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Heather Stockman

Bio: Heather Stockman is an academic researcher from University of Iowa. The author has contributed to research in topics: Macular degeneration & Factor H. The author has an hindex of 4, co-authored 5 publications receiving 2100 citations.

Papers
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Journal ArticleDOI
TL;DR: It is shown that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium, implicating HF1 function in the pathogenetic mechanisms underlying AMD.
Abstract: Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ≈900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, χ2 = 26.1 and P = 3.2 × 10-7 and Y402H, χ2 = 54.4 and P = 1.6 × 10-13). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.

2,012 citations

Journal ArticleDOI
TL;DR: In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment, and greater SHRM dimensions were associated with worse VA.

127 citations

Journal ArticleDOI
TL;DR: GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss, and the genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA.

112 citations

Journal ArticleDOI
TL;DR: The genetic associations of drusenoid pigment epithelial detachment associated with age-related macular degeneration are consistent with genes associated with AMD progression, and progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD.

35 citations


Cited by
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Journal ArticleDOI
TL;DR: An updated view of the function, structure and dynamics of the complement network is described, its interconnection with immunity at large and with other endogenous pathways is highlighted, and its multiple roles in homeostasis and disease are illustrated.
Abstract: Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

2,986 citations

Journal ArticleDOI
07 Jun 2007-Nature
TL;DR: What constitutes replication of a genotype–phenotype association, and how best can it be achieved, is investigated.
Abstract: What constitutes replication of a genotype–phenotype association, and how best can it be achieved?

1,355 citations

Journal ArticleDOI
TL;DR: Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% ofThe controls, expanding and refine the understanding of the genetic risk for AMD.
Abstract: Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries. Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD. Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histocompatibility complex class III region, for genetic variation in two independent cohorts comprising approximately 900 individuals with AMD and approximately 400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.

1,106 citations

Journal ArticleDOI
TL;DR: This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex, and discuss the importance of structure–function relationships.
Abstract: Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins and the membrane attack complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly we will discuss the development and benefits of therapies using complement inhibitors.

1,042 citations

Journal ArticleDOI
10 Nov 2006-Science
TL;DR: It is reported that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD.
Abstract: Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.

846 citations