Jennifer Harmon

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case–control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 × 10−3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10−8; and Boston: P = 2.1 × 10−2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications.

Further mapping of 10q26 supports strong association of HTRA1 polymorphisms with age-related macular degeneration

Age-related macular degeneration (AMD) is a complex disorder with genetic and environmental influences. The genetic influences affecting AMD are not well understood and few genes have been consistently implicated and replicated for this disease. A polymorphism (rs11200638) in a transcription factor binding site of the HTRA1 gene has been described, in previous reports, as being most significantly associated with AMD. In this paper, we investigate haplotype association and individual polymorphic association by genotyping additional variants in the AMD risk-associated region of chromosome 10q26. We demonstrate that rs11200638 in the promoter region and rs2293870 in exon 1 of HTRA1, are among the most significantly associated variants for advanced forms of AMD.

Association of HTRA1 polymorphism and bilaterality in advanced age-related macular degeneration

Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p=.02 and p=.03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients.

Familial aggregation of age-related macular degeneration in the Utah population.

We examined familial aggregation and risk of age-related macular degeneration in the Utah population using a population-based case-control study. Over one million unique patient records were searched within the University of Utah Health Sciences Center and the Utah Population Database (UPDB), identifying 4764 patients with AMD. Specialized kinship analysis software was used to test for familial aggregation of disease, estimate the magnitude of familial risks, and identify families at high risk for disease. The population-attributable risk (PAR) for AMD was calculated to be 0.34. Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases. There were 16 extended large families with AMD identified for potential use in genetic studies. Each family had five or more living affected members. The familial aggregation of AMD shown in this study exemplifies the merit of the UPDB and supports recent research demonstrating significant genetic contribution to disease development and progression.

Using the Utah Population Database to assess familial risk of primary open angle glaucoma

PURPOSE Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness in the elderly. Previous epidemiological studies have identified family history, ethnic origin, age, high intraocular pressure and diabetes mellitus as risk factors. However, it is difficult to assess the extent family history plays in this disease process. The Utah Population Database (UPDB), created by the University of Utah, has recently become a resource for which greater than 9 million records are available for use. The UPDB is divided into two major data sets from which family members can be identified, namely 1.6 million genealogy records and 2 million Utah birth certificates. This study utilizes these resources to assess the familial risk of POAG within the Utah Population. METHODS The University of Utahs hospital and clinic records were searched for patients with primary and chronic open angle glaucoma (ICD9 codes 365.04 and 365.11) between the years 1995 and 2005. A case-control analysis was then performed with specialized UPDB software that was modified to constrain the control and pedigree populations to over 1 million University of Utah-UPDB linked records. Controls were matched to cases by gender and birth year (±2.5years) with only one control being used per case. Population-attributable risk (PAR) to familial factors and relative risk (RR) were computed using conditional logistic regression (CLR). RESULTS From the original 1.5 million medical records, 6198 patients with glaucoma were identified. Of these, 3391 met the inclusion criteria, which required patients to have at least one parent or one child in the UPDB. The PAR in this population was found to be 0.20, indicating 20% of the risk for glaucoma is attributable to genetic factors. CLR computations also showed a significantly increased relative risk (p<0.05) in first cousins (RR=1.45 (95% confidence interval (CI) 1.16-1.8)), second cousins (RR=1.19 (95% CI 1.08-1.32)), siblings (RR=3.76 (95% CI 2.66-5.31)), parents (RR=6.25 (95% CI 3.94-9.9)) and children (RR=6.77 (95% CI 3.39-13.5)). CONCLUSIONS Based on these familial data, there is a significantly higher prevalence of glaucoma in both first and second generation relatives of those affected as compared to relatives in the control group. When compared with other epidemiologic studies, such as an analysis of first-degree relatives of patients from the Rotterdam study, which showed a PAR of 16%, our study actually demonstrates a greater familial contribution to glaucoma. The UPDB is a valuable and unique resource providing a large population from which to analyze the familial risk of glaucoma.

A Reappraisal of the Clinical Spectrum of North Carolina Macular Dystrophy

PURPOSE To characterize the clinical phenotypes and genotype of a large family with North Carolina macular dystrophy (NCMD). DESIGN Observational, retrospective case series. PARTICIPANTS Thirteen participants who were at risk of inheriting a dominantly transmitted disease gene from a 4-generation family from Baltimore were examined. METHODS Thirteen participants underwent ophthalmic examination and genomic linkage analysis. Fundus photography, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography, ultrasonography, full-field electroretinography, and electro-oculography were performed on some patients. MAIN OUTCOME MEASURES Description of clinical phenotypes with genomic linkage to the MCDR1 locus. RESULTS Nine of 13 participants were affected with NCMD. There are variable and previously unreported clinical manifestations among affected individuals with NCMD, including drusen, macular staphyloma, choroidal neovascularization, a retinal pigment epithelial tear, and geographic atrophy. The distinctive and virtually pathognomonic grade 3 lesions in NCMD are neither staphylomas nor colobomas, as previously thought. As shown by ultrasonography and SD-OCT, they are deep chorioretinal excavations not involving the sclera, for which the authors propose a new term: macular caldera. Linkage analysis was performed, and the disease-causing gene in this family was mapped to the MCDR1 locus. CONCLUSIONS North Carolina macular dystrophy has a wide spectrum of clinical phenotypes that resemble age-related macular degeneration except for their early age of onset.

10q26 Is Associated with Increased Risk of Age-Related Macular Degeneration in the Utah Population

Age-related macular degeneration (AMD) includes a wide range of phenotypes. Early AMD is mainly characterized by the presence of soft dusen in the macula without visual loss, while advanced AMD is characterized by geographic atrophy (GA or dry AMD) and neovascular AMD (wet AMD) with visual loss. Despite the rising prevalence of AMD as a result of increasing life expectancy, its underlying etiology is poorly understood and there is no specific therapy. Nutritional supplements and antagonists of vascular endothelial growth factor (VEGF) have been reported to halt the progression of visual loss in wet AMD (Bressler et al., 1988). Wet AMD is usually associated with an aggressive form of visual loss due to choroidal neovascularization (CNV). Previous reports by several groups have identified a significant association between a common missense variant (Y402H) and non-coding variants in CFH and AMD in the United States (Edwards et al., 2005; Fisher et al., 2005; Hageman et al., 2005; Haines et al., 2005; Klein et al., 2005; Li et al., 2006; Maller et al., 2006) and Europe (Fisher et al., 2005; Souied et al., 2005; Despriet et al., 2006; Magnusson et al., 2006; Postel et al., 2006; Sepp et al., 2006; Simonelli et al., 2006). Recently, it was reported that rs10490924 in LOC387715 is the second major locus for AMD located at 10q locus (Conley et al., 2005; Rivera et al., 2005; Haddad et al., 2006; Maller et al., 2006; Schmidt et al., 2006). In this study we performed an association study incorporating SNP data for LOC387715 and PLEKHA1 at 10q26 and for CFH at 1q31.3 in the Utah AMD cohort. Our results support previous findings that