Identification of diabetic retinopathy genes through a genome-wide association study among Mexican-Americans from Starr County, Texas

To identify genetic susceptibility loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas completed detailed physical and ophthalmologic examinations including fundus photography for diabetic retinopathy grading. 103 individuals with moderate-to-severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy were defined as cases for this study. DNA samples extracted from study subjects were genotyped using the Affymetrix GeneChip® Human Mapping 100K Set, which includes 116,204 single nucleotide polymorphisms (SNPs) across the whole genome. Single-marker allelic tests and 2- to 8-SNP sliding-window Haplotype Trend Regression implemented in HelixTreeTM were first performed with these direct genotypes to identify genes/regions contributing to the risk of severe diabetic retinopathy. An additional 1,885,781 HapMap Phase II SNPs were imputed from the direct genotypes to expand the genomic coverage for a more detailed exploration of genetic susceptibility to diabetic retinopathy. The average estimated allelic dosage and imputed genotypes with the highest posterior probabilities were subsequently analyzed for associations using logistic regression and Fisher's Exact allelic tests, respectively. To move beyond these SNP-based approaches, 104,572 directly genotyped and 333,375 well-imputed SNPs were used to construct genetic distance matrices based on 262 retinopathy candidate genes and their 112 related biological pathways. Multivariate distance matrix regression was then used to test hypotheses with genes and pathways as the units of inference in the context of susceptibility to diabetic retinopathy. This study provides a framework for genome-wide association analyses, and implicated several genes involved in the regulation of oxidative stress, inflammatory processes, histidine metabolism, and pancreatic cancer pathways associated with severe diabetic retinopathy. Many of these loci have not previously been implicated in either diabetic retinopathy or diabetes. In summary, CDC73, IL12RB2, and SULF1 had the best evidence as candidates to influence diabetic retinopathy, possibly through novel biological mechanisms related to VEGF-mediated signaling pathway or inflammatory processes. While this study uncovered some genes for diabetic retinopathy, a comprehensive picture of the genetic architecture of diabetic retinopathy has not yet been achieved. Once fully understood, the genetics and biology of diabetic retinopathy will contribute to better strategies for diagnosis, treatment and prevention of this disease.^

DIABETIC RETINOPATHY IN NON-INSULIN-DEPENDENT DIABETES MELLITUS IN BLACK WOMEN: A DESCRIPTIVE STUDY OF RISK FACTORS

This cross-sectional study examines the prevalence of selected potential risk factors by stage of diabetic retinopathy (DR) among Black American women with non-insulin-dependent diabetes mellitus (NIDDM) followed at a university diabetes clinic. DR was assessed by ophthalmoscopy and five-field retinography, and graded on counts of microaneurysms, hemorrhages and/or exudates, and presence of proliferative DR. Prevalence of other vascular diseases was assessed from medical records. Potential risk factors included age, known duration of diabetes, type of hypoglycemic treatment, concentrations of random capillary blood glucose, glycosylated hemoglobin, urine protein and fibrinogen, body mass index, and blood pressure. Prevalence of these risk factors is reported for three categories: No DR, mild background DR, severe background or proliferative DR (including surgically treated DR). Duration, age at diagnosis and treatment of diabetes, concentration of urine protein and average blood glucose, hypertension and cardiovascular disease were significantly associated with DR in univariate analysis. The covariance analysis employed stratification on duration, age at diagnosis and therapy of diabetes. The highest DR scores were calculated for those diagnosed before age 45, regardless of duration, therapy, or average blood glucose. Only individuals diagnosed before age 45 had high blood glucose concentrations in all categories of duration. These findings suggest that in this clinic population of Black women, those diagnosed with NIDDm before age 45 who eventually required insulin treatment were at the greatest risk of developing DR and that longterm poor glucose control is a contributing factor. These results suggest that greater emphasis be placed on this subgroup in allocating the limited resources available to improve the quality of glucose regulation, particularly through measures affecting compliance behavior.^ Findings concerning the association of DR with concentration of blood glucose and urine protein, blood pressure/hypertension and weight were compared with those reported from American Indian and Mexican American populations of the Southwestern United States where prevalence of NIDDM, hypertension and obesity is also high. Additional comparative analyses are outlined to substantiate the preliminary finding that there are systematic differences between these ethnic populations. ^

Risk factors for diabetic retinopathy in Mexican Americans in Starr County, Texas

The prevalence of diabetes in Mexican Americans is disproportionately higher than in non-Hispanic whites. The rate of diabetic retinopathy resulting from prolonged diabetes is also greater in Mexican Americans than in non-Hispanic whites. A longitudinal study was carried out on data collected from Mexican Americans in Starr County, Texas to assess the association between socioeconomic and acculturation factors with diabetic retinopathy prevalence, incidence, and progression in those free of diabetic retinopathy or who had only early non-proliferative diabetic retinopathy. A multivariable analysis was done. ^ The incidence rate was 12.78 cases per year and the progression rate was 8.55 cases per year. The baseline characteristics of the population revealed that more people with occupations synonymous with lower income jobs like trade workers and machine operators had early non-proliferative diabetic retinopathy. A multivariable analysis revealed that those with early non-proliferative diabetic retinopathy were more likely to have been born in Mexico as compared to those free of diabetic retinopathy. Surprisingly, a multivariable analysis also showed that those that progressed in diabetic retinopathy disease status were more likely to have been employed as compared to those that did not. ^ This analysis reveals that Mexican Americans are heterogeneous in socioeconomic and acculturation factors that may be used to deter the incidence and progression of diabetic retinopathy severity. These findings could be targeted to create culturally sensitive intervention programs that will improve the detection and treatment of diabetic retinopathy in the work arena in addition to programs that will impact those that do not work. Workplace preventative health screenings and dissemination of language-specific informational brochures is warranted to curb the rates of progression in those employed. ^ A limitation of this study is the narrow surrogates used for assessing socioeconomic and acculturation status. To fully evaluate these variables, a study using a questionnaire with a multitude of surrogates for socioeconomic and acculturation factors should be employed.^