless of the smoking exposure index under examination. Women had higher risk of invasive bladder cancer than men even they smoked comparable amount of cigarettes as men. There was no gender difference in the association between smoking and risk of low-grade superficial bladder cancer. The heterogeneous effect of cigarette smoking was attenuated among heavy users of NSAIDs. Our results indicate that cigarette smoking was more strongly associated with increased risk of invasive bladder cancer than with low-grade superficial bladder cancer.

Genome-wide association studies have associated common variations at chromosomes 5p15 and 15q25 with lung cancer risk. The 5p15 locus has also been associated with increased bladder cancer risk in a recent report. The 15q25 locus has been associated with nicotine dependence and self-reported number of cigarettes smoked per day in some studies and it was proposed that its association with lung cancer may be mediated through differences in smoking behavior. Here, we investigated the roles of variations at 5p15 (rs401681, rs402710, rs2736098 and rs2736100) and 15q25 (rs1051730 and rs8034191) in bladder cancer etiology in two case-control studies conducted separately in Los Angeles County, CA, USA (498 cases and 588 controls) and in Shanghai, China (506 cases and 530 controls). We replicated the association between the 5p15 locus and bladder cancer among non-Hispanic whites (NHW) in Los Angeles [for rs2736100, per C allele odds ratio (OR) = 1.23; 95% confidence interval (CI), 1.02-1.48; P = 0.029] and among Chinese in Shanghai (OR = 1.22; 95% CI, 1.02-1.47; P = 0.033). Both rs1051730 and rs8034191 at 15q25 were rare among Chinese. Among NHW, a significant association was found between rs8034191 and bladder cancer which persisted after adjustment for cigarette smoking status, number of cigarettes smoked per day and number of years of smoking (per C allele OR = 1.26; 95% CI, 1.04-1.54; P = 0.017). Our results support 5p15 and 15q25 as susceptibility regions for bladder cancer risk.