Genetics and Disease Prevention: Complementary or Contradictory?

Article Outline

• Abstract
• Introduction
  • Genome-Wide Association Studies (GWAS)
• Current Applications
  • Family History
  • Cancer
  • Pharmacogenomics
  • Lifestyle
    • Hypertension
    • Obesity
  • Birth Defects
    • Neural Tube Defects and Folic Acid
    • Congenital Cardiac and Maternal Glucose
    • Orofacial Clefts and Maternal Smoking
    • Asthma and Maternal Grandmother Smoking Behaviors
  • Newborn Screening
  • Prenatal Testing
• Future Applications
  • Gene Therapy
  • Information Technology
  • Epigenetics
  • Metagenomics
• References
• Copyright

Abstract 

Clinicians may feel that nothing can be done to change genes, so prevention in a genetic context seems ridiculous. The reality is that genetic preventive healthcare has been a part of clinical practice for years and that future applications are almost limitless. It will soon be possible to sequence an individual's genome, scan it for important gene variations, and create an individualized health plan to modify the effects of these variations, optimizing that individual's health over a lifetime. This article presents an overview of selected clinical disorders, describes ways in which genetics is already being used to improve clinical outcomes, and offers a glimpse into the future of personalized medicine.

Keywords:  disease prevention , epigenetics , family history , genetics , health promotion , human genome , metagenomics , pharmacogenomics

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Introduction 

The completion of the human genome in April 2003 was such an important accomplishment that it was number 1 on the list of the 10 most important medical advances in the first decade of the 21st century.¹ This simple “codebook” opened the door into a future that offers unimaginable opportunities for advances in medical science and clinical care. Although most clinicians appreciate the accomplishment and believe that genomics may change clinical practice in the future, many believe these changes will come so slowly that they will be retired before they will be expected to provide genomic healthcare themselves. Many do not realize that they have been providing a version of genomic healthcare all along.

Environment and lifestyle behaviors are known to influence health outcomes, but risk counseling must be done “generically” at this time, because individual vulnerabilities are unknown. Dr Collins, the director of the National Institutes of Health (NIH), predicts that within the next 5 years it will be financially feasible to sequence everyone's genome.² When that occurs, the era of personalized genomics and individualized risk assessment will begin. Scientists around the globe are moving in that direction through the haplotype map (HapMap) project³ and genome-wide association studies (GWAS).

Genome-Wide Association Studies (GWAS) 

The International HapMap³ is a global catalog of common human genetic variants. The catalog contains a description of each variant, identifies where that variant occurs in human DNA, and describes how the variant is distributed across and within different populations. The HapMap is not intended to identify variants associated with disease; it is a genetic databank that allows scientists to examine relationships between genetic differences and diseases. Researchers use this HapMap database to search for genetic patterns across thousands of human genomes.⁴ The resulting GWAS are rapidly linking genetic markers with human traits (blood pressure) and/or the presence or absence of disease. As GWAS connect genomic information to clinical features, scientists learn more about basic biological processes and are better able to predict disease, develop new treatments, and ultimately move healthcare toward the promise of personalized medicine.

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Current Applications 

The leading causes of death in the United States⁵ (Table 1) are tightly linked to the Healthy People 2010 leading health indicators (Table 2),⁶ and virtually every element on the two lists links to genetics in ways that are just now becoming understood. As researchers isolate the genes responsible for regulating biologic pathways, new drugs and therapies will be developed to modulate gene behavior and improve human health. In the near future, it may be possible to quickly scan an individual's genome, identify gene variants that may contribute to disease, and develop an individualized plan to optimize that individual's health. Personalized medicine accomplishes many of the over aching goals of health promotion. Genetic knowledge can empower people to organize, prioritize, and act on health issues,⁷ to prevent or delay the onset of disease.⁸ This article presents a broad overview of some of the ways genetics is currently being used to promote wellness and prevent disease and offers a glimpse into the future of personalized medicine.

Table 1. Leading Causes of Death in the United States, 2006

Table 2. Healthy People 2010 Leading Indicators

Family History 

The first step to helping someone improve his or her health is to understand what an individual's environmental and inherited risks are. A detailed family history provides insight into both, because genetic as well as shared environmental and behavioral risks are revealed. Although clinicians commonly ask about family history, many providers structure the discussion around a select list of disorders, typically, hypertension, heart disease, cancer, and diabetes, limiting the usefulness of the tool. Nongenetics providers rarely gather detailed information about other close relatives or develop a third-generation pedigree. There are very practical reasons for this omission, detailed in an Agency for Healthcare Research and Quality (AHRQ) report published in September 2009.⁹, ¹⁰ The report found that significant system barriers to collecting and interpreting a detailed family history, exist, particularly in primary care settings. When a detailed family history was collected, improvements in healthy behaviors were noted, perhaps because seeing familial disease patterns encouraged individuals to make needed lifestyle changes.

In 2005, the American Academy of Family Physicians devoted an entire year to genetics education with the goal of developing tools and providing education to help family practice physicians develop additional skills in the area of genetics.¹¹ As a part of this effort, they developed two mnemonics to help clinicians quickly assess patient risk.¹¹ The first, SCREEN (some concern; reproduction; early disease/death/disability; ethnicity; and nongenetic or not necessarily genetic), is intended to be integrated into a complete history and physical or used to quickly elicit concerns and/or risk factors regarding a patient's family history. The second mnemonic, family GENES (family history [multiple affected siblings or individuals in multiple generations]; groups of congenital anomalies; extreme or exceptional presentation of common conditions; neurodevelopmental delay or degeneration; extreme or exceptional pathology; and surprising laboratory values) addresses some of the important primary care red-flag categories. These two mnemonics help clinicians identify high-risk patients and families so that appropriate screening and management can be implemented.

Cancer 

Cancer is estimated to cause nearly one-fourth of all deaths in the United States,⁴, ¹² and the probability of developing an invasive cancer varies with age and gender. Although the incidence of childhood cancer has risen slightly since 1975, mortality has declined almost 3% per year between 1975 and 1997.¹² Young women (<40 years old) are at greater risk for developing an invasive cancer than young men (1:48 vs. 1:70), but that pattern reverses with advancing age. The American Cancer Society estimated that in 2009, nearly 50% of men and 30% of women over the age of 70 will develop an invasive cancer.¹²

Cancer develops when cells lose their ability to self-regulate and begin to divide unrelentingly, piling up on top of one another. If the cells remain attached to the main tumor mass, the tumor is considered benign, and when cells are capable of invading other body structures, the tumor is considered cancerous. If it is capable of spreading to far distant organs, it has become metastatic. Even benign tumors can cause significant morbidity and mortality depending on their location.

When tumors develop, something has gone wrong with the genes responsible for controlling cellular division. This loss of cellular control is caused either by mutations in genes that promote cell division (oncogenes) or in genes that normally repress cell division (tumor suppressor genes).

Cancer is recognized as a genetic disease, regardless of the type of cancer, the gender of the individual, or the age at which the cancer occurs. Several distinct patterns point to a genetic cause for cancer. First, when cancer cells divide, all daughter cells are cancerous; second, viruses are known to induce tumors; third, chemicals and radiation are known mutagens; fourth, certain cancers clearly run in families; and fifth, specific chromosomal abnormalities are associated with leukemia and lymphoma.¹³

In the context of this article, cancer prevention is focused primarily on adults. Childhood cancers are still genetic, but they more commonly result from mutations that are inherited or acquired at conception, in utero, or very early in life, offering few opportunities to intervene. Most cancers develop later in life as metabolic activities and environmental exposures accumulate.¹³ The American Cancer Society and a number of other professional organizations have published cancer screening guidelines to identify cancer early in people at population (or average) risk.¹² Earlier screening should be offered to people identified (usually through family history) to be at increased risk.

Screening timelines vary by disease. People at population risk for colorectal cancer, screening should begin at age 50¹²; whereas cervical cancer screening begins many years earlier. The recommendations are different because the genetics of the two diseases are different; cervical cancer is caused by the interaction of human papilloma virus (HPV) genes with cervical epithelial cells, while nonsyndromic colorectal cancers are caused by the accumulation of genetic mutations described above. The HPV vaccine is an example of a primary prevention strategy, and colorectal cancer screening in the general population is an example of secondary prevention.

Genetic information is rapidly changing the face of cancer care, making therapies more effective or less toxic depending on the cancer and the treatment. Two examples of tumor profiling in breast cancer care are provided here, but many other important changes in cancer care are emerging as a direct result of improved understanding of genetics and biochemical pathways.

Breast and prostate cancers are common cancers that typically arise in later adulthood. They are often caused by mutations that respond predictably to radiation and chemotherapy. One of the first clinically significant tumor mutations was the human epidermal growth factor receptor 2 (HER2) gene, which is responsible for cell growth and repair. Normal breast tissue has two copies of the HER2 gene, but approximately 15% to 20% of breast cancers develop a third copy of the HER2 gene, increasing the growth rate of these tumors. Screening breast tumors for a HER2 mutation is now standard practice because these tumors respond better to trastuzumab (Herceptin) chemotherapy.¹⁴

The Oncotype DX test (Genomic Health, Inc., Redwood City, CA), developed in 2004, has been used to screen over 65,000 women with breast cancer for specific tumor mutations. Oncotype DX screens for 21 specific gene mutations, 16 of which are known to influence chemotherapy response and disease recurrence. These results are used along with individual risk factors (age, tumor size, node involvement, estrogen receptor/progestin receptor activity, and HER2 receptor activity) to assist clinicians in deciding whether to add chemotherapy, with its attendant risks, to the treatment plan.¹⁵

Pharmacogenomics 

Drug metabolism is orchestrated by complex interactions between dozens of different genes, and prior to the completion of the human genome, it was impossible to predict a person's response to a particular drug. Scientists are making great strides in understanding drug response and are exploring new ways to predict whether a patient will respond well, respond poorly, or will not respond at all to a given drug.

Pharmacogenomics offers the promise of better, safer drugs, more accurate dosing, advanced disease screening, better vaccines, and reduced cost.¹⁶ Two examples of current uses of pharmacogenomics principles are discussed here, both of which offer a glimpse into the future of personalized medicine.

Warfarin is the classic example of a drug with a narrow therapeutic index; if dosage is too little, clots form; if dosage is too much, serious bleeding can occur. Predicting a warfarin starting dose based on age and height only “gets it right” about 15% of the time, but dosing accuracy improves by over 50% if genetic testing is done to evaluate the characteristics of two specific alleles.¹⁷ Some of the wide clinical variability appears to be linked to genetic polymorphisms affecting a pharmacokinetic (CYP450) pathway and a pharmacodynamic (vitamin K epoxide reductase complex 1) pathway.¹⁸ These two genetic tests are believed to be so useful that the US Food and Drug Administration has suggested that genetic testing be done prior to starting warfarin.¹⁹

Genetic testing is now routine prior to starting treatment with mercaptopurine⁴ because 1 in 300 people in the general population carries a mutation in the gene encoding an enzyme (thiopurine methyltransferase [TPMT]) required to break down mercaptopurine. People with a TPMT mutation eventually metabolize mercaptopurine, but they do it very slowly, putting them at risk for lethal drug toxicity. Because mercaptopurine is used to treat a number of different clinical conditions, including acute lymphocytic leukemia, TPMT mutation testing is routinely carried out prior to starting mercaptopurine therapy. If an individual has a TPMT mutation, mercaptopurine is prescribed at a much lower dose, and patients are monitored closely for side effects.

Lifestyle 

Factors like sedentary lifestyle, obesity, substance abuse, smoking, and risky sexual behaviors have long been known to adversely impact health. But the biologic processes involved in these adverse health outcomes are complex, interwoven, and poorly understood. The ability to combine family history, genetic information, and clinical manifestations is slowly beginning to reveal the impact of lifestyle on genes and ultimately on human health.

Hypertension is very common and often poorly controlled, and blood pressure regulation is highly complex, involving multiple genes and environmental risk factors. In a recent publication from the ongoing Heart Strong Family Study,²⁰ cigarette smoking, alcohol consumption, and lack of exercise all influenced blood pressure through significant gene-by-environment (GxE) interactions. Cigarette smoke and lack of exercise interacted with genes influencing diastolic blood pressure, and alcohol intake influenced genes regulating both diastolic and systolic blood pressure. As data from large population based studies like this one continue to emerge, the physiologic basis for hypertension will become clearer, which will improve screening and treatment options.

Obesity is one of the most difficult and pervasive preventable diseases facing patients, clinicians, and the healthcare system. As the numbers of overweight and obese people have skyrocketed, research efforts have intensified to find the causes and develop effective treatments for this disease. The basic problem appears simple: people take in more calories than they expend, and it appears to be primarily an environmental problem, particularly since the epidemic so closely correlates with access to inexpensive, calorie-dense food.²¹ That is not to say that genetics do not play a role. Single-gene obesity disorders like Prader-Willi syndrome exist, but they account for a small number (5%) of the obesity cases worldwide. Using data from global GWAS, scientists have isolated several genes that appear to predispose people to obesity. As of June 2009, a total of 17 autosomal obesity genes had been identified, but these alleles appear to account for only 2% of the differences in body mass index.²¹ Although this area of investigation is in its infancy, greater understanding of metabolic pathways involved in energy storage increases the number of therapeutic targets.

Birth Defects 

Like cancer, most birth defects are the result of a genetic failure at a specific point along the developmental continuum. Unlike cancer mutations, which are often caused by a loss or gain in function of a single gene, most congenital defects are the result of multiple GxE interactions, making individual disease genes difficult to isolate.²² In this section, the GxE interactions for four common birth defects will be reviewed.

After heart defects, nonsyndromic neural tube defects (NTD) are the most common birth defects in the United States, occurring in approximately 1 of 1,000 births. Genetic factors have long been suspected because the prevalence of NTD varies with gender and ethnicity, increases with parental consanguinity, and demonstrates familial inheritance patterns. Nutritional deficiencies in general are associated with adverse birth outcomes.²³ One of the first reports of the association between nutritional status and neural tube defect was described by an 18th century Dutch midwife. She noted that when crop yields were low, more infants were born with NTD, and she also found that poor inner city families were more likely to have infants with NTD.²³ Similar patterns were noted during the Second World War and after Jamaican food crops were destroyed by a hurricane.

Folic acid is a water-soluble B vitamin that plays an active role in many interconnected metabolic pathways, directly or indirectly effecting cell function, division, and differentiation. For this reason, folic acid requirements increase 5- to 10-fold during pregnancy and adequate levels are particularly important during embryogenesis. Folic acid is widely available in the diet but is lost during cooking, and some common drugs, including oral contraceptives, interfere with its absorption and metabolism.

NTD develop between the third and fourth gestational weeks as specialized embryonic cells begin to fuse and curl, eventually rolling into a tube. Although folic acid deficiency is not the only cause of NTD, it is a significant environmental risk factor because it acts as a substrate for enzymes involved in DNA synthesis. Known genetic causes for NTD include trisomies 13 and 18, as well as genes associated with maternal folic acid metabolism and transport and fetal folic acid metabolism. Fetal folic acid gene mutations appear to increase an infant's risk for developing an NTD in the presence of low folic acid levels.²² Although the underlying mechanisms have still not been completely worked out, folic acid supplementation has been shown to reduce the incidence of NTD by more than 50%.²⁴

Babies born to mothers with elevated serum glucose levels are at increased risk for a number of healthcare problems. Their risk for congenital anomaly is three-fold higher than infants born to mothers with normal blood glucose levels,²⁵ and the risks increase as the maternal blood glucose level rises. Although the malformation rate of infants born to women with type 1 diabetes is significantly higher than for the general population (9.5% vs 5.7%),²⁶ babies born to mothers with type 2 and gestational diabetes face increased risks as well. Risks include cardiac and skeletal deformities; macrosomia, or intrauterine growth restriction; complicated delivery, hypoglycemia, neonatal jaundice, respiratory distress syndrome, and fetal demise.

Recent studies have shown that other healthcare risks may emerge throughout life as well. Children born to mothers with gestational diabetes have significantly higher blood pressure and lower high-density lipoprotein cholesterol persisting into adulthood. Elevated umbilical cord insulin levels at birth have also been associated with abnormal glucose tolerance in later life.²⁷ Although the genetics are far from being completely understood, most of the suspected genes are thought to be involved in maternal regulation of metabolic fuel.²⁸ High maternal glucose levels may alter genes regulating cell growth or may increase oxidative stress, which damages the developing embryo. In the animal model, the use of antioxidants in pregnant diabetic mothers has been shown to decrease diabetic embryopathy.²⁸ The impact of the obesity epidemic appears to extend across multiple generations, and the message to both patients and providers is that genes do not belong solely to the individual in which they currently reside. Helping women control their blood glucose when they are pregnant can prevent significant harm to generations of individuals.

Nonsyndromic fetal cleft lip and/or palate (CL/P) appears to be strongly associated with both genetic vulnerabilities and environmental insults, and maternal smoking is very much associated with an increased risk for CL/P.²² Several putative genes have been examined. In one study, maternal smoking doubled the risk for developing CL/P, but infants who carried a transforming growth factor a mutation had a six-fold increase in risk for CL/P if their mothers smoked.²² In another study, infants with at least one copy of a nitric oxide synthase 3 gene variant, who were born to mothers who smoked and did not take vitamin supplements, had a 4.4-fold increased risk for CL/P. It appears that in genes carrying CL/P mutations, several GxE factors influence risk, which demonstrates the complexity of the developmental processes and highlights the challenges facing researchers.²²

Clinicians have long advised patients with asthma to stop smoking because of the known association between smoking and worsening asthma symptoms. Passive exposure to tobacco smoke has been shown to promote the development of asthma in children and can cause persistent wheezing,²⁹ even in nonsmokers. More recent research reveals that maternal exposure to passive smoking can impact future generations as well. Children whose mothers smoked during pregnancy are 1.5 times more likely to develop asthma than children whose mothers did not smoke; stunningly, that risk was almost twice as high if the maternal grandmothers smoked. Children whose grandmothers smoked were more than 2.1 times more likely to develop asthma than children whose grandmothers did not smoke.³⁰ This increased risk persisted even if the child's mother never smoked. If both mother and grandmother smoked during their pregnancies, grandchildren were more than 2.5 times more likely to develop asthma. This is perhaps one of the clearest examples of a GxE effect. Those authors postulate that smoking damages fetal mitochondrial DNA and, if this occurs to a female fetus, that the damage extends to the mitochondrial DNA stored in the brand new eggs settling into her ovaries.³⁰

Newborn Screening 

Nowhere is the application of genetics in primary care more evident than in the area of newborn screening. In 2010, over 4 million American infants will be screened for genetic and other congenital disorders.³¹ These genetic tests offer early identification of newborns with inherited metabolic, endocrine, hemoglobin, infectious, hearing, and other asymptomatic disorders. Phenylketonuria (PKU) is perhaps the disorder most people associate with newborn screening. If an infant is born with mutations in both of the phenylalanine hydroxylase genes, he will be unable to metabolize phenylalanine, a common byproduct of protein (including milk) ingestion. Babies with PKU deficiency rapidly develop irreversible brain damage unless their diet is modified to exclude foods containing phenylalanine. Newborn screening identifies these infants early enough to intervene with dietary modification, a clear example of primary prevention.

Newborn screening policies in the United States are quickly becoming more uniform, but differences still remain in the number and types of disorders tested for in each state. State-directed consent, state policies, and educational materials vary between states as well, so providers at the point of care must understand newborn screening and genetic testing issues in general and their individual state policies in particular if they are to actively engage in a dialogue about newborn screening with patients, colleagues, and state legislators. Clinicians must also know where to turn for information if an infant receives abnormal screening results. Because these disorders are rare, locating accurate clinical information can be challenging. The best current resources are the Newborn Screening ACT sheets, developed by the American Board of Medical Genetics and published on the National Newborn Screening and Genetics Resource Center (http://www.acmg.net/resources/policies/ACT/condition-analyte-links.htm). ACT sheets are designed to be helpful to nongenetics providers. They provide succinct, clinically helpful information (differential diagnoses, condition description, and action steps) and management algorithms as well.

Prenatal Testing 

Prenatal testing began in the late 1970s, when high levels of a serum marker called maternal serum alpha fetoprotein (MSAFP) were found to be associated with NTD. A short time later, an association between low MSAFP levels and trisomy 21 was reported, and over the past 2 decades, three other serum markers have been added to the screening panel, significantly increasing the detection rates for fetuses who may have chromosomal or structural anomalies. These serum markers also help to identify pregnancies that may become complicated by fetal growth restriction, fetal demise, preeclampsia, or abnormal plecentation. Parallel, complementary advances in ultrasound technologies have further increased fetal anomaly detection rates. Simply adding a genetic ultrasound to a quad-serum screen increases the trisomy 21 detection rate to approximately 90%.³² If a genetic disorder is suspected, further testing using chorionic villus sampling or amniocentesis can be performed to verify the diagnosis.

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Future Applications 

Genetic applications in healthcare are virtually limitless. A brief description of some possible future applications are discussed below.

Gene Therapy 

Over the past two decades, gene therapy has come into and fallen out of favor as a promising treatment for “fixing” defective genes. Several gene therapy techniques have been developed, but none has yet been shown to be completely effective or reliable, and little progress has been made since the first gene therapy clinical trials began in 1990. Several significant barriers to the use of gene therapy will have to be overcome before this therapy will be clinically useful. For more information, please refer to http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml.

Information Technology 

The amount of information contained within a single human genome is overwhelming. Four simple amino acids (A, C, T and G), form the “letters” of our genome, but the spelling is highly complex and small differences (e.g., A substituting for a C) can make a big difference in clinical presentation. The human genome contains approximately 30,000 genes composed of 3.1 billion base pairs. Using GWAS, scientists are beginning to learn which spelling errors are clinically important for various diseases; sometimes the difference between health and disease manifestations is a single base pair. Soon it may become financially feasible to replace newborn screening with whole genome mapping; when that happens, computers will be needed to efficiently scan the genome for significant mutations. Electronic health records are not yet ready for this challenge, but in the near future, it may become possible to link pertinent family history with genomic information.

Researchers and information technology experts are working toward a future where computers interact with clinicians in real time to assist with diagnostic decisions. During a patient encounter in the future, a pop-up window might appear suggesting that this patient may be clinically symptomatic for hereditary hemochromatosis based on clinical features and a background scan of the patient's genome. HFE mutations are common, particularly in Caucasians, and people who inherit two copies (homozygous) of the gene are at increased risk for developing iron overload and liver failure. Many homozygous individuals will never develop clinical symptoms,³³ so treatment is based upon manifestations and serum transferrin saturation levels. The computer would reveal the link between the subtle clinical features and genetic predisposition and suggest appropriate confirmatory testing and provide links to additional information.

Epigenetics 

Epigenetics literally means “above genetics,” and is commonly defined as inherited changes in appearance or gene expression that are not caused by changes in DNA sequences.³⁴ In a study described by Rachel Saslow in the Washington Post,³⁵ two mice with identical DNA were born to two different mothers. In adulthood, one mouse had brown fur and was normal weight, and the other had yellow fur, was obese, and was predisposed to developing diabetes and cancer. Why the difference? During the pregnancy, researchers supplemented the thin brown mouse's mother's diet with folic acid, vitamin B₁₂ and other nutrients. The obese yellow mouse's mother did not receive these supplements, and the agouti gene, which drives appetite, remained turned on. These supplements did not directly affect the agouti gene; they regulated a group of molecules sitting on top of the DNA that told the agouti gene whether to turn on or turn off. These epigenomic “on/off” instructions are usually operationalized by methylating the DNA, and making the base pairs impossible to “read”; the genetic code is still present, still has normal spelling, but is inaccessible.

Epigenetics has long been known to regulate DNA at specific points in development (in utero and in infancy and puberty), but methylation has not been thought to function outside those time windows. More recently, researchers have begun to examine the role of the epigenome in diseases emerging in midlife. In 2008, the National Institutes of Health awarded grant funding in excess of $190 million to study the role of the epigenome across a wide range of disorders, including cancer, Alzheimer's disease, autism, bipolar disorder, schizophrenia, asthma, kidney disease, glaucoma, muscular dystrophy, and more conditions.³⁵

Metagenomics 

Our gastrointestinal (GI) tract is home to microbial communities containing more than 100 times more DNA than the DNA we have in our own genome. Most of these microbial communities are helpful; they protect us from overgrowth of more aggressive organisms, they help us digest food, and they synthesize essential amino acids and vitamins. More than 70 divisions of bacteria and 13 types of archaebacteria have been isolated in humans, but over 99% of the organisms residing in our gut can be classified into one of two bacterial groups: the Bacteroidetes and the Firmicutes.³⁶

The genetics of GI flora may seem to be more intellectually interesting than clinically important, but it appears that these microbial communities may play a significant role in the human obesity epidemic. In recent studies, human obesity seems to be related to alterations in the relative abundance of the Bacteroidetes and Firmicutes groups. When obese people lost weight, the total numbers of Bacteroidetes in their guts increased, and that increase was significantly correlated with weight loss, not caloric intake. It appears that obese individuals may have an “obese microbiome.” They harbor organisms that are more efficient at extracting nutrients from food transiting through the GI tract than other people do. The microbiome also appears to be transmissible. If mice with sterile GI tracts are colonized with “obese microbiota,” they will gain weight much more rapidly than mice colonized with a “lean microbiota.”³⁷ Human families share genetics, but they also share dietary patterns and their GI metagenomes. Newborns are born with sterile guts, but over time, they acquire intestinal organisms from their environment, shifting numbers and types of organisms across their lifetime.

The obesity epidemic is perhaps one of the best and most convoluted examples of a GxE interaction. Individuals may be born with genes that predispose them to or protect them from obesity; they may harbor microbial DNA that absorb more or fewer nutrients from food transiting through their GI tract; their epigenome may have been altered during fetal life, and they learn dietary habits and food preferences from their families.

Genetics has been a part of clinical practice for many years, disguised as “family history taking,” and more recently, some clinicians have actively engaged in genetic healthcare through their management of patients with abnormal newborn screen results or ordering and interpreting prenatal tests. Since the completion of the human genome project, our understanding of the biologic underpinnings of human disease has exploded. As the cost of sequencing the human genome plummets, finding the connections between the basic building blocks of inheritance and environmental exposures will finally be possible at the level of the patient and personalized healthcare will become a reality. Nurse practitioners are perfectly positioned in the healthcare system to assist in this transition, because prevention has been at the heart of nursing for over 150 years.³⁸ This article presents a very cursory overview of how genetic knowledge is currently being used to reduce disease risk and offers a glimpse of the future of healthcare.

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