Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration.

BACKGROUND: Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries. METHODS/PRINCIPAL FINDINGS: We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75 x 10(-9); non-AMD controls and OR 2.79, p = 2.78 x 10(-19), blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%. CONCLUSIONS/SIGNIFICANCE: Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index.

Glycodelin: a novel serum anti-inflammatory marker in type 1 diabetic retinopathy during pregnancy.

PURPOSE: Inflammation may play a role in the development of diabetic retinopathy during pregnancy. Glycodelin is a glycoprotein whose secretion from the endometrial glands increases during pregnancy. Glycodelin has immunosuppressive properties thought to play a role in the protection of the fetoplacental unit. We studied the role of glycodelin in the development and progression of retinopathy in type 1 diabetes during pregnancy. METHODS: Retinopathy was graded from fundus photographs in 45 diabetes subjects and nine non-diabetes subjects prospectively during pregnancy. Serum glycodelin concentration was measured by an immunofluorometric assay. RESULTS: In women with diabetes with progression of retinopathy, serum glycodelin concentration was 263 ng/ml (range 116-505 ng/ml) during the first trimester, 61 ng/ml (range 30-106 ng/ml) during the second trimester, and 29 ng/ml (range 13-53 ng/ml) during the third trimester, compared with values of 595 ng/ml (range 376-870 ng/ml), 104 ng/ml (range 75-228 ng/ml) and 45 ng/ml (range 32-74 ng/ml), respectively, in diabetes subjects without progression (p = 0.005 between the groups). Low glycodelin concentration was associated with progression of diabetic retinopathy in multiple regression analysis. Serum glycodelin concentration was similar in women with and without diabetes throughout pregnancy (p = 0.63 by repeated measures ANOVA). CONCLUSIONS: Low glycodelin concentration is associated with progression of retinopathy in pregnant women with diabetes. A possible causal relationship between low glycodelin levels and progression of retinopathy may be mediated by the immunomodulatory properties of glycodelin.