Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate understanding of AMD biology and help design new therapies, we executed a collaborative genomewide association study, examining >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 genomic loci associated with AMD with p<5×10−8 and enriched for genes involved in regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include 7 loci reaching p<5×10−8 for the first time, near the genes COL8A1/FILIP1L, IER3/DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9/MIR548A2, and B3GALTL. A genetic risk score combining SNPs from all loci displayed similar good ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry matched controls revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Oncology patients undergoing cancer treatment experience an average of fifteen unrelieved symptoms that are highly variable in both their severity and distress. Recent advances in Network Analysis (NA) provide a novel approach to gain insights into the complex nature of co-occurring symptoms and symptom clusters and identify core symptoms. We present findings from the first study that used NA to examine the relationships among 38 common symptoms in a large sample of oncology patients undergoing chemotherapy. Using two different models of Pairwise Markov Random Fields (PMRF), we examined the nature and structure of interactions for three different dimensions of patients’ symptom experience (i.e., occurrence, severity, distress). Findings from this study provide the first direct evidence that the connections between and among symptoms differ depending on the symptom dimension used to create the network. Based on an evaluation of the centrality indices, nausea appears to be a structurally important node in all three networks. Our findings can be used to guide the development of symptom management interventions based on the identification of core symptoms and symptom clusters within a network.

These findings provide insights into the most common symptom clusters in patients undergoing CTX for breast cancer. In addition, the most common symptoms within each cluster appear to be relatively stable across the two dimensions, as well as across time.

Context: Patients with lung cancer who undergo chemotherapy (CTX) experience multiple concurrent symptoms. An evaluation of how these symptoms cluster together and how these symptom clusters change over time may provide insights into how to treat these multiple cooccurring symptoms. Objectives: The purposes of this study, in a sample of lung cancer patients (n=145) who were receiving chemotherapy (CTX) were to evaluate for differences in the number and types of symptom clusters at three time points (i.e., before CTX, the week after CTX, and two weeks after CTX) using ratings of symptom occurrence and severity and to evaluate for changes in these symptom clusters over time. Methods: At each of the three assessments, a modified version of the Memorial Symptom Assessment Scale was used to assess the occurrence and severity of the 38 symptoms. Exploratory factor analyses were used to extract the symptom clusters. Results: Across the two symptom dimensions (i.e., occurrence and severity) and the three assessments, six distinct symptom clusters were identified. However, only three of these clusters were relatively stable across both dimensions and across time (i.e., lung cancer specific, psychological, nutritional). Two additional clusters varied by time but not by symptom dimension (i.e., epithelial/gastrointestinal, epithelial). A sickness behavior cluster was identified at each assessment with the exception of the week before CTX using the severity dimension. Conclusion: These findings provide insights into the most common symptom clusters in patients undergoing CTX for lung cancer. The most common symptoms within each cluster appear to be relatively stable across the two dimensions, as well as across time.

Context Evidence suggests that chemotherapy-induced neuropathy (CIN) is a significant problem for cancer survivors. However, a detailed phenotypic characterization of CIN in cancer survivors is not available. Objectives To evaluate between group differences in demographic and clinical characteristics, as well as in measures of sensation, function, and postural control, in a sample of cancer survivors who received a platinum and/or a taxane-based CTX regimen and did (n=426) and did not (n=197) develop CIN. Methods Survivors completed self-report questionnaires and underwent objective testing (i.e., light touch, pain sensation, cold sensation, vibration, muscle strength, grip strength, Purdue Pegboard test, Timed Get Up and Go Test, Fullerton Advanced Balance test). Parametric and non-parametric statistics were used to compare between group differences in study outcomes. Results Of the 426 survivors with CIN, 4.9% had CIN only in their upper extremities, 27.0% only in their lower extremities, and 68.1% in both their upper and lower extremities. Demographic and clinical characteristics associated with CIN included: older age, lower annual income, higher body mass index, a higher level of comorbidity, being born prematurely, receipt of a higher cumulative dose of chemotherapy, and a poorer functional status. Survivors with CIN had worse outcomes for all of the following objective measures: light touch, pain, temperature, vibration, upper and lower extremity function and balance. Conclusions This study is the first to provide a detailed phenotypic characterization of CIN in cancer survivors who received a platinum and/or a taxane compound. These data can serve as a benchmark for future studies of CIN in cancer survivors.

SUMMARYObjective: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1b) gene, Il-1b levels in cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1b ratios would predict PTE development post-TBI. Methods: We investigated PTE development in 256 Caucasian adults with moderateto-severe TBI. IL-1b tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1b levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1b gene variants, and also PTE. Temporally matched CSF/serum IL-1b ratios were also generated to reflect the relative contribution of serum IL-1b to CSF IL-1b. Results: Multivariate analysis showed that higher CSF/serum IL-1b ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1b levels (p = 0.014) and higher IL-1b CSF/serum ratios (p = 0.093). Significance: This is the first report implicating IL-1b gene variability in PTE risk and linking (1) IL-1b gene variation with serum IL-1b levels observed after TBI and (2) IL-1b ratios with PTE risk. Given these findings, we propose that genetic and IL-1b ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1b production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1b CSF/serum associations with PTE, and (3) evaluating targeted IL-1b therapies that reduce PTE.

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