Rare and Common Genetic Variants, Smoking, and Body Mass Index: Progression and Earlier Age of Developing Advanced Age-Related Macular Degeneration.

Purpose: To determine behavioral and genetic factors associated with incidence and age of progression to advanced age-related macular degeneration (AMD), geographic atrophy (GA), and neovascular disease (NV), and to quantify these effects. Methods: Longitudinal analyses were conducted among 5421 eyes with nonadvanced AMD at baseline in 2976 participants in the Age-Related Eye Disease Study (mean age of 68.8 (±5.0), 56.1% female). Progression was confirmed based on two consecutive visits on the AMD severity scale. Separate analyses for progression and age of progression were performed. All analyses adjusted for correlation between eyes, demographic and behavioral covariates, baseline severity scale, and genetic variants. Results: A higher genetic risk score (GRS) including eight genetic variants was associated with a higher rate of progression to advanced AMD within each baseline severity scale, especially for the highest risk intermediate level AMD category, and smoking further increased this risk. When assessing age when progression to advanced disease occurred, smoking reduced age of onset by 3.9 years (P < 0.001), and higher body mass index (BMI) led to earlier onset by 1.7 years (P = 0.003), with similar results for GA and NV. Genetic variants associated with earlier age of progression were CFH R1201C (4.3 years), C3 K155Q (2.15 years), and ARMS2/HTRA1 (0.8 years per allele). Conclusions: Rare variants in the complement pathway and a common risk allele in ARMS2/HTRA1, smoking, and higher BMI can lead to as much as 11.5 additional years of disease and treatment burden. Closer adherence to healthy lifestyles could reduce years of visual impairment.

Functional Analysis of Rare Genetic Variants in Complement Factor I (CFI) using a Serum-Based Assay in Advanced Age-related Macular Degeneration.

Purpose: Factor I (FI) is a serine protease regulator of the complement system. Genetic variants in CFI are associated with advanced age-related macular degeneration (AAMD). However, the clinical and functional impact of these variants is unknown. This study assessed the functional significance of rare CFI variants using a serum-based assay. Methods: Carriers of rare variants with (n = 78) and without AAMD (n = 28), and noncarriers with (n = 49) and without AMD (n = 44) were evaluated. Function of FI was determined by measuring the proteolytic cleavage of C3b to iC3b, using the cofactor protein, Factor H. Results: CFI variants were categorized into three groups based on antigenic and functional assessments. Type 1 variants (n = 18) in 35 patients with AAMD demonstrated low serum FI levels and a corresponding decrease in FI function. Type 2 variants (n = 6) in 7 individuals demonstrated normal serum FI antigenic levels but reduced degradation of C3b to iC3b. Type 3 variants (n = 15) in 64 individuals demonstrated normal antigenic levels and degradation of C3b to iC3b. However, iC3b generation was low when measured per unit of FI. Thus most rare CFI variants demonstrate either low antigenic levels (type 1) or normal levels but reduced function (types 2 or 3). Conclusions: Results provide for the first time a comprehensive functional assessment in serum of CFI rare genetic variants and further establish FI's key role in the pathogenesis of AAMD. Translational Relevance: Stratifying patients in the clinic with a rare CFI variant will facilitate screening and targeting patients most likely to benefit from complement therapies.

Characteristics of keratinocyte carcinomas in Hispanics compared to non-Hispanic whites: A retrospective 5-year study.

BACKGROUND: Hispanics are one of the fastest growing populations in the United States. Few studies have characterized the patterns of keratinocyte carcinoma presentation in Hispanics. OBJECTIVE: The study aimed to compare the clinical and histologic characteristics of keratinocyte carcinomas in Hispanics and non-Hispanic whites. MATERIALS AND METHODS: A five-year retrospective chart review was conducted at a single academic center to identify all histologically-confirmed cases of keratinocyte carcinomas. Tumor characteristics were then compared between Hispanics and non-Hispanic whites. RESULTS: A total of 197 tumors were identified of which 76% occurred in non-Hispanic whites and 24% in Hispanics. Tumor diameter was not larger and histologic subtype was not more aggressive in Hispanics compared to non-Hispanic whites. Age of diagnosis of basal cell carcinoma was younger among Hispanics compared to non-Hispanic whites (P < .05). CONCLUSION: Hispanics were not more likely to present with more high-risk keratinocyte carcinomas compared to non-Hispanic whites in terms of tumor diameter, differentiation and subtype.

Relation of Patellofemoral Joint Alignment, Morphology, and Radiographic Osteoarthritis to Frequent Anterior Knee Pain: Data from the Multicenter Osteoarthritis Study.

OBJECTIVE: Patellofemoral (PF) alignment and trochlear morphology are associated with PF osteoarthritis (OA) and knee pain, but whether they are associated with localized anterior knee pain is unknown, which is believed to be a symptom specific to PF joint pathology. We therefore aimed to evaluate the relation of PF alignment and morphology, as well as PFOA and tibiofemoral OA, to anterior knee pain. METHODS: The Multicenter Osteoarthritis Study is a cohort study of individuals with, or at risk for, knee OA. We evaluated cross-sectional associations of PF alignment, trochlear morphology, and PF and tibiofemoral radiographic OA, with localized anterior knee pain (defined with a pain map). We used 2 approaches: a within-person knee-matched evaluation of participants with unilateral anterior knee pain (conditional logistic regression), and a cohort approach comparing those with anterior knee pain to those without (binomial regression). RESULTS: With the within-person knee-matched approach (n = 110; 64% women, mean age 70 years, body mass index [BMI] 30.9), PF alignment, morphology, and tibiofemoral OA were not associated with unilateral anterior knee pain. Radiographic PFOA was associated with pain, odds ratio 5.3 (95% confidence interval [95% CI] 1.6-18.3). Using the cohort approach (n = 1,818; 7% of knees with anterior knee pain, 59% women, mean age 68 years, BMI 30.4), results were similar: only PFOA was associated with pain, with a prevalence ratio of 2.2 (95% CI 1.4-3.4). CONCLUSION: PF alignment and trochlear morphology were not associated with anterior knee pain in individuals with, or at risk for, knee OA. Radiographic PFOA, however, was associated with pain, suggesting that features of OA, more so than mechanical features, may contribute to localized symptoms.

Association Between Perifoveal Drusen Burden Determined by OCT and Genetic Risk in Early and Intermediate Age-Related Macular Degeneration.

Purpose: The purpose of this study was to determine associations between macular drusen parameters derived from an automatic optical coherence tomography (OCT) algorithm, nonadvanced age-related macular degeneration (AMD) stage, and genetic variants. Methods: Eyes classified as early or intermediate AMD with OCT imaging and genetic data were selected (n = 239 eyes). Drusen area and volume measurements were estimated using the Zeiss Cirrus advanced retinal pigment epithelium analysis algorithm in a perifoveal zone centered on the fovea. Associations between drusen measurements and common genetic variants in the complement and high-density lipoprotein (HDL) lipid pathways and the ARMS2/HTRA1 variant were calculated using generalized estimating equations and linear mixed models adjusting for age, sex, smoking, body mass index, and education. Results: Drusen area ≥ the median was independently associated with a higher number of risk alleles for CFH risk score and risk variants in C3 and ARMS2/HTRA1 compared with eyes with no measurable drusen. Similar results were obtained for drusen volume. When all genes were analyzed in the same model, only CFH score and ARMS2/HTRA1 were associated with drusen measurements. HDL pathway genes were not significantly related to drusen parameters. Nonadvanced AMD stages were associated with OCT-derived drusen area and volume. Conclusions: Variants in CFH and ARMS2/HTRA1, commonly associated with advanced AMD, were independently associated with an increase in drusen burden determined by OCT in an allele dose dependent manner, in eyes with early and intermediate AMD. Biomarkers such as a quantitative classification of nonadvanced AMD and other OCT-derived subphenotypes could provide earlier anatomic endpoints for clinical trials and facilitate the development of new therapies for AMD.

Willingness-to-pay and Time Trade-off: The Burden of Disease in Patients with Benign Hyperpigmentation.

Objective: We assessed willingness-to-pay (WTP) and time trade-off (TTO) as methods to quantify the disease burden of benign hyperpigmentation. Design: This was a cross-sectional pilot study that included 85 adults. A paper survey was used to collect demographic and health utility information; an accompanying dermatological exam assessed disease severity. Setting: This was a single-site study performed at an urban dermatology clinic. Participants: Adults 18 years of age or older who spoke English, Spanish, or Portuguese were included. Measurements: Utility measures included WTP, TTO, and time spent concealing the condition; correlation with quality of life was also assessed. Results: Mean WTP for 25-percent improvement (WTP25) of the skin condition was $38.95; for a 50-percent improvement (WTP50), $83.18. Participants were willing to give up 1.4 hours per day to receive a therapy that would completely cure their condition. The average proportion of monthly income that participants were willing to spend on a therapy that could cure their condition was 13.3 percent. Daily concealment time was, on average, 20.8 minutes, which correlated with a worsened quality of life. Conclusion: Disease burden was high, overall, for benign hyperpigmentation conditions. Health utilities offer a patient-centered method of assessing impact on quality of life.

Appearance-based vs health-based sun protective messages: A randomized, double-blind controlled study.

BACKGROUND: Appearance-based messages have shown promise in improving sun protection habits among Caucasians but have scarcely been investigated in Hispanic populations. OBJECTIVE: To compare the effectiveness of appearance-based vs health-based messages in an ethnic patient population, where hyperpigmentation disorders are prevalent and often cosmetically concerning. METHODS: One hundred thirty-seven patients were randomized to receive images of (a) skin cancer, (b) hyperpigmentation, or (c) wrinkles. Analysis of variance tests for repeated measures were used to estimate the effects of the different stimuli on participants' knowledge and intention to sun protect. RESULTS: Appearance-based interventions were more effective in improving intentions to sun protect among both Hispanics and non-Hispanic Whites (P < 0.05). They were furthermore more effective among younger patient populations (≤40 years old) and patients who thought that a tanned appearance is attractive (P < 0.05). CONCLUSIONS: Appearance-based photos of sun damage were more effective than health-based messages among Hispanics, younger patient populations, and those who find tanned appearances to be attractive.

Effect of stimuli on sun protective habits: A randomized double-blind controlled study.

BACKGROUND: Visual imagery has been shown to improve adherence to health messages but has scarcely been investigated in sun protection campaigns. OBJECTIVE: To determine the effectiveness of pictorial- and textual-based sun protective messages in a largely Hispanic population. METHODS: One hundred and forty-five participants received standard of care (SOC) as defined as sun protective counseling and were then randomized to receive either (a) images of sun damage, (b) a textual pamphlet about sun damage, or (c) no further messages. Analysis-of-variance tests for repeated measures were used to estimate the effects of the different stimuli on participants' knowledge and intention to sun protect. RESULTS: All stimulus groups demonstrated an improvement in perceived effectiveness of sun protective habits (p < 0.05). However, pictorial and textual stimuli were both more effective than SOC in improving intentions to sun protect (p < 0.05), but there was no differential effect between the two. CONCLUSIONS: Both pictorial and textual stimuli were more effective than SOC in improving intentions to sun protect, but there was no differential effect between the two.

Relationship of Trochlear Morphology and Patellofemoral Joint Alignment to Superolateral Hoffa Fat Pad Edema on MR Images in Individuals with or at Risk for Osteoarthritis of the Knee: The MOST Study.

Purpose To determine the relationship of patellofemoral joint alignment and trochlear morphology to superolateral Hoffa fat pad (SHFP) edema on magnetic resonance (MR) images in older adults with or at risk for osteoarthritis of the knee. Materials and Methods Institutional review board approval and written informed consent were obtained from all subjects. The Multicenter Osteoarthritis Study is a prospective cohort study of older adults with or at risk for osteoarthritis of the knee. Subjects were recruited from Birmingham, Alabama, and Iowa City, Iowa. In this cross-sectional study, patellofemoral joint alignment (bisect offset, patellar tilt angle, and Insall-Salvati ratio), trochlear morphology (sulcus angle, lateral and medial trochlear inclination, and trochlear angle) and SHFP edema were assessed on MR images of the knee. Measures of alignment and morphology were divided into quartiles, and SHFP was determined to be present or absent. Separate logistic regression models were used to determine the relationship of each measure of alignment and morphology to the presence of SHFP edema, with adjustments for age, sex, and body mass index. Results SHFP edema was present in 152 (13.4%) of the 1134 knees that were included. When compared with knees with measurements in the lowest quartile, knees with measurements in the highest quartile for trochlear angle, bisect offset, and Insall-Salvati ratios were 1.6 (95% confidence interval [CI]: 1.0, 2.6), 2.3 (95% CI: 1.3, 4.0), and 8.9 (95% CI: 4.7, 16.9) times more likely to show SHFP edema, respectively. No relationship was found between other measures and SHFP edema. Conclusion A more anterior trochlear facet, a more laterally displaced patella, and knees with patella alta were significantly associated with SHFP edema on MR images in subjects with or at risk for osteoarthritis of the knee. © RSNA, 2017.