Complement Factor H Haplotypes and Smoking in Age-related Macular Degeneration

2014-08-27 03:14:00 | BioPortfolio


Risk factors for Age-related Macular Degeneration (AMD) involves genetic variations in the alternative pathway of complement inhibitor factor H. The complement system is part of the innate and adaptive immune system. Smoking is the only environmental factor known to increase the risk of Age-related Macular Degeneration (AMD). Using serum samples of Age-related Macular Degeneration (AMD) patients and controls we will test the hypothesis that smoking increases Age-related Macular Degeneration (AMD) by increasing complement activation; and that this is positively corrleated with known disease variations in the complement factor H (CFH) gene.


ABSTRACT Age-related Macular Degeneration (AMD) is a slowly progressing multifactorial disease involving genetic ab-normalities and environmen tal insults. Age-related Macular Degeneration (AMD) is the leading cause of blindness for Americans over age sixty. As the population ages, the prevalence of Age-related Macular Degeneration (AMD) will continue to grow, reaching a maximum risk rate of ~30% at age 75. Since smoking significantly increases the risk of Age-related Macular Degeneration (AMD) and there is a 20% higher incidence of smoking in veterans than in the general U.S. adult civilian population, the U.S. Department of Veterans Affairs healthcare system will have to provide care for potentially up to 7 million or more Age-related Macular Degeneration (AMD) cases. Current available treatments focus on the late stage of the disease (choroidal neovascularization; CNV); however, those come with significant risks and only target subpopulations of Age-related Macular Degeneration (AMD) patients. No treatment is available for early Age-related Macular Degeneration (AMD) (i>85% of all cases). Thus, it is paramount that we learn on how to detect Age-related Macular Degeneration (AMD) early and develop treatments that allow for early disease prevention. While mechanistic studies have shown that inflammation and smoking are fundamental components of both forms of Age-related Macular Degeneration (AMD), genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing Age-related Macular Degeneration (AMD). One of the most detrimental mutations occurs in factor H (fH) an essential inhibitor in the complement cascade (fH risk haplotype). Overall, it has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis in Age-related Macular Degeneration (AMD). Here we wish to answer an essential question: do smoking and complement act synergistically in the disease process. For this proposal we will be guided by our overall hypothesis that pathologic activation of the alternative pathway (AP) has direct effects on the retinal pigment epithelium (RPE), generating a permissive cellular environment for Age-related Macular Degeneration (AMD) pathology. Thus, for this aim we will recruit patients with AMD and control subjects, selecting both smokers and non-smokers, to determine whether smoking influences complement activation, or whether smoking acts through a yet undefined pathway to promote Age-related Macular Degeneration (AMD) development. A complete exam to determine pathology and visual impairment will be performed on day 1 of the study. Serum will be analyzed for both factor H genotype and complement levels, focusing on levels of Ba, C3d and fD.


A) Study design Determine whether smoking increases complement activation and whether there are specific AMD genotypes that are particularly sensitive to this elevated level of serum complement components.

Thus, we will recruit patients with AMD and control subjects, selecting both smokers and non-smokers, to determine whether smoking influences complement activation, or whether smoking acts through a yet undefined pathway to promote AMD development. A complete exam to determine pathology and visual impairment will be performed on day 1 of the study. Serum will be analyzed for both factor H genotype and complement levels, focusing on levels of Ba, C3d and fD.

Data collection will be performed by clinical staff. Data analysis will be performed by trained professionals who will be masked to the patient evaluation.

B) Selection of subjects and controls

Subjects Case and age-matched (i.e., within 5 years) control subjects will be recruited under a protocol approved by the Charleston VA and the MUSC Review Board. All patients will provide written informed consent. The case and control subjects will be derived from a group of veterans. The following criteria were used for inclusion and exclusion in the study based on a previous, successful study conducted by our consultant Dr. AO Edwards.

Inclusion Criteria

1. Subjects will have a clear diagnosis of AMD; inclusion criteria for controls will be less than five small (< 63 um) hard drusen, at least a 20/40 view of the fundus, the ability to provide a blood sample, and the absence of exclusion criteria listed above.

2. Inclusion criteria for controls will be less than five small (< 63 um) hard drusen, at least a 20/40 view of the fundus and the absence of exclusion criteria listed below.

3. Subjects, must have the ability to provide a blood sample.

4. Subjects must be able to provide their own consent or have a legal representative available to provide consent for them.

5. Participants must be able to complete all aspects of testing

6. Participants must be in generally good medical health in the opinion of the study physician

7. Participants must have study informant/caregiver to participate in this study.

Exclusion Criteria

1. Participants who are unable to provide consent and who lack a legal representative

2. Participants will be excluded if best corrected visual acuity for both eyes is worse than 20/40.

3. Participants will be excluded if they are taking a medication known to cause retinopathy

4. Subjects will be excluded if they are unable to cooperate to complete testing.

5. Participants will be excluded if they present themselves with ocular diseases that might simulate AMD or preclude its diagnosis. Those might include prior laser photocoagulation, cryopexy, media opacity, and inflammatory diseases. It is important for potential control subjects not to exhibit media opacity (e.g., cataract), which will prevent visualization of the macula.

6. Participants will be excluded if they exhibit diseases that phenotypically overlap with AMD such as drusen or pigmentary disturbance of the retinal pigment epithelium (RPE), or that provided insufficient evidence to diagnose AMD.

7. Participants will be excluded if they present themselves with macular dystrophies, toxoplasmosis, histoplasmosis, degenerative myopia, central serous chorioretinopathy, or any disease or treatment that would diminish the ability to recognize drusen such as laser photocoagulation, prior retinal detachment surgery, posterior uveitis, and trauma.

Sample size / power estimation. A total of 150 subjects with AMD and 150 age-matched controls will be recruited for this study. This sample size was determined by statistically simulating the study findings 1,000 times using the following assumptions. We assumed an alpha level of 0.05, 2-sided hypothesis testing, and an expected distribution across the CC, CT, and TT factor H genotypes of 8.1%, 52%, and 39.9%, respectively (combining observed data for Caucasians and African Americans, [65]). We also assumed that approximately 35% of the cases and controls will be current smokers (see people/jeffrey/HarrisVARept97.pdf; Report commissioned by the Department of Veterans Affairs Assistant Secretary for Policy and Planning). Finally, we assumed that smoking status in combination with haplotype status had a multiplicative interactive effect on the measurement parameter of interest (i.e. complement protein Ba, D and C3d levels). That is, smoking was allowed to have a negligible impact on the measurement parameter among those in the low risk genotype, but those in the heterozygous and homozygous risk genotypes had 1.5-fold and 2-fold greater measurements, respectively. The simulation also included a direct effect of AMD status (case/control), with AMD cases having higher values than controls. Through this simulation process, we were able to show that the sample size of 150 cases and 150 controls will provide 85% power to detect a significant smoking by genotype interaction, the main focus of Aim 2. Note that our sample size is comparable to similar prior studies, one of which used 112 AMD patients and 67 controls [64], and another (conducted by our collaborator) that used 274 samples in total [63].

Recruitment. Case and age-matched (i.e., within 5 years) control subjects will be recruited. Recruitment will take place in two ways: 1) If patients that have been seen at the VA within the last two years, have been diagnosed with AMD or qualify as a control subject, they will be called to see whether they wish to participate in the study. For this group, the subjects will be consented at their next visit, they will be asked to provide information about their smoking status, and a blood sample will be collected. 2) Patients will be recruited after the diagnosis in the doctor's office (i.e., they have been diagnosed with AMD or qualify as a control subject). At this point, the subjects will be consented, they will be asked to provide information about their smoking status, and a blood sample will be collected. Flyers will be posted at the VA to alert patients of this clinical trial and flyers will be made available to the Ophthalmologists involved in the study to provide to their patients.

C) Clinical tests Diagnosis of age-related macular degeneration

Flowchart of patient workup Medical History

1. Chief complaint of vision changes is noted

2. A patient history is obtained, focusing on vision changes. If AMD-related symptoms were noted (blurry vision, metamorphopsia, scotoma, etc.), the approximated time it started is noted, the affected eye(s), whether the patient is taking vitamins (specific type and dosing) and whether previous treatments for AMD have been provided (type, dosing, frequency)?

3. Past medical history is obtained, focusing on any other eye problems/ disease, stroke or heart attack history, surgery planned in future, rheumatologic disease, and kidney disease (MPGN-II).

4. Family history is obtained, whether AMD is in the family.

5. Medications the patient is taking

6. Social history is obtained, including smoking behavior (years smoked and packs/year)?

Medical Exam Snellen visual acuity with pinhole testing

1. Pupillary exam is performed followed by confrontational visual fields or visual field test to determine the amount of vision loss.

2. Intraocular pressure is assessed by tonopen tonometry

3. Eyes are pharmacologically dilated using Phenylephrine 2.5% and 1% tropicamide

4. Slit lamp biomicropscopy including non-contact-lens exam of the macula and peripheral retina to determine anatomical alternation of the fundus.

5. If recent significant vision changes have occurred, or blood, exudate or subretinal fluid were noted on the fundus exam, ancillary including macular SD-OCT (both eyes) and Fluorescein angiogram (both eyes) with arterial phase of the eye of most concern.

Treatment options

1. If active choroidal neovascular membranes are found on exam and ancillary testing, treatment options (anti-VEGF-based therapies such as Lucentis, Macugen and Avastin) are discussed.

2. If intermediate AMD is determined in both eyes, or advanced AMD in one eye, treatment options include the AREDS vitamin supplements and the need to self-monitor their central vision for changes.


Confrontational visual field. The examiner will ask the patient to cover one eye and stare at the examiner. The examiner will then move her hand out of the patient's visual field and then bring it back in. The patient signals the examiner when her hand comes back into view. This is frequently done by an examiner as a simple and preliminary test.

Tonometry. Intraocular pressure (IOP) will be measured with the Tono-Pen XL in the central cornea in both primary gaze and upgaze.

Eye exam. After subjects will be dilated (mydriasis with one drop of each: 2.5% phenylepinephrin and 1% tropicamide to achieve at least 6 mm pupil diameters) and the back of the eye examined by slitlamp.

STRATUS OCT. OCT images will be acquired with a STRATUS-OCT imaging system. STRATUS OCT images will be obtained using the high-resolution "Radial Lines" protocol of six high-resolution B-scans (transverse resolution of 512 A-scans per B-scan) on a single StratusOCT machine (Carl Zeiss Meditec). Additionally, total retinal volume values as provided by the "Retinal Map Analysis" program of the Stratus software will be collected. Data will be analyzed qualitatively or based on the automated measurements provided by the StratusOCT software. CNV size is quantitatively measured, including the maximum CNV diameter as well as the maximum CNV thickness. Retinal structure was qualitatively judged as (1) wet, revealing unchanged fluid conditions; (2) dry, revealing no fluid; and (3) less edema, revealing incomplete fluid regression.

Fluorescein Angiography. The fluorescein angiogram contains stereoscopic views of 2 fields at specified times after injection. These fields include the macula (Field 2) and the disc field (Field 1M). Stereoscopic red-free photographs are taken of the macula prior to the injection of the fluorescein dye. Fluorescein is injected rapidly (less than 5 seconds) into either the anticubital or other convenient vein according to usual clinic procedures. Photographs taken at time zero and at the moment the injection is complete are taken as control photographs, to document the integrity of the interference filters and to document the rate of injection. Stereo pairs of Field 2 and then of Field 1M of the study eyes are then taken between minutes 1 and 3, followed by two additional pairs at 5 minutes and at 10 minutes.

Collection of plasma, genotyping and complement protein analysis. Whole blood will be collected into dipotassium ethylenediaminetetraacetic acid (EDTA) tubes resulting in a final EDTA concentration of 4.5 mM. Blood samples will be collected at the Ralph H Johnson VA Medical Center lab services. Plasma will be separated from whole blood by centrifugation (10 minutes at 3000 RPM) and frozen at -80 C until further use. We aim to have plasma processed within 3 hours from collection.

Subjects will be genotyped for signal nucleotide polymorphisms (SNPs) for I62V and Y402H using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA) as described in material and methods.

Complement pathway protein analysis will be performed by ELISA. ELISAs have been described in detail by our collaborator [63]; however, the protocol is described here in brief. Factor B will be quantified using a monoclonal capture antibody P21/15 which recognizes an epitope present on factor B and Ba and a biotinylated rabbit anti-Bb as a detection antibody. For measurement of Ba, plasma will be depleted of factor B using Biomag magnetic beads coupled to an anti-B/Bb antibody (mAb M13/12), followed by Ba quantification using an anti-B/Ba antibody (mAb P21/15) as a capture antibody and a biotinylated antibody specific for an epitope on B/Ba (mAb M20/6) as a detection antibody. Factor D will be measured by paired capture and detection antibodies (mAb D10/4 and biotinylated mAb I8/1) specific to factor D. The capture antibody used in the C3d assay (mAb I3/15) reacts with a neoepitope present on C3b, iC3b and C3dg and was used in combination with a biotinylated rabbit anti-C3d detection antibody for quantification of C3d. For all assays, incubation with the detection antibody will be followed by application of streptavidin-horseradish peroxidase conjugate. The substrate, 2 mM ABTS (2,2'-azino-di-(3-ethyl benzthiazolinesulfonate) in buffer containing 2.5 mM H2O2 will be added and absorbance at 410 nm (490 nm reference) will be read using a microplate photometer. All samples will be run in triplicate.

Assessment of Smoking status. Regular cigarette smoking will be assessed by a brief questionnaire administered by clinic staff, to determine whether the subject has ever smoked on a regular basis, whether he/she is a current smoker, and (for ever smokers) their pack-year history.

D) Outcome measures The incidence of AMD will be defined based on the published definition of the Rotterdam Study, a population-based prospective cohort study in Rotterdam, The Netherlands, in which 6780 out of a total population of 10,275 participants over 55 participated in the ophthalmic examination (van Leeuwen et al., 2003).

The fundus photographs will be graded with 12.5x magnification, according to the International Classification and Grading System for ARM and AMD (The International ARM Epidemiological Study Group, 1995). In this system, all ARM fundus signs within a standard circular area (diameter 6000 m) around the fovea are recorded. Graders, trained according to the Wisconsin ARM grading system will graded the photographs blinded to the patient information.

AMD will be defined as the presence of large ( 63 m), soft, distinct drusen with pigmentary irregularities, or indistinct ( 125 m) or reticular drusen, or atrophic or neovascular AMD. Atrophic AMD will be defined as any sharply demarcated round or oval area of apparent absence of the RPE, larger than 175 m, irrespective of distance from the foveola but within the grid, with visible choroidal vessels and no neovascular AMD. Neovascular AMD will be defined as the presence of a serous or hemorrhagic neuroretinal or RPE detachment, and/or a subretinal neovascular membrane, and/or a subretinal hemorrhage, and/or a periretinal fibrous scar. Lesions that were considered to be the result of generalized disease (see exclusion criteria) will be excluded from AMD diagnosis.

Additional outcome measures will help characterize the severity of the disease. In the visual field test, the loss of vision, which occurs predominantly in the central retina will be quantified. The choroidal and retinal vascular will be analyzed using fluorescein angiograms, which should reveal abnormal blood vessels and leakage in subjects with systemic vascular problems.

E) Data analysis Data assembled as normalized serum levels of complement factors Ba, C3d and fD levels will be initially evaluated with univariate statistics to assure that the quality of the data is adequate for further analyses. The association between each measured parameter (i.e., serum levels of complement factors), AMD diagnosis, and smoking will be assessed in a stratified bivariate fashion using t-tests or Wilcoxon rank sum tests, as appropriate, and standard measure assessments will be used to check for normality, skewing, etc.

Multivariable analyses will be conducted through the use of general linear mixed models [66]. The models will include random subject effects to account for dependence among subject's repeated measurements. This type of model is ideal when there are multiple measurements on subjects, such as when laboratory measurements are performed in triplicate. The dependent variables of interest will be the complement level measurements (log transformed if necessary), while independent variables will include AMD status (case / control), factor H genotype (CC, CT, TT), smoking (current, former, never), and an interaction term involving factor H genotype and smoking status. The interaction term will help us determine whether the impact of factor H genotype and smoking on serum complement levels is linear (additive), or non-linear (e.g. multiplicative). The model will also include adjustments for age, gender, and race, which may all affect serum complement factors. Thus any differences among haplotypes will be adjusted (corrected) for effects that may be attributed to age, gender, or race. Different correlation structures will be examined for the random subject effects, and we will use Akaike's Information Criterion to select the most appropriate model. Secondary analyses will involve excluding never smokers, so that we can assess the nature of the association (if any) between subjects' pack-year histories, their factor H genotypes, and their complement levels. An additional analysis (using conditional logistic regression) will be conducted to determine whether smoking interacts with a subject's factor H genotype with respect to the risk of AMD. Again, this model will adjust for age, gender, and race and the results will be expressed as odds ratios associated with the risk of AMD.

F) Predicted results and interpretation:

Published as well as data from our collaborator have provided ample evidence that AMD is correlated with increased serum levels of Ba, C3d and fD; whereas elevated levels Ba and C3d were documented in V62I subjects. We expect to confirm and extend the findings on I62V subjects and hope to identify a positive correlation between elevated levels of complement activation proteins and Y402H. Since smoke exposure has been shown to result in increased levels of alternative pathway activation [67], we predict that some components (i.e, C3d or Ba) might be further elevated in the factor H risk population that smokes.

D) Potential Risks Subjects will receive a comprehensive eye examination as part of this study. This examination will include visual inspection by a trained neuro-ophthamologist, assessment of visual acuity, SD-OCT, visual fields, and fluroscein angiography. The subjects and their physicians will be made aware of any identified abnormalities. The potential risk to subjects is relatively modest. All of the planned tests are identical to thoses tests routinely performed for purposes of diagnosing acquired macular degeneration (AMD) or other diseases of the eye. Such studies are performed routinely in outpatient settings by ophthamologists. In addition, information obtained from this study may provide an important link in understanding the pathogenesis of AMD, and its link with complement factor H haplotypes and smoking. Any relationship between the three could potentially lead to future therapies for this conditions.

Visual field tests - The risks include the following: fatigue of the neck; pain in the neck; pressure under the chin or sweating; photophobia; tearing. None of the above is a permanent or substantial loss. Change in position or rest will resolve the complication.

Tonometry - The risks include the following: Pressure under the chin; Fatigue; feeling of temporary pressure against your eye.

Eye examination with dilation - The risks include the following: fatigue of the neck; pain in the neck; pressure under the chin or sweating; photophobia; acute angle closure from the dilating drops; conjuctival injection (red eye from the drops- temporary); Impaired near vision for less than 24 hours - caused by the dilating drops; burning from the dilating drops lasting g less than 5 minutes; anesthesia of the eye for less than 2 hours.

STRATUS-OCT- The risks include the following: Photophobia; Pressure under the chin; Fatigue.

Fluorescein angiography - The risks include the following: pain from the needle stick; inflammation at the injection site; allergy to the dye (fluorescein); feeling of warmth or cold from the dye; infection at the needle stick site; anaphylactic reaction to the dye; nausea 20%- most common; vomiting 0-7%; headache; hypotension; convulsions; basilar artery ischemia, cardiac arrest, severe shock; thrombophlebitis at injection site.

Venipuncture - A small risk of pain or bruising at the site of the needle stick for the fluoroscein dye IV, but this is temporary. Some people may experience fainting or dizziness and there is also a slight risk of infection at the site of the needle stick. To minimize these risks, experienced medical personnel will perform the venipuncture procedures and sterile conditions will be maintained.

Collection of plasma - A small risk of pain or bruising at the site of the needle stick for the collection of blood, but this is temporary. Some people may experience fainting or dizziness and there is also a slight risk of infection at the site of the needle stick. To minimize these risks, experienced medical personnel will perform the venipuncture procedures and sterile conditions will be maintained.

Genetic risk: Research to identify genes that cause or contribute to a disease or trait is an increasingly important way to try to understand the role of genes in human disease. You have been given this consent form because the Ralph H. Johnson VA Medical Center investigators want to include your tissue, cell or blood sample in a research project, or because they want to save such biological samples for future research. There are several things you should know before allowing your tissues, cells or blood to be studied or to be stored.

1. Your tissue, cell or blood sample will be stored under your name or some other type of identifier which could be linked to you. Sometimes these samples are shared for research purposes with other investigators at other research sites. If this is done, the other investigators would not know your name.

2. In addition to your name, other information about you might be connected to your blood or tissue sample. For instance, information about race, ethnicity, sex, your medical history, and so forth might be available to investigators studying your tissue or blood. Such information is important for scientific reasons and sometimes for public health. It is possible that genetic information might come to be associated with your racial or ethnic group.

3. Genetic information about you will often apply (in one degree or another) to family members. It is not generally the Ralph H. Johnson VA Medical Center's policy to provide genetic information about you to your family members. However, certain studies, called "pedigree studies", share such information among family members. For this and related research you will be asked if you are willing to share your genetic information with your family members.

4, You have the right to refuse to allow your tissue or blood to be studied or saved for future research studies. You may withdraw from this study at any time and remove any samples that contain identifiers from research use after the date of your withdrawal. This means that while the University might retain the identified samples-the law often requires this-they would not be used for research.

5. South Carolina law, mandates that your genetic information obtained from any tests or from this research, be kept confidential. Our state law prohibits any insurer using this information in a discriminatory manner against you or any member of your family in issuing or renewing insurance coverage for you or your family. Our state law further prohibits our sharing your genetic information with anyone except in a few narrow circumstances, one of these being a research project of this type, approved by the Institutional Review Board and then we must take all steps to protect your identity. You will still be responsible for paying for health care, however. The Ralph H. Johnson VA Medical Center will not be responsible for such costs, even if care is needed for a condition revealed during research or clinical testing.

6. Genetic research raises difficult questions about informing you and other subjects of any results, or of future results. Some people feel anxious about the possibility of having a defective gene that would place them or their children at risk. Some people want to know what is found out about them; others do not. The risks of knowing include anxiety and other psychological distress. The risks of not knowing what is found include not being aware if there is treatment for the problem being studied. But these risks can change depending on whether there is a treatment or cure for a particular disease, and on how clear the results are. If there is a medical reason to seek specific information from you, your doctor will tell you this. A process called "genetic counseling" is often appropriate in such cases; you should ask your doctor or nurse about this if you have any questions.

Investigators in this study may try to recontact you in the future to find out about your health. If you are recontacted and want to know what the investigators have learned about your samples, you should understand that the following are the kinds of things the investigators or your health team might tell you:

1. Information is too sketchy to give you particular details, but you will receive a newsletter informing you about the results of the project.

2. You carry a gene for a particular disease that can be treated.

3. You can carry a gene for a particular disease for which there is no current treatment. This news might cause severe anxiety or other psychological distress, depending on the severity of the disease.

4. You carry a gene for a disease and might consider informing relatives that they, too, might carry the gene. It can be very difficult to decide whether to share such information with relatives. Genetic counselors can help sort out the various options in such a case.

Also, for any future research, we may contact you with a new consent form giving you additional information.

7. If you are concerned about a potential genetic disorder, you and your doctor might choose to test specifically for it. This would require additional blood or tissue samples and would not be part of this research project. You should discuss this option with your doctor or genetic counselor.

8. The presence of a genetic marker does not necessarily mean that an individual will develop a disease. Informing people of all such markers independently of medical need can cause unnecessary anxiety. On the other hand, the absence of a marker does not mean that someone will not get the disease. Genetic diseases appear as a result of a complex mixture of hereditary, environmental, behavioral and other factors.

These are the best-known risks and challenges of genetic research. There might be other risks we do not know about yet.

It is important that you talk to your doctor, nurse or genetic counselor if you have questions or concerns about the research study.

Unknown risks - The researchers will let the subject know if they learn of anything that might make the subject change their mind about participating in this study.

Study Design

Observational Model: Cohort, Time Perspective: Prospective


Macular Degeneration


Ralph H Johnson VA Medical Center, Charleston
South Carolina
United States


Not yet recruiting


Department of Veterans Affairs

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:14:00-0400

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