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Other Studies

Principal Investigator: Lisa Cannon-Albright, PhD

Investigators are seeking to understand several disorders through the examination of a number of large health databases. The conditions being reviewed for genetic predisposition include the following.

    It is reasonable to hypothesize heritable predispositions in biochemical response or metabolic pathways underlie an individual’s response to, or sensitivity to, pain. For example, clinical investigations have shown that chronic pain patients may have lower-than-normal levels of endorphins in their spinal fluid. Mendelian Inheritance in Man lists over 100 entries for heritable conditions involving chronic pain, suggesting that some individual differences in pain response or sensitivity have an inherited component; but the genetics of common chronic pain is not well understood.

    The UPDB, with linked University of Utah Hospital and Clinic diagnosis data, provides the opportunity to study the familial nature of chronic pain. Analysis of this Utah resource will enable us to determine whether a genetic component seems evident, and to further identify the resources necessary for identification of predisposition loci.

    Approximately 20% of all breast cancer cases exhibit familial aggregation. Of these, an estimated 20-25% of cases are attributable primarily to a highly penetrant, single inherited mutation in a predisposing gene such as BRCAI or BRCA2; for this study we term these "Major Gene" cancers. The remaining inherited breast cancer cases most likely include the interactions of many low penetrant genes, which we will term "Polygenic" breast cancers. Genes in the DNA repair pathway are strong potential breast cancer susceptibility genes because if DNA damage is not repaired properly, genetic instability results, which in turn may increase the rate of cancer development.

    In this study, we will focus on the following genes in the DNA repair pathway:

    • ATM
    • MREllA
    • XRCC4
    • BRCAl
    • BRCA2
    • NBSl
    • RAD50
    • LIG4

    Association/Linkage Disequilibrium (LD) based techniques for genetic analysis offer a powerful tool for detecting small effect genes. One of these tools is the Transmission/Disequilibrium Test (TDT), and has been used in fine-mapping and identifying small effect genes in complex traits. The TDT is robust to population structure and admixture, which can be problematic in standard case-control designs. The Utah resource has not been used extensively for association studies, since pedigree-based association methods have not previously been available. We, and others, have begun to develop such techniques.

    Our objective is to use the Utah breast cancer resource, including both Major Gene and Polygenic disease, to begin dissecting the genetic contribution of the small effect genes in the DNA repair pathway genes with heritable breast cancer. We plan to develop a pedigree-based TDT methodology, which we will then apply to the breast cancer data set to test for associations with the DNA repair pathway.

    It is known that genes play a role in the risk of breast cancer. The identification of two high-risk breast cancer genes (BRCA1 and BRCA2) has made considerable impact on diagnosis and treatment strategies. However, BRCA1/2 genes are rare and only account for a small percentage of all breast cancer cases.

    The current thinking is that other genes involved in breast cancer risk are common with low risk. However, if an individual has many of these low-risk genes malfunctioning, together they produce a high risk. It has been suggested that the discovery of these common, low-risk genes would provide significant improvements in intervention and prevention. Identifying these genes is, therefore, very valuable. The challenge is to isolate those genes from the total of ~30,000 that exist in humans. A promising route is to study genes based on what is already known about their particular purpose. For example, apoptosis genes transmit signals to cells telling them to die when they stop working properly. Without apoptosis, faulty cells are not managed, and tumors can develop. Apoptosis genes have only just begun to be studied in breast cancer and already show promise of being useful. It has recently been shown that a SNP in the apoptosis gene, CASP8, is associated with breast cancer risk.

    The aim of this project is to test the hypothesis that CASP8 and other genes of the apoptosis pathway act as low penetrance breast cancer genes. Understanding the role of apoptosis genes in breast cancer will help us understand susceptibility and characteristics of, and survival from, the disease.

    The identification of two high-risk breast cancer genes (BRCA1 and BRCA2) has made considerable impact on diagnosis and treatment strategies of breast cancer. However, mutations in BRCA1/2 account for only a small percentage of all breast cancer cases. Discovery of further risk genes have the potential to provide further and significant improvements in intervention and prevention. Identifying these other genetic risk variants is, therefore, very valuable.

    There is strong evidence that the genetic variants to be identified will include both additional rare risk variants likely to confer high risk and common risk variants likely to confer low risk. Different genetic epidemiology study designs and analysis techniques will be required to identify these different types of underlying risk variants.

    Heterogeneity is a major issue that hinders genetic epidemiologic research. In breast cancer, many levels of heterogeneity exist, including clinical, molecular and genetic. Study designs that address these sources of heterogeneity will have more power to identify risk variants and move breast cancer genetic research forward more quickly.

    This research will utilize multiple, large, existing collections of biospecimens/genetic databases, together with the unique and powerful resource of the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). These will be used to design and perform powerful genetic epidemiologic analyses to identify genetic risk variants for breast cancer.

    Diabetes mellitus includes a number of metabolic diseases that result in hyperglycemia.

    As a consequence of hyperglycemia and other genetic factors, individuals with diabetes of any cause are at risk for micro- and macrovascular complications. Type I diabetes is insulin-dependent. The more prevalent, later-onset form of diabetes that results from a combination of insulin resistance and defective insulin secretion is called Type 2 Diabetes.

    Diabetes is a diverse disease with variable presentation, variable prevalence in different populations and variable degrees of insulin deficiency and impaired insulin action. The genetic basis for the disease will likely show similar diversity.

    Most pituitary tumors are non cancerous, non spreading tumors; malignant pituitary gland tumors are rare. The cause of pituitary tumors remains unknown. Pituitary tumors can occur at any age, but are most likely in older people. Individuals with a family history of multiple endocrine neoplasia type 1 (MEN 1) have an increased risk of pituitary tumors, but this heritable disorder is responsible for only a minority of pituitary tumors.

    The primary aim of this research is to explore the familial/genetic contribution to pituitary tumors using the Utah population-based resource.

    Individuals with Down's syndrome (DS) have been reported to have unique cancer profile compared to the general population, even after taking into account issues of survival and aging.

    Children with DS have a 10- to 20-fold increased risk of leukemia that tends to have an earlier age at onset compared to non-DS children, and they specifically have an increased risk of acute megakaryoblastic leukemia. However, researchers in Denmark have reported that both children and adults with DS have a reduced risk for developing solid tumors. For example, breast cancer is almost absent, and the risk of a second malignant disease after treatment for leukemia also appears to be decreased.

    Little is known about the cancer incidence or mortality patterns of individuals with DS in Utah or about the cancer profile in their relatives. Individuals with DS and their relatives may provide clues about the etiology of solid tumor cancers that are highly prevalent in the general population. Furthermore, study of individuals with DS and their relatives may cast additional light on the specific cancers that afflict individuals with DS.

    The purpose of this project is to study cancer incidence and mortality patterns in individuals with DS in Utah and their relatives. We will identify familial/genetic contributions to, or protection from, specific cancers among these individuals. We will compare our findings to other published cancer incidence and mortality reports for DS subjects and their families.

    Auditory Processing Disorder (APD) is a diagnosis used to describe someone with “normal hearing” but poor performance in one or more of the following skills (Moore 2006, 2007).

    We hypothesize that the underlying defect in APD is an auditory variation on a general disorganization of forebrain systems, arising from mutations in genes affecting brain development that confers susceptibility to the constellation of developmental learning and language disorders. Thus, these other diagnoses are sometimes misapplied to an individual with APD, or could be alternative manifestations of the same underlying cause. Multiple brain regions and mechanisms are now known to affect the recognition and processing of sounds (Banai and Kraus, 2007) so that the identification of the best phenotype(s) for classifying individuals with APD and identifying high-risk families remains an important challenge in the field (Moore, 2007).

    It is reasonable to hypothesize heritable predispositions in brain structure or function underlying individual patients’ ability to process sound. Family clustering has been reported, but the genetics of auditory processing are not well understood. Auditory processing refers to what happens when the brain recognizes and interprets sound. Auditory Processing Disorder (APD) indicates that something is adversely affecting the processing or the interpretation of sound. Multiple different mechanisms could be postulated to affect the recognition and processing of sounds, and it is likely that multiple genes contribute, and that there is variability in the expression of the underlying genetic defect in different individuals.

    Asthma is a reversible obstructive respiratory disease, in which the hereditary component has been widely demonstrated by familial and identical twin studies. Asthma has been estimated to afflict between 1 and 7% of the general population; it causes morbidity in about 6% of the population and, occasionally mortality. Asthma has an enormous economic impact on society.

    Utah is an excellent place for genetic studies of asthma. The Utah population is appropriate for inferences about disease in populations of Northern European descent and has been widely studied because of its unique lifestyle characteristics (Lyon et al., 1977, 1980).

    The primary aim of this study is to define the familial/genetic contribution to asthma. We will use the Utah Population Database (UPDB) and the University of Utah Health Sciences Center (UUHSC) data warehouse to study asthma morbidity.

    Endometrial cancer is the most common gynecologic malignancy among U.S. women, with 39,080 new cases and 7,400 deaths in the United States projected for 2007 (American Cancer Society, 2007). There are several known risk factors for the disease, including obesity, estrogen replacement therapy, and low parity. These risk factors relate to unopposed estrogen stimulation of the endometrium and are common and multifactorial, limiting their clinical usefulness for screening and prevention.The primary aim of this research study is to define the familial/genetic contribution to endometrial cancer.

    Although there are recognized environmental risk factors for pancreatic cancer, the most significant risk factors are genetic. About 10% of cases aggregate in families.

    Some rare syndromes have known mutations associated with pancreatic cancer. Germline mutations of BRCA1, BRCA2 and p16 are associated with pancreatic cancer. Mutation carriers with hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis (FAP) have about a 5% lifetime risk of pancreatic cancer. These rare syndromes are unlikely to account for all familial clustering of pancreatic cancer.

    The Utah population has proven valuable to the study of many common cancers, and to the isolation of multiple cancer predisposition genes. Several Utah studies have included investigation of pancreas cancer familiality (Cannon et al., 1982; Cannon-Albright et al., 1994; Goldgar et al., 1994; Kerber and O’Brien (2005). We propose a specific analysis of familiality for pancreas cancer and associated cancers in the UPDB to define the familial/genetic contribution to pancreas cancer.

    In addition to studying the familiality of pancreatic cancer, these data also provide a valuate resource for the development and validation of pancreatic cancer risk assessment tools. There is a growing need for accurate risk assessment tools in order to appropriately identify high risk patients for research studies and due to the growing demand for clinical genetic services by families concerned about their risk for pancreatic cancer. PancPro is a recently developed pancreas cancer risk assessment model developed by Johns Hopkins Medical Center (Wang et al., 2007). This model uses Bayesian theory to adjust the probability an individual has inherited a pancreatic cancer susceptibility allele assuming Mendelian inheritance patterns.

    In addition to studying the familiality of pancreatic cancer, we will also use these data to conduct validation analysis of the PancPro model.

    Although age, pathogenesis and severity of disease, drug interaction, nutritional status, renal and liver function, and co-morbid conditions can lead to individual variations in medication response, inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy may have an even greater influence on the efficacy and toxicity of medications. Genetic polymorphisms in drug metabolizing enzymes, transporters, receptors and other drug targets have been linked to individual differences in efficacy and toxicity of medications. An understanding of the genetic role of variable drug response will have significant clinical implications for treatments for all disease. Polymorphisms or mutations in drug metabolizing enzymes can lead to acute toxic responses, drug to drug interaction, or therapeutic failure.

    Although population level association studies have identified effects for some common polymorphisms in drug metabolizing enzymes, the familial or heritable nature of such effects is not well investigated.

    Using the unique Utah genealogy resource, we previously provided an initial description of the familial nature of cancer (Hill et a11980; Cannon et al, 1982; Cannon-Albright et aI. 1994). We propose to similarly use the Utah genealogy resource to provide description of the familial nature of medication response. We hypothesize that, in addition to the known metabolizing gene polymorphism associations recognized to be responsible for such differences, there may also exist as yet undefined loci responsible for more penetrant, heritable differences observed in medication response. We propose to perform a population-based study of the familiality of medication response in an effort to identify evidence for such loci, and to identify pedigree resources useful in future localization of such loci.

    One of the first steps in understanding the genetics of medication response is to define its familial nature. This has not been accomplished, nor will it prove as easy as defining the familial nature of disease. There will be no evident phenotype in the absence of medication use, so a study of distant relationships is necessary to identify genetic patterns. Confounding of diagnosis and treatment (e.g. medication) in relatives will be a significant issue.

    We will utilize Intermountain Healthcare computerized diagnosis and medication records to identify patients of interest, and we will look for evidence of familiality of medication response. This resource will allow us to recognize medication response phenotypes in close and distant relatives (something which cannot be achieved by clinicians or in "family" studies), and will allow for a comparison with controls selected from the same genealogy.

    The phenotypes of interest in this study are adverse drug events (ADEs). Using the Intermountain Healthcare computerized medication data, we will identify individuals who have confirmed ADEs. We hypothesize that we will observe an excess of familiality among individuals in some ADE categories (by medication or type of ADE) due to heritable predispositions to medication response. This research will allow us to define the familial nature of medication response, and to identify the specific Utah resources available for localization and isolation of the responsible predisposition genes.

    Although a familial component to brain tumors, primarily gliomas, has been examined multiple times in the literature, the genetics underlying these observations remains poorly defined. Of the approximately 5% of gliomas thought to be hereditary 1,2, the majority are associated with known neoplastic syndromes. The incidence of brain tumors, specifically glioma, which are “hereditary” but not associated with one of these well-described inherited syndromes, is less clear.

    The primary aim of this proposal is to continue to explore the familial/genetic contribution to brain tumors using the Utah population-based resource. We will specifically explore the association of non-brain cancers with brain tumors in close and distant relatives.

    Peripartum cardiomyopathy (PPCM) is a rare disease with significant morbidity and mortality. Strictly-defined PPCM is the onset of heart failure secondary to decreased left ventricular systolic function (ejection fraction <45%) without other etiology in the month prior to, or within 5 months of, delivery (Demakis 1971). In the United States, it affects women in approximately 1/3,500 pregnancies resulting in live births (Sliwa 2006). Prior studies have been largely descriptive, focusing on the identification of prognostic and risk factors for the development of PPCM. However, the underlying etiology of PPCM remains unclear. Proposed etiologies include autoimmune dysfunction, or the effect of a viral antigen trigger (Bultmann 2007).

    A genetic-link to PPCM has also been postulated. Case reports of immediate family members affected by PPCM have been published including several mother-daughter pairs (Fett 2002, Voss 1984, and Pearl 1995). Pierce et al (1963) reported that 3 of 17 patients in his cohort of women with heart failure within 120 days of delivery had a family history of other women with “postpartum heart failure”. Additionally, a clustering of PPCM cases in certain populations, namely Haitian women, has raised questions regarding a potential genetic predisposition (Fett 2002). However, no studies have been performed to elucidate any specific mode of inheritance, or attempt to generate a population-based risk to relative of affected family members. Pearl et al did suggest that there may be value in assessing cardiac function in relatives of women with PPCM prior to pregnancy; however, this has not been widely adopted by the obstetrical community.

    Our objective is to define the heritable nature of Peripartum Cardiomyopathy (PPCM) and hypertensive disorders of pregnancy.

    Ewing's sarcoma is a highly malignant tumor of children and young adults. The pelvis is the most common location, followed by the femur, tibia, humerus, and scapula. However, Ewing’s sarcoma can involve the muscle and the soft tissues around the tumor site as well. Ewing's sarcoma cells can also spread (metastasize) to other areas of the body including the bone marrow, lungs, kidneys, heart, adrenal gland, and other soft tissues.

    Ewing's sarcoma accounts for about 2 to 3 percent of childhood cancers. About 250 children and adolescents are diagnosed with Ewing sarcoma each year in the US. It is the second most common malignant bone tumor in children and adolescents. Ninety percent of cases occur in patients between 5 and 25 years of age. After age 25, it is exceptionally rare. Approximately 10% of patients are older than 20 years when they are diagnosed. Boys and young men are affected more frequently than girls and young women. Males also do less well than females.

    The first aim of this research is to define the familial/genetic contribution to sarcomas; the second aim is to begin molecular analysis of sarcoma patients in Utah.

    Systemic Autoimmune Rheumatic Diseases (SARDs) have been suggested to affect cancer risk. We will explore the association of cancer of defined types with systemic autoimmune rheumatic diseases.

    Diagnoses of SARDs to be considered include:

    • rheumatoid arthritis
    • systemic lupus erythematosus
    • Sjogren’s syndrome
    • systemic sclerosis
    • dermatomyositis
    • polymyositis
    • Eosinophilia myalgia syndrome
    • unspecified connective tissue disease

    In 2006, Bernatsky et al reviewed malignancy and autoimmunity and concluded that continued studies were necessary given the potential impact of increased understanding for both cancer and autoimmune disease (Bernatsky et al., 2006). Leandro and Isenberg (2001) and Carsons (1997) published similar reviews reaching the same conclusions. Gadalla SM et al., 2009 report on an investigation of breast cancer risk associated with SARDS in a population-based case-control study using SEER Medicare-linked data from 1993-2002 and concluded that systemic inflammation may affect breast epithelial neoplasia. Bernatsky et al., 2003 suggested that the risk of breast cancer in an SLE cohort (n=583) was not completely explained by traditional factors found in the GAIL breast cancer model.

    The "Gail model" is a breast cancer risk assessment tool named after Dr. Mitchell Gail, Senior Investigator in the Biostatistics Branch of NCI's Division of Cancer Epidemiology and Genetics. The model uses a woman's own personal medical history (number of previous breast biopsies and the presence of atypical hyperplasia in any previous breast biopsy specimen), her own reproductive history (age at the start of menstruation and age at the first live birth of a child), and the history of breast cancer among her first-degree relatives (mother, sisters, daughters) to estimate her risk of developing invasive breast cancer over specific periods of time.

    Our objective is to define the association of cancer with systemic autoimmune rheumatic diseases (SARDs). Other cancers will be considered as the research progresses, but we will begin with an investigation of breast cancer, as it is widely reported to be associated with SARDs.

    Food allergy, defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food, is emerging as a major clinical and public health problem worldwide. It affects approximately 5-8% of children and 1-5% of adults. Many studies have estimated increasing prevalence rates of food allergies over time (Jarvis et al., 2005, Grundy et al., 2002).

    Despite the risk of severe allergic reactions and even death, there is no current treatment except specific food avoidance and treatment of the symptoms associated with a severe reaction.

    Food allergies broadly encompass IgE mediated or non-IgE mediated reactions. Some cases of food allergies are strongly associated with certain other allergic diseases such as asthma and atopic dermatitis.

    Our current understanding of the biological etiology of food allergies is limited. It is generally believed that food allergies are caused by a combination of both environmental and genetic factors. While family history has previously been shown to be a strong predictor of food allergies, these observations have all been limited to studies of nuclear families. Within a nuclear family is difficult to differentiate between shared genetic factors and shared environmental factors.

    There are no published genome-wide association studies (GWAS) studies for food allergies to date. As can be seen, the genetics of food allergies is very much in its infancy. The long-term objective of this project is to define the familial/genetic contribution to food allergies and to identify and understand predisposition genes for this disease.

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