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)
(www.niddk.nih.gov)
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
http://www.niddk.nih.gov/fund/other/genetic/gmmt/abstract-book.pdf
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 (http://www.niddk.nih.gov/fund/fund.htm#1)and
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
https://grants.nih.gov/grants/funding/modular/modular.htm). 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: cm67w@nih.gov
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: ks48e@nih.gov
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: cm67w@nih.gov
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
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
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
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step
guidance for preparing modular grants. Additional information on modular
grants is available at
https://grants.nih.gov/grants/funding/modular/modular.htm.
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:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
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: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
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
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
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
https://grants.nih.gov/grants/funding/children/children.htm.
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
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
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
http://www.health.gov/healthypeople.
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
https://grants.nih.gov/grants/policy/policy.htm 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.