Pilot Study to Evaluate the Contribution of Gene Variants to Idiopathic Urolithiasis
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Nephrology, Nephrology |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/17/2018 |
| Start Date: | December 2009 |
| End Date: | December 2018 |
Recent investigations from this group have identified that genetic variants of genes
associated with monogenic forms of nephrolithiasis are expressed in idiopathic calcium
oxalate kidney stone patients and could influence stone forming risk. Utilizing patient
samples from the Mayo Clinic Florida Kidney Stone Registry, we will demonstrate that
expression of these heterozygous mutations in idiopathic nephrolithiasis act as genetic
modifiers of disease presentation increasing risk of kidney stone formation. Complimented by
the analysis of environmental and lifestyle risk factors, these studies will define
environmental and genetic susceptibility factors involved in kidney stone formation and
reoccurrence.
associated with monogenic forms of nephrolithiasis are expressed in idiopathic calcium
oxalate kidney stone patients and could influence stone forming risk. Utilizing patient
samples from the Mayo Clinic Florida Kidney Stone Registry, we will demonstrate that
expression of these heterozygous mutations in idiopathic nephrolithiasis act as genetic
modifiers of disease presentation increasing risk of kidney stone formation. Complimented by
the analysis of environmental and lifestyle risk factors, these studies will define
environmental and genetic susceptibility factors involved in kidney stone formation and
reoccurrence.
Nephrolithiasis occurs in approximately 1 in 10 individuals in the United States with
increasing prevalence noted over the past three decades (ref: Worcester E, Coe F.
Nephrolithiasis. Prim Care Clin Office Pract 35 (2008) 369-391). Recurrence is common -
occurring in more than 50% of these patients, many of whom require surgical intervention. An
estimated 5-6 billion dollars a year is spent on the treatment of kidney stones. Symptoms of
kidney stones include flank pain, blood in the urine, and nausea and vomiting. Beyond acute
attacks associated with considerable morbidity and cost, recent reports have identified an
association between kidney stone formation and an increased risk for the development of
hypertension, chronic kidney disease, end stage renal disease and myocardial infarction.
Therefore, nephrolithiasis not only impacts socioeconomics but also has broader public health
implications. Genetic and environmental risk factors have both been linked to nephrolithiasis
with about 40% of the patients presenting with kidney stones having at least one relative who
is also a stone former. Genetic variants that are causative of monogenic forms of
nephrolithiasis have been well defined. However the frequency of these monogenic mutations
and their presence as predisposing factors of disease is poorly understood within the
idiopathic stone forming population.
We recently identified that heterozygous mutations of HOGA1, a gene that is associated with
the onset of primary hyperoxularia Type III, are also present within the idiopathic stone
forming population and absent in matched controls. These findings suggest that the presence
of these mutations could be indicative of an increased risk for kidney stone formation within
these patients. We therefore propose to; Aim 1: Validate and expand our previous studies to
define that genetic variations of HOGA1 are a predisposing factor for idiopathic
calcium-oxalate stone formation, and Aim 2: Mutational analysis of genes involved in kidney
stone formation for determination of genetics of risk. These clinical studies will identify
the frequency of known genetic variants associated with monogenic forms of nephrolithiasis
within idiopathic stone forming populations and associate their presence with heightened
risk. Patient genomic DNA, blood, clinical data and risk data are available from the Mayo
Clinic Florida Kidney Stone Registry. Genomic DNA and RNA will be assessed for mutations
within HOGA1 and their significance as predisposing factors for disease evaluated through
statistical analysis and compared to environmental factors for risk. Evaluations will also be
undertaken in control patient samples, identifying that these mutations are specific for
idiopathic kidney stone formation risk. Furthermore, genetic variants within AGXT, GRHPR,
HOGA1, CLCN5, OCRL1, SLC3A1, SLC7A9, and APRT will be analyzed for frequency in idiopathic
nephrolithiasis patients and control patient populations to determine their role as
predictive genetic markers for idiopathic disease risk.
This proposed study has the potential to identify genetic variants that are predisposing
factors for idiopathic kidney stone formation and are predictive of disease risk. These
studies have relevance to personalized treatment regimens for disease intervention and
targeted prevention of reoccurrence. Furthermore, the knowledge gained pertaining to genetic
variants in idiopathic stone formers may lead to the creation of genetic tests for the early
diagnosis of those patients at higher risk of idiopathic nephrolithiasis.
Nine hundred idiopathic kidney stone formers and 900 non-kidney stone forming controls will
be examined for the evaluation of HOGA1 genetic variants. We propose to use the patient
resources provided by the Kidney Stone Registry and control samples from the Mayo Clinic
BioBank in Florida. Briefly, for the Kidney Stone Registry, all cases presenting with kidney
stones are invited to enroll in the Registry. Enrolled patients are approached for data
abstraction, risk factor questionnaire completion, biospecimen collection (blood and DNA) and
long-term follow-up. At this time we have over 1500 phenotypically well characterized
patients enrolled within the registry with approximately 500 new patient enrollments each
year. For these studies, we will only utilize samples and patient histories from idiopathic
calcium oxalate stone formers and controls. The PI of this application oversees the running
of this registry. Controls will be selected from patients who have consented genomic DNA
samples to the Mayo Clinic Biobank (http://mayoresearch.mayo.edu/mayo/research/biobank/).
These controls are defined as patients who have a negative personal history of symptomatic
urolithiasis and no family history of kidney stone formation. Dr. Parker oversees the running
of the Mayo Clinic BioBank in Florida. Patient records and information will only be available
to the PI, co-investigator and biostatistician named on this proposal. Phenotypical Analysis:
Phenotype data will be extracted from patient's medical records. All patients provide
informed consent to DNA testing and record review under research protocols approved by the
Mayo Clinic Institutional Review Board. Risk Factor Data Collection: A self-administered
questionnaire is provided to each patient on their initial visit by the practitioner, is
provided within the Appendix. Those patients that have consented to be enrolled in the Kidney
Stone Registry and consented to be included in this study will be our case study group. The
questionnaire requests patients to provide information pertaining to family history,
lifestyle and environmental risk factors for kidney stone formation. All questionnaires are
reviewed by the study coordinator for completeness and accuracy of responses.
increasing prevalence noted over the past three decades (ref: Worcester E, Coe F.
Nephrolithiasis. Prim Care Clin Office Pract 35 (2008) 369-391). Recurrence is common -
occurring in more than 50% of these patients, many of whom require surgical intervention. An
estimated 5-6 billion dollars a year is spent on the treatment of kidney stones. Symptoms of
kidney stones include flank pain, blood in the urine, and nausea and vomiting. Beyond acute
attacks associated with considerable morbidity and cost, recent reports have identified an
association between kidney stone formation and an increased risk for the development of
hypertension, chronic kidney disease, end stage renal disease and myocardial infarction.
Therefore, nephrolithiasis not only impacts socioeconomics but also has broader public health
implications. Genetic and environmental risk factors have both been linked to nephrolithiasis
with about 40% of the patients presenting with kidney stones having at least one relative who
is also a stone former. Genetic variants that are causative of monogenic forms of
nephrolithiasis have been well defined. However the frequency of these monogenic mutations
and their presence as predisposing factors of disease is poorly understood within the
idiopathic stone forming population.
We recently identified that heterozygous mutations of HOGA1, a gene that is associated with
the onset of primary hyperoxularia Type III, are also present within the idiopathic stone
forming population and absent in matched controls. These findings suggest that the presence
of these mutations could be indicative of an increased risk for kidney stone formation within
these patients. We therefore propose to; Aim 1: Validate and expand our previous studies to
define that genetic variations of HOGA1 are a predisposing factor for idiopathic
calcium-oxalate stone formation, and Aim 2: Mutational analysis of genes involved in kidney
stone formation for determination of genetics of risk. These clinical studies will identify
the frequency of known genetic variants associated with monogenic forms of nephrolithiasis
within idiopathic stone forming populations and associate their presence with heightened
risk. Patient genomic DNA, blood, clinical data and risk data are available from the Mayo
Clinic Florida Kidney Stone Registry. Genomic DNA and RNA will be assessed for mutations
within HOGA1 and their significance as predisposing factors for disease evaluated through
statistical analysis and compared to environmental factors for risk. Evaluations will also be
undertaken in control patient samples, identifying that these mutations are specific for
idiopathic kidney stone formation risk. Furthermore, genetic variants within AGXT, GRHPR,
HOGA1, CLCN5, OCRL1, SLC3A1, SLC7A9, and APRT will be analyzed for frequency in idiopathic
nephrolithiasis patients and control patient populations to determine their role as
predictive genetic markers for idiopathic disease risk.
This proposed study has the potential to identify genetic variants that are predisposing
factors for idiopathic kidney stone formation and are predictive of disease risk. These
studies have relevance to personalized treatment regimens for disease intervention and
targeted prevention of reoccurrence. Furthermore, the knowledge gained pertaining to genetic
variants in idiopathic stone formers may lead to the creation of genetic tests for the early
diagnosis of those patients at higher risk of idiopathic nephrolithiasis.
Nine hundred idiopathic kidney stone formers and 900 non-kidney stone forming controls will
be examined for the evaluation of HOGA1 genetic variants. We propose to use the patient
resources provided by the Kidney Stone Registry and control samples from the Mayo Clinic
BioBank in Florida. Briefly, for the Kidney Stone Registry, all cases presenting with kidney
stones are invited to enroll in the Registry. Enrolled patients are approached for data
abstraction, risk factor questionnaire completion, biospecimen collection (blood and DNA) and
long-term follow-up. At this time we have over 1500 phenotypically well characterized
patients enrolled within the registry with approximately 500 new patient enrollments each
year. For these studies, we will only utilize samples and patient histories from idiopathic
calcium oxalate stone formers and controls. The PI of this application oversees the running
of this registry. Controls will be selected from patients who have consented genomic DNA
samples to the Mayo Clinic Biobank (http://mayoresearch.mayo.edu/mayo/research/biobank/).
These controls are defined as patients who have a negative personal history of symptomatic
urolithiasis and no family history of kidney stone formation. Dr. Parker oversees the running
of the Mayo Clinic BioBank in Florida. Patient records and information will only be available
to the PI, co-investigator and biostatistician named on this proposal. Phenotypical Analysis:
Phenotype data will be extracted from patient's medical records. All patients provide
informed consent to DNA testing and record review under research protocols approved by the
Mayo Clinic Institutional Review Board. Risk Factor Data Collection: A self-administered
questionnaire is provided to each patient on their initial visit by the practitioner, is
provided within the Appendix. Those patients that have consented to be enrolled in the Kidney
Stone Registry and consented to be included in this study will be our case study group. The
questionnaire requests patients to provide information pertaining to family history,
lifestyle and environmental risk factors for kidney stone formation. All questionnaires are
reviewed by the study coordinator for completeness and accuracy of responses.
Inclusion Criteria:
Cases:
- History of calcium oxalate stones
- 18 years of age or older
- Willing to provide a blood sample, and questionnaire
Controls:
- 18 years of age or older
- No personal history of urolithiasis
- Willing to provide a blood sample and questionnaire
Exclusion Criteria:
Cases:
- Secondary causes of urolithiasis including: Bowel disease, Renal tubular acidosis,
hyperparathyroidism
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