Heritability of the Severity of Diabetic Retinopathy: The FIND-Eye Study

Abstract

PURPOSE Diabetic retinopathy (DR) and diabetic nephropathy (DN) are serious microvascular complications of diabetes mellitus. Correlations between severity of DR and DN and computed heritability estimates for DR were determined in a large, multiethnic sample of diabetic families. The hypothesis was that (1) the severity of DR correlates with the presence and severity of nephropathy in individuals with diabetes mellitus, and (2) the severity of DR is under significant familial influence in members of multiplex diabetic families. METHODS The Family Investigation of Nephropathy and Diabetes (FIND) was designed to evaluate the genetic basis of DN in American Indians, European Americans, African Americans, and Mexican Americans. FIND enrolled probands with advanced DN, along with their diabetic siblings who were concordant and discordant for nephropathy. These diabetic family members were invited to participate in the FIND-Eye study to determine whether inherited factors underlie susceptibility to DR and its severity. FIND-Eye participants underwent eye examinations and had fundus photographs taken. The severity of DR was graded by using the Early Treatment Diabetic Retinopathy Study Classification (ETDRS). Sib–sib correlations were calculated with the SAGE 5.0 program FCOR, to estimate heritability of retinopathy severity. RESULTS This report summarizes the results for the first 2368 diabetic subjects from 767 families enrolled in FIND-Eye; nearly 50% were Mexican American, the largest single ethnicity within FIND. The overall prevalence of DR was high; 33.4% had proliferative DR; 7.5%, 22.8%, and 9.5% had severe, moderate, and mild nonproliferative DR, respectively; 26.6% had no DR. The severity of DR was significantly associated with severity of DN, both by phenotypic category and by increasing serum creatinine concentration (χ2 = 658.14, df = 20; P < 0.0001). The sib–sib correlation for DR severity was 0.1358 in the total sample and 0.1224 when limited to the Mexican-American sample. Broad sense heritabilities for DR were 27% overall and 24% in Mexican-American families. The polygenic heritability of liability for proliferative DR approximated 25% in this FIND-Eye sample. CONCLUSIONS These data confirm that the severity of DR parallels the presence and severity of nephropathy in individuals with diabetes mellitus. The severity of DR in members of multiplex diabetic families appears to have a significant familial connection.

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

“…Familial clustering of DR cases across different ethnicities suggests that genetic susceptibility may underlie this risk [108,109]. The genetic heritability of DR in the FINDEye cohort was estimated at 25% [110]. Retinopathy develops in approximately 21% of patients newly diagnosed with T2D and in approximately 60% of patients with T2D within the first 2 decades after diagnosis [111].…”

Risk factors for development and progression of nonproliferative retinopathy in normoalbuminuric patients with type 1 diabetes

“…Retinopathy and nephropathy are most important microvascular complications in patients with diabetes. It is assumed that retinopathy and nephropathy occurs at the same time and that the severity of retinopathy parallels the presence and severity on nephropathy in diabetes mellitus [8,9]. In addition, it is suggested that relationship between renal abnormalities and retinopathy are more frequent in patients with type 1 diabetes than type 2 diabetes [10].…”

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

“…Interestingly, there is a higher concordance of DR in T2D monozygotic twins (95%) than in T1D monozygotic twins (68%), suggesting that in T1D the initiation and development of its complications are less dependent on genetic factors than in T2D [11]. Additional family studies have shown that, depending on the DR phenotype and the ethnic population examined, siblings and relatives of diabetic patients with DR have approximately a 2-to 4-fold risk of developing the complication compared with relatives of diabetic patients without DR complication [5,[13][14][15][16][17][18]. The degree of familial aggregation is greater for more severe forms of retinopathy.…”