GENETIC MODIFIERS OF MENDELIAN DISEASES OF INTEREST TO NIDDK RELEASE DATE: November 19, 2002 RFA: DK-03-008 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( LETTER OF INTENT RECEIPT DATE: February 11, 2003 APPLICATION RECEIPT DATE: March 11, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The National Institute of Diabetes and Digestive and Kidney Diseases invites research applications to identify and characterize genetic modifiers for Mendelian diseases affecting organs and tissues within the mission of NIDDK. Striking variations are seen in clinical expression of genetic diseases, presumably due to differences in the genetic makeup and environmental exposure of the individual. Even though a mutation in a single gene may play a predominant role in the development of a Mendelian disorder, individuals with identical genotypes at that locus may display considerable variation in the prevalence, severity, and clinical symptoms of the disorder. To understand this variation and to exploit it as a target for therapy, it is important to identify genes or other factors that contribute to this variation. RESEARCH OBJECTIVES Background On September 9 and 10, 2002, NIDDK sponsored a meeting entitled, "Genetic Modifiers of Mendelian Diseases" highlighting progress toward the identification of modifier genes in diseases of interest to NIDDK. Investigators described approaches to identifying genetic modifiers and presented the clinical evidence for the presence of significant modifiers for several genetic diseases. Additional information on the presentations can be found in the abstracts at Many genetic diseases within the mission of NIDDK have evidence for clinically significant genetic modifiers. Some examples of these diseases are genetic metabolic diseases such as Gaucher disease, adrenoleukodystrophy and cystic fibrosis; genetic hematologic diseases such as thalassemia, sickle cell disease and hemochromatosis; genetic liver diseases such as alpha-1- antitrypsin deficiency and Wilson disease; genetic pancreatic diseases such as hereditary pancreatitis; and genetic kidney diseases such as polycystic kidney disease. A complete description of the diseases of interest to NIDDK can be found on the NIDDK Website ( several illustrative examples are included below. Hemochromatosis is a common, recessively inherited disease of iron overload. Increased iron storage, particularly in the liver, leads to the clinical sequelae of cirrhosis, diabetes and cardiomyopathy, but the iron accumulation and the associated clinical presentation can be highly variable, even within one family. Most patients with the disease have been shown to have mutations in the HFE gene with the predominant mutation being a missense mutation, C282Y. However, population studies have found that only a small percentage of those who are homozygous for this HFE mutation have clinical features of hemochromatosis. It appears most likely that other genetic factors are involved in modifying the expression of the gene, although some environmental factors may play a role. The obvious candidate genes are those encoding proteins known to be important in iron transport, but it is not known to what degree variations in the iron transport genes contribute to the clinical presentation of hemochromatosis and other iron disorders. Although several important genes of iron transport have been identified in recent years, there may be others not yet discovered that impact on the expression of hemochromatosis. Another explanation for diseases that appear to show reduced penetrance such as hemochromatosis and Gaucher disease, may be the presence of a genetic suppressor of the disease phenotype. This is an intriguing possibility since identification of a suppressor gene could lead to new targets for therapy. Cystic Fibrosis is one of the most common, life-limiting genetic diseases in children. The predominant mutation, deltaF508, results in the deletion of a single amino acid in the CFTR protein. Approximately 90% of CF patients carry at least one deltaF508 mutation. Despite the presence of a predominant mutation, there is a large variation in the clinical severity of this disease. Meconium ileus is a severe intestinal obstruction that occurs at birth in 15-20% of CF patients. In a CF mouse model, a modifier gene was detected on mouse chromosome 7 that contributed to fatal intestinal disease. In humans, there is strong evidence for a modifying locus linked to 19q13, syntenic to a region of mouse chromosome 7 which contains a modifier contributing to fatal intestinal disease. Candidate genes in this region are being studied to identify the gene or genes responsible for this phenotype. The identification of this modifier gene could lead to better understanding of the factors underlying the clinical heterogeneity in CF. Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian diseases in humans and a major cause of renal failure. ADPKD patients present with progressive, bilateral cysts in the kidney. Other common symptoms include hypertension, liver cysts and intracranial aneurysms. Symptoms commonly appear in midlife but have been known to occur in childhood. Modifier genes may contribute to the variable age of onset seen in this disease. Genetic modifiers for severity of the renal disease have been mapped in two animal models of PKD but have not been yet been studied in humans. Modifier genes have also been implicated in the occurrence of intracranial aneurysms, which are found in approximately 10% of patients with ADPKD. This complication has been shown to cluster in some PKD families. Alpha-1-antitrypsin (AAT) deficiency is a recessive genetic disease affecting both the lung and the liver. Alpha-1-antitrypsin is a protease inhibitor made by the liver and by alveolar macrophages. Deficiency of this enzyme produces obstructive lung disease and liver fibrosis. The lung disease is caused by destruction of lung tissue by proteases such as elastase that are released by macrophages but not properly inactivated when AAT is absent. The liver disease, in contrast, seems to be caused by aggregation of the defective alpha-1-antitrypsin protein in the endoplasmic reticulum of the hepatocytes. Since the pathophysiology is different for the lung disease and the liver disease, not all mutations of AAT lead to both problems. Approximately 17% of patients homozygous for the common Pi*Z mutation have liver disease. This observation suggests that a genetic modifier may contribute to the liver disease phenotype. Many of the examples cited above have organ-specific phenotypes such as meconium ileus in CF, aneurysm in ADPKD and liver disease in AAT that seem to be influenced by genetic modifiers. Since the organ-specific phenotypes occur in a significant proportion of the patient population, the genetic modifiers for these phenotypes must be fairly common in the general population. These modifiers may also contribute to other genetic diseases or complex disease conditions affecting the same organ. Identification of organ-specific modifier genes may lead to an understanding of genetic risks for other more common conditions and provide new targets for the development of diagnostic tests and therapeutics. Scope This initiative is soliciting research grant applications to identify modifier genes responsible for variation in the clinical presentation of genetic Mendelian diseases affecting organs and tissues of interest to NIDDK. Approaches to characterize putative modifier genes could include studying either physiological or positional candidate genes as well as the development of analytical and computational tools to systematically investigate the genetic and physiologic control of relevant traits and diseases. Following the identification of the modifier gene, these studies should characterize the allelic variants of these gene(s), and determine which variants are responsible for the phenotypic variation. Mouse models of genetic diseases provide a powerful tool to demonstrate the effect of modifier genes. By breeding the main genetic defect onto different background strains of mice, the severity of the phenotype of the genetic disease can be altered. This approach has been used to identify regions that may contain genetic modifiers. This approach will become more powerful as the DNA sequences of different inbred mouse strains become available for analysis. In addition, random mutagenesis could be used to screen for genetic modifiers in mouse strains bearing a disease-predisposing mutation. Other model systems such as Drosophila and zebrafish have been used to screen for modifier genes for particular phenotypes. These models could be developed to screen for modifier genes that contribute to human genetic diseases. These models are ideal for identifying pathways that influence a phenotype generating candidates for modifier genes. Careful phenotyping of patient populations can also lead to the identification of genetic modifiers. For these studies, the applicants must be able to demonstrate the availability of well-characterized patient populations in which the variation can be evaluated. In order to be able to accurately phenotype individuals as well as carry out the genetic analysis each project should include effort for individuals who have clinical experience in the disease as well as individuals with experience in genotyping and statistical genetics. Genotype/phenotype studies may be performed to reveal the degree to which disease severity can be attributed to allelic differences or gene environment interactions. The following examples, while not an exhaustive list, are relevant to the goals of this initiative: o Studies in animal models of Mendelian diseases to identify genetic modifiers of disease loci o Developing sensitized mutagenesis screens to search for mutations that modify the disease phenotype o Using model systems to identify interacting pathways or networks to use as candidate genes for the identification of modifier genes o Studies in human populations, including twin or family studies, to identify aspects of a disease phenotype that are inherited independently of the disease gene mutation o Studies in human population that use genome-wide screening techniques, such as SNP typing and microarray technology, to identify regions, genes or pathways involved in development of the clinical variation o Studies in humans and animals demonstrating the presence of an independently inherited suppressor of the disease phenotype o Studies of genes involved in regulating cellular processes such as DNA transcription, RNA processing, protein modification, protein folding, trafficking to the membrane, and RNA and protein degradation as likely candidates for genetic modifiers of diseases o The development of analytical and computational tools as well as public databases to integrate information on genetic variability and to systematically investigate the genetic and physiologic control of relevant traits and diseases on genetically defined populations. MECHANISM OF SUPPORT This RFA will use NIH regular research grant (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE The NIDDK intends to commit approximately $3,000,000 in FY 2003 to fund 6 to 8 grant applications in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $500,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues: o Direct your questions about scientific/research issues to: Catherine McKeon. Ph.D. Senior Advisor for Genetic Research Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm.6103 Bethesda, MD 20892-5460 Telephone: (301) 594-8810 FAX: (301) 480-3503 Email: o Direct your questions about financial or grants management matters to: Kathleen Shino Supervisory Grants Management Specialist Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm.708 Bethesda, MD 20892-5452 Telephone: (301) 594-8869 FAX: (301) 480-3504 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Catherine McKeon. Ph.D. Senior Advisor for Genetic Research Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm.6103 Bethesda, MD 20892-5460 Telephone: (301) 594-8810 FAX: (301) 480-3503 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and five signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK Staff. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIH in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Diabetes, Digestive and Kidney Diseases Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 11, 2003 Application Receipt Date: March 11, 2003 Peer Review Date: July 2003 Council Review: September 24-25,2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.849, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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