Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.

Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations.

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear.

Long-term cognitive outcomes in tuberous sclerosis complex.

Aim: To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC).

Method: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo).

Secular changes in severity of intellectual disability in tuberous sclerosis complex: A reflection of improved identification and treatment of epileptic spasms?

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in or . Epilepsy occurs in 80%-90% of affected individuals during their lifetime, and up to one-third of children with TSC will develop epileptic (infantile) spasms, for which vigabatrin has been shown to be particularly effective. Epilepsy severity and epileptic spasms are consistent markers of risk for the development of intellectual impairment in TSC.

Association of C-Reactive Protein Genetic Polymorphisms With Late Age-Related Macular Degeneration.

Importance: C-reactive protein (CRP) is a circulating inflammatory marker associated with late age-related macular degeneration (AMD). It remains uncertain whether the association between CRP concentrations and AMD is causal.

Objective: To assess whether CRP (OMIM 123260) single-nucleotide polymorphisms that influence circulating CRP concentrations are associated with late AMD.

Analysis of copy number variation at DMBT1 and age-related macular degeneration.

Background: DMBT1 is a gene that shows extensive copy number variation (CNV) that alters the number of bacteria-binding domains in the protein and has been shown to activate the complement pathway. It lies next to the ARMS2/HTRA1 genes in a region of chromosome 10q26, where single nucleotide variants have been strongly associated with age-related macular degeneration (AMD), the commonest cause of blindness in Western populations. Complement activation is thought to be a key factor in the pathogenesis of this condition.

Intellectual development before and after the onset of infantile spasms: a controlled prospective longitudinal study in tuberous sclerosis.

Objective: Infantile spasms (IS) have long been suspected to be a risk factor for impairment in intellectual development, but there are no controlled, prospective longitudinal data in well-characterized conditions to confirm this suspicion. We tested the hypothesis in a longitudinal study of children with tuberous sclerosis (TS), who have a high risk of developing IS.

Methods: Eleven infants with TS were recruited and studied longitudinally using the Mullen Scales of Early Learning.

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls.

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8).

Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability.

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

Background: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.

Methods: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry.

Genetic variation in complement regulators and susceptibility to age-related macular degeneration.

Objectives: Age-related macular degeneration (AMD) is the commonest cause of blindness in Western populations. Risk is influenced by age, genetic and environmental factors. Complement activation appears to be important in the pathogenesis and associations have been found between AMD and genetic variations in complement regulators such as complement factor H.

Complement factor D in age-related macular degeneration.

Purpose: To examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations.

Methods: Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay.

Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported.

Age-related macular degeneration: the importance of family history as a risk factor.

Background: Family history is considered a risk factor for age-related macular degeneration (AMD). With the advent of effective therapy for the disease, the importance of family history merits further investigation. This study quantifies the risk associated with family history, first, by a case-control study of reported family history and, second, by examining the siblings of AMD cases.

The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management.

Aims: The Tuberous Sclerosis 2000 Study is the first comprehensive longitudinal study of tuberous sclerosis (TS) and aims to identify factors that determine prognosis. Mode of presentation and findings at initial assessments are reported here.

Methods: Children aged 0-16 years newly diagnosed with TS in the UK were evaluated.

Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome).

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.

Charles Bonnet syndrome in age-related macular degeneration: the nature and frequency of images in subjects with end-stage disease.

Introduction: The term Charles Bonnet syndrome (CBS) is used to describe visual hallucinations resulting from ocular pathology. As part of a larger case-control study we assessed factors which may predispose to this phenomenon in Age-related macular degeneration (AMD).

Methods: Three-hundred and sixty cases of late AMD underwent a detailed questionnaire about visual symptoms experienced.

The Early Childhood Epilepsy Severity Scale (E-Chess).

Purpose: We have developed the Early Childhood Epilepsy Severity Scale (E-Chess) to quantify the severity of epilepsy in infants and young children with tuberous sclerosis as an aid to the evaluation of treatment efficacy and the investigation of the influence of epilepsy severity on development.

Methods: Twenty infants aged 11-36 months with a diagnosis of tuberous sclerosis participated in the study. From the literature, six potential measures of epilepsy severity were identified: time period over which seizures occurred; seizure frequency; number of seizure types; occurrence and duration of status epilepticus; number of anticonvulsant medications used; response to treatment.

Complement C3 variant and the risk of age-related macular degeneration.

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.