Cystic Fibrosis Genetic Risk Determination

Cystic Fibrosis Genetic Risk Determination

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Let's say Jane has Cystic Fibrosis and we know her brother doesn't. What are the chances of her brother's future child having CF? (The chances of Cystic Fibrosis in the general population can be taken as 1 in 25)

My apologies for the very incomplete question, this was all I could remember of the actual question. And the solution went like something along the lines of:

Possibility of Jane's brother's partner having CF: 1 in 25

Possibility of Jane's brother being a carrier: 2 in 3

And this is the part that I am not getting. For me, Jane's brother could only have a 1 in 2 chance of being a carrier (Cc or CC). But the solution went CC, Cc or cC-- this last one, cC, how is that possible? If it's a recessive trait, do we not write the dominant one first? Then how could there be cC and Cc as two separate possibilities?

And this is the part that I am not getting. For me, Jane's brother could only have a 1 in 2 chance of being a carrier (Cc or CC).

Wrong, because those are not equally likely.

There are 4 equally likely possibilities for any of Jane's siblings:

inherit good allele from Mom, good from Dad,

inherit bad allele from Mom, good from Dad,

inherit good allele from Mom, bad from Dad,

inherit bad allele from Mom, bad from Dad.

We know that the last is not the case for the brother. The first 3 are still equally likely. And in 2/3, brother is a carrier.

Let me elaborate on swbarnes2's answer.

The “Possibility of Jane's brother being a carrier” is indeed the trickiest part of the overall question. I have seen that even some teachers of genetics were puzzled when seeing the correct answer (2/3).

It is true that before the brother is born the probability of he being Cc is given by the standard Mendelian rule, which states, for a Cc x Cc mating, ¼ of the offspring will be CC, ¼ cc, and ½ Cc.

But that answer ignores the fact that the brother is already born and (presumably) has an age by which all cc homozygotes have been recognized. Then, we know that he is not cc and can only be CC or Cc, whose probabilities sum up to ¾. It follows that he is Cc with probability ½ / ¾ = 2/3.

This kind of problems are generally tackled by using the Bayes theorem, which is a way to transform a prior probability into a posterior probability. In this case, we know that the prior probability, Pr(Cc), of the brother being a carrier is 50%, and want to calculate the posterior probability, Pr(Cc | not-cc), which is the probability that he is a carrier given that he is not affected. The Bayesian rule has the general form

Pr(A|B) = Pr (B|A) x Pr(A)/P(B),

which in our case reads

Pr(Cc|not-cc) = Pr(not-cc|Cc) x Pr(Cc)/Pr(not-cc).

As the first factor in this equation equals 1 (it is certain that a subject is not cc if he is Cc), it easy to see that the solution corresponds to the above, perhaps more intuitive, calculation. In more complex situations (consider for example if Jane's brother is young, and a certain proportion of cc subjects are diagnosed only late in life) the Bayes rule is useful, as it help decomposing the problem.

Cystic Fibrosis


Cystic fibrosis (CF) is a single gene recessive disorder that affects ∼70,000 individuals worldwide. Median survival for individuals with CF has progressively increased to over 40 years for an affected child born in the United States. Affected individuals manifest disease in the lungs, pancreas, intestine, male reproductive tract, and sweat gland. CF transmembrane conductance regulator (CFTR), the dysfunctional protein in CF, conducts chloride across the apical membranes of polarized epithelia. Loss of CFTR function affects the transport of chloride, sodium, and water across epithelial tissues, leading to inadequate hydration of mucous secretions. Obstruction of luminal space in airways and secretory ducts follows, and recurrent cycles of inflammation and fibrosis ultimately destroy affected organs. Disease of the exocrine pancreas leads to malabsorption and an abnormal nutritional status in most individuals with CF. Lung disease is the cause of death in almost 90% of individuals. A minor fraction of individuals with CF (∼10%) manifest disease in a subset of the aforementioned organ systems and are termed nonclassic CF.

Over 2000 disease-associated variants have been reported in the CFTR gene, although one variant, F508del, accounts for approximately 70% of CF alleles worldwide. The F508del variant causes misfolding of CFTR that leads to intracellular degradation and loss of functional product. The functional consequences of only a minor fraction of the remaining variants have been evaluated. The commonness of F508del homozygosity among individuals with individuals with CF (approximately 50%) creates a reference population for analyzing the phenotypic consequences of variability in CFTR genotype. CFTR genotype correlates with several key features of CF including sweat chloride concentration, severity of pancreatic exocrine disease, and variation in severity of lung disease. Genetic modifiers that influence severity of lung disease and risk for complications such as diabetes, intestinal obstruction, and liver disease have been identified. There are rare cases of genetic heterogeneity in cases of nonclassic CF.

Diagnosis of CF is based on clinical features and demonstration of elevated concentrations of chloride in sweat. Variant analysis of CFTR and evaluation of ion transport in nasal epithelium can aid in diagnosis. Variants in CFTR can cause congenital bilateral absence of the vas deferens (CBAVD obstructive male infertility) or pancreatitis and can be a risk factor for bronchiectasis and chronic rhinosinusitis. Newborn screening for CF is now widespread in North America, Europe, and Australasia. Population screening for CF carriers has been in effect in the United States and regions of Europe for 2 decades. Molecular-based therapies that augment function of defective forms of CFTR have produced substantial clinical improvements for a subset of individuals with CF. Efforts are underway to extend CFTR-targeted treatment to all individuals with CF.

Cystic Fibrosis Among Asians: Why Ethnicity-Based Genetic Testing is Obsolete

A hypothetical heterosexual couple living in the US or UK takes tests to learn if they are carriers of the more prevalent recessive diseases. They&rsquore relieved to find out that cystic fibrosis (CF) isn&rsquot something they need worry about passing to their children &ndash neither has any of the few dozen mutations the test panel includes.

The couple do not carry the most common 32, 106, or even 139 disease-causing mutations in the CFTR gene, the number depending upon the testing lab. But that could be a problem &ndash a false negative &ndash if the woman and man are anything other than non-Hispanic whites.

More than 2,000 variants (alleles) of CFTR are known, and their prevalence varies in different populations. That&rsquos not because DNA recognizes the race or nationality of the person whose cells it&rsquos in, but because of how we choose our partners.

For people of Asian ancestry, the available CF test panels are pretty much useless, according to an article (&ldquoEthnicity impacts the cystic fibrosis diagnosis: A note of caution&rdquo) and an accompanying editorial (&ldquoDon&rsquot judge a book by its cover: the emerging challenge of diagnosing CF in non-Caucasians&rdquo), in the latest issue of the Journal of Cystic Fibrosis (both unfortunately behind a paywall).

Barbara Bosch, from the University Hospitals Leuven in Belgium and colleagues, compared CF symptoms among 234 Asians represented in the international CFTR2 database to 53 patients in the UK CF database.

CF affects more than the respiratory system.

In European whites, CF tends to cause lung congestion (often with Pseudomonas aeruginosa infection), pancreatic insufficiency, salty sweat, and likely one or two copies of the mutation F508del, which deletes one of the protein&rsquos 1480 amino acids. Asians had been thought to have more severe lung disease than the classic European cases, but it turns out that they have poorer lung function overall, making CF seem worse. Asians also have less salty sweat, much better pancreatic function, and fewer cases of CF-associated male infertility. It isn&rsquot surprising that CF cases among Asians can be missed or misdiagnosed.

The most important distinction between European white and Asian populations, for treatment purposes, is the CFTR mutations. While 73% of people recognized to have CF worldwide have at least one copy of F508del and 70% of Europeans with CF have two copies, the mutation accounts for only 12-31% of CF alleles among Asians, and none (so far noted) in Korea, Japan, Thailand, and Vietnam. Last year researchers discovered a CFTR mutation in the Chinese not yet found in other populations. Having F508del or a handful of other specific mutations is a prerequisite for the targeted treatment ivacaftor (Kalydeco) and only F508del for ivacaftor combined with lumacaftor (Orkambi).

&ldquoAsian roots impact on all 3 CF diagnostic pillars,&rdquo the researchers conclude, referring to the lung and pancreas symptoms, the salty sweat, and the mutations. To avoid misdiagnosis as something like tuberculosis, which has happened to Chinese children with CF, the investigators suggest a more personalized approach to diagnosing the condition that considers ancestry. But parsing populations to better target genetic tests is running up against genetic admixture &ndash diversity at the DNA level when parents are from different backgrounds.

Cystic fibrosis results from an absent or malformed chloride channel.

In this age of ads everywhere and even dog breed DNA tests available at Wal-Mart, shouldn&rsquot we gear genetic disease tests to ancestry, restricting the mutations? But there&rsquos a catch-22. Returning to the example of CF, if Asians (and presumably other non-whites) are misdiagnosed when their clinical presentations don&rsquot match the classic &ldquowhite&rdquo phenotype, then their mutations won&rsquot enter the databases that guide test development.

A better approach than meticulously cataloging ancestors and testing for the few identified mutations in prospective parents, especially given faster and cheaper DNA sequencing, is what the company GenePeeks is pioneering: mining as much information about a gene as possible, and applying it to all patient samples. That means deducing every way that a gene can vary, with extra, missing, and substituted DNA bases. So far they&rsquove interrogated more than 1,000 genes.

For CF, GenePeeks&rsquo curation process predicts changes in the 188,702 DNA base sequence of CFTR that alter the encoded protein&rsquos structure or function in ways that could affect health. F508del entraps CFTR protein in the twists and turns of the cell&rsquos secretory network, so it can&rsquot reach the surface where it should monitor ion (salt) transport. A different mutation might slow the protein&rsquos journey to the cell membrane, and another close the ion channels too quickly. For some genotypes, symptoms might be so mild that a clinician not familiar with the diverse guises of CF wouldn&rsquot make the diagnosis. Chronic sinusitis or male infertility may be the lone manifestations.

GenePeek&rsquos analysis extends to interactions of mutations. For example, their algorithms can pick up when two people have mutations in different parts of the gene that complement, so that together in their child, the protein functions well enough to support lung health. A lab just cataloging mutations without considering how a pair of them might theoretically interact (based on biochemistry) might conclude that the risk of the child inheriting CF is 25%, when it&rsquos not. In the future, analysis will ideally include gene-gene interactions.

Several recently announced collaborations are bringing GenePeeks&rsquo expertise to parts of the world where populations are young and more global genetic testing needed: Saudi Arabia, the United Arab Emirates, Oman, Qatar, Bahrain, Kuwait, Lebanon, Jordan, Turkey, India, Pakistan, South Africa, Egypt, Ghana, and Kenya. &ldquoThe desire to protect a future child from serious disease is universal. We&rsquore trying to meet that need with better screening tools in markets that have been underserved historically,&rdquo GenePeeks CEO Anne Morriss recently told me. Whenever the company becomes aware of a clinically important variant of any gene, they add it to their list for anyone &ndash not just a member of the population in which the mutation was discovered.

While genetic testing companies are expanding their offerings, some of them are still not keeping up with admixture. Even recent recommendations to increase the roster of genes in preconception carrier screens require that a disease have a carrier frequency of at least 1 in 100. But where? Among whom? That criterion might miss a disease that&rsquos rare in a larger population yet concentrated in a subgroup.

That&rsquos the case for Steel syndrome, which causes joint pain, hip dislocation, pinching of the spinal cord in the neck, short stature, and characteristic facial features, due to a mutation in a collagen gene. It&rsquos much more common among residents of East Harlem in New York City who are of Puerto Rican ancestry than among other groups. Hip surgery, which is done for the same symptoms arising from an injury, could harm a person with Steel syndrome. Because some people who identify as Hispanic may not be aware of Puerto Rican ancestry, adding the Steel syndrome mutation to orthopedic genetic testing panels or collagen panels makes sense. The 1 in 100 carrier frequency rule would miss the disease in East Harlem. (I told the Steel syndrome story here.)

GenePeeks&rsquo approach celebrates the dynamic complexity of the human gene pool. &ldquoThe protocol recognizes the realities of global migration and diversity. People move &ndash they always have and always will. A couple with Middle Eastern ancestry can just as easily walk into a doctor&rsquos office in LA as Dubai,&rdquo says Morriss.

Direct-to-consumer genetic testing websites can oversimplify the situation, presenting carrier testing as a yes/no situation: you have a mutation or you don&rsquot. &ldquoIf you are starting a family, find out if you are a carrier for certain inherited conditions,&rdquo advertises 23andme. &ldquoA carrier&rdquo can actually mean hundreds if not thousands of different things! We have two copies of each gene (except the X in males), and each gene, because it has thousands of building blocks, comes in many flavors.

So before we all load our genome sequences onto our smartphones and start doling out dough for analysis to the companies that are now planning this new addictive service, researchers need to learn all there is to know about specific genes &ndash in us all.

Molecular genetic risk screening

Under the impetus of the Human Genome Project, new disease-associated genes are being discovered at a rapid pace. Mutations in many of these genes are present in a high enough proportion of the general population, or of particular ethnic groups, that global or targeted population screening can be contemplated. If performed early enough, identification of these mutations by molecular genetic testing can be used not merely to diagnose disease but to predict risk of future disease, either in the individual being tested or in his or her offspring. In some cases this knowledge can be the rationale for heightened surveillance and/or preventive or therapeutic interventions. Mass screening has already commenced for cystic fibrosis mutations and has been discussed for such diverse diseases as hereditary hemochromatosis, thrombophilias, familial cancer predispositions, and pharmacogenetic risk factors. However, implementation of such programs is often impeded by the complexity of the gene mutations, by incomplete penetrance, and by thorny ethical and social issues. This chapter reviews the basic criteria to be considered before embarking on population genetic risk screening, and examines multiple disease-screening examples representing a variety of modes of inheritance and technical challenges.

Genetic Testing for Family Planning

Doctors offer genetic, or carrier, testing to all couples who are pregnant or thinking about becoming pregnant. This panel screen allows you to find out your chances of having a child with CF. It may help you make decisions when planning your family.

Genes come in pairs. To have CF, a child needs to inherit two flawed copies of the CFTR gene -- one from each parent. A child with only one copy is called a “carrier.” That means they don’t have the disease, but they can pass the gene on to their children.

If you’re a carrier but your partner isn’t, the odds of your having a child with the disease are very small. If both of you are carriers, there’s a 25% chance that your child will have CF.

You may want to speak with a genetic counselor about your risk and options. If you’re pregnant, a follow-up genetic test can show if the fetus has CF. There are two types of tests:

  • Chorionic villus sampling (CVS): This checks cells from the placenta. It’s done after 9 weeks of pregnancy, usually between the 10 th and 12 th weeks.
  • Amniocentesis: This test uses cells from the amniotic fluid. You can get it between the 15 th and 20 th weeks of pregnancy.

If you’re planning to have kids in the future, your options include:

In vitro fertilization with an egg or sperm from a donor who’s not a carrier (or you may have your own fertilized egg tested for CF before it’s implanted)

23andMe Genetic Health Risk Reports: What you should know

Genetic Health Risk reports tell you about genetic variants associated with increased risk for certain health conditions. They do not diagnose cancer or any other health conditions or determine medical action.

Having a risk variant does not mean you will definitely develop a health condition. Similarly, you could still develop the condition even if you don't have a variant detected. It is possible to have other genetic risk variants not included in these reports.

Factors like lifestyle and environment can also affect whether a person develops most health conditions. Our reports cannot tell you about your overall risk for these conditions, and they cannot determine if you will or will not develop a condition.

These reports do not replace visits to a healthcare professional. Consult with a healthcare professional for help interpreting and using genetic results. Results should not be used to make medical decisions.

All U.S. states require that newborns be tested for cystic fibrosis (CF). This means that parents can know if their baby has the disease and can take precautions and watch for early signs of problems.

The following are the most common symptoms of CF. However, people may experience symptoms differently, and the severity of symptoms can vary, too. Symptoms may include:

Thick mucus that clogs certain organs, such as the lungs, pancreas, and intestines. This may cause malnutrition, poor growth, frequent respiratory infections, breathing problems, and chronic lung disease.

Many other medical problems can point to cystic fibrosis, as well. These include:

Clubbing of fingers and toes. This means thickened fingertips and toes because of less oxygen in the blood.

Collapse of the lung often due to intense coughing

Enlargement of the right side of the heart due to increased pressure in the lungs (Cor pulmonale)

Excess gas in the intestines

Rectal prolapse. In this condition, the lower end of the bowel comes out of the anus.

Pancreatitis, or inflammation of the pancreas that causes severe pain in the belly

Congenital bilateral absence of the vas deferens (CBAVD) in males. This causes blockages of the sperm canal.

The symptoms of CF differ for each person. Infants born with CF usually show symptoms by age 2. Some children, though, may not show symptoms until later in life. The following signs are suspicious of CF, and infants having these signs may be further tested for CF:

Diarrhea that does not go away

Frequent pneumonia or other lung infections

Skin that tastes like salt

Poor growth despite having a good appetite

The symptoms of CF may resemble other conditions or medical problems. See a healthcare provider for a diagnosis.

FDA approves new breakthrough therapy for cystic fibrosis

The U.S. Food and Drug Administration today approved Trikafta (elexacaftor/ivacaftor/tezacaftor), the first triple combination therapy available to treat patients with the most common cystic fibrosis mutation. Trikafta is approved for patients 12 years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population.

“At the FDA, we’re consistently looking for ways to help speed the development of new therapies for complex diseases, while maintaining our high standards of review. Today’s landmark approval is a testament to these efforts, making a novel treatment available to most cystic fibrosis patients, including adolescents, who previously had no options and giving others in the cystic fibrosis community access to an additional effective therapy,” said acting FDA Commissioner Ned Sharpless, M.D. “In the past few years, we have seen remarkable breakthroughs in therapies to treat cystic fibrosis and improve patients’ quality of life, yet many subgroups of cystic fibrosis patients did not have approved treatment options. That’s why we used all available programs, including Priority Review, Fast Track, Breakthrough Therapy, and orphan drug designation, to help advance today’s approval in the most efficient manner possible, while also adhering to our high standards. The FDA remains committed to advancing novel treatment options for areas of unmet patient need, particularly for diseases affecting children.”

Cystic fibrosis, a rare, progressive, life-threatening disease, results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body. It leads to severe respiratory and digestive problems as well as other complications such as infections and diabetes. Cystic fibrosis is caused by a defective protein that results from mutations in the CFTR gene. While there are approximately 2,000 known mutations of the CFTR gene, the most common mutation is the F508del mutation.

Trikafta is a combination of three drugs that target the defective CFTR protein. It helps the protein made by the CFTR gene mutation function more effectively. Currently available therapies that target the defective protein are treatment options for some patients with cystic fibrosis, but many patients have mutations that are ineligible for treatment. Trikafta is the first approved treatment that is effective for cystic fibrosis patients 12 years and older with at least one F508del mutation, which affects 90% of the population with cystic fibrosis or roughly 27,000 people in the United States.

The efficacy of Trikafta in patients with cystic fibrosis aged 12 years and older was demonstrated in two trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had an F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical F508del mutations.

In each trial, the primary analysis looked at increases in the percent predicted forced expiratory volume in one second, known as ppFEV1, which is an established marker of cystic fibrosis lung disease progression. Trikafta increased the ppFEV1 in both trials. In the first trial, it increased mean ppFEV1 13.8% from baseline compared to placebo. In the second trial, it increased mean ppFEV1 10% from baseline compared to tezacaftor/ivacaftor. In the first trial, treatment with Trikafta also resulted in improvements in sweat chloride, number of pulmonary exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared to placebo.

The safety profile of Trikafta is based on data from the 510 cystic fibrosis patients in the two trials. The safety profile was generally similar across all subgroups of patients. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta compared to placebo were rash and influenza (flu) events. The most common adverse drug reactions included headaches, upper respiratory tract infections, abdominal pains, diarrhea, rashes, increased liver enzymes (alanine aminotransferase and aspartate aminotransferase), nasal congestion, increased blood creatine phosphokinase (an enzyme that can be associated with muscle damage), rhinorrhea (mucus in the nasal cavity), rhinitis (swelling of the mucous membrane of the nose), influenza, sinusitis and increased blood bilirubin (may be caused by problems involving the liver, gallbladder or red blood cells).

The prescribing information for Trikafta includes warnings related to elevated liver function tests (transaminases and bilirubin), use at the same time with other products that are inducers or inhibitors of another liver enzyme called Cytochrome P450 3A4 (CYP3A), and the risk of cataracts. Patients and their caregivers should speak with a health care professional about these risks and any medicines they take before starting treatment.

Patients with cystic fibrosis should speak with a health care professional and have tests performed to understand which gene mutations they have. The presence of at least one F508del mutation should be confirmed using an FDA-cleared genotyping assay prior to treatment. The safety and effectiveness of Trikafta in patients with cystic fibrosis younger than 12 years of age have not been established.

The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Trikafta also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. Drugs approved under expedited programs are held to the same approval standards as other FDA approvals. Because of Trikafta’s benefit to the cystic fibrosis community, the FDA reviewed and approved Trikafta in approximately three months, ahead of the March 19, 2020 review goal date. The approval of Trikafta was granted to Vertex Pharmaceuticals Incorporated, which will receive a Rare Pediatric Disease Priority Review Voucher for developing this therapy.

Get Medical Advice from a Genetic Expert

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Consultations are available anywhere in the U.S. by phone or video. During a consultation, the genetic counselor will answer your questions and take you through a comprehensive discussion to determine what steps and/or genetic tests would be appropriate for you. The cost of the consultation will vary, depending on whether an insurance claim is submitted for the service. You can make an appointment over the phone, or through an online process.

If you'd prefer, you can also submit questions to a Genetic Counselor by email. This service is provided by ThinkGenetic and is free.

Connect with a Genome Medical care coordinator and make your appointment online.

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Cystic fibrosis heterozygosity: Carrier state or haploinsufficiency?

Cystic fibrosis (CF) is a common genetic disorder, caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a transmembrane chloride channel, which is important for key physiological functions, such as production of sweat and mucus, as well as mucociliary clearance in the lungs (1). Affected individuals are homozygous for mutated copies of CFTR and are at elevated risk for a variety of diseases, including bronchiectasis and repeated pulmonary infection gastrointestinal disorders, including malabsorption and nutritional deficiency states and pancreatitis and diseases of the hepatobiliary system (1). While management of CF has improved drastically in recent decades, individuals with CF experience reduced life expectancy relative to the general population (2). The prevalence of carrier state of mutated CFTR genes is high [greater than 3% in some subpopulations (3)], leading to the suggestion that the carrier state must be positively selected for due to positive health effects, analogous to protection against malaria conferred by carrier states in sickle cell anemia (4, 5).

CF has been regarded as a classical autosomal recessive disorder, with no adverse health effects associated with the carrier state. I use the past tense, because in PNAS Miller et al. (6) provide convincing evidence that CF heterozygosity may represent a haploinsufficiency state, analogous to that seen with thalassemia, where individuals with a single copy of the disease-causing allele do suffer adverse health effects, presumably due to production of the gene’s product at lower levels than would be seen in noncarriers. Beta-thalassemia is an autosomal recessive disorder of hemoglobin, but the carrier state is often characterized as “thalassemia minor” with individuals experiencing anemia that is less severe than homozygotes (who experience thalassemia major or thalassemia intermedia) (7). The contrast with CF relates to the multisystemic nature of CF, and the numerous disease states linked to CF, compared to beta-thalassemia as a hematological disease.

Miller et al. (6) were able to link genetic testing information to diagnostic codes using a very large, commercial health analytics database built on insurance claims data [the Truven Marketscan Database (8)]. They evaluated the risk of 59 diseases that occur with higher frequency in individuals with cystic fibrosis in a cohort of 19,802 CF carriers matched by age, gender, and duration of enrollment to 99,010 controls. Remarkably, they found that individuals with the CF carrier state were at significantly increased risk of nearly all of the diseases evaluated (57/59). In a second analysis, they calculated odds ratios for the same 59 diseases in individuals with CF compared to matched controls and found strong correlation in odds ratios (OR) for disease states between CF carriers and individuals with CF. In other words, the higher the OR of the disease in individuals with CF, the higher the OR in CF carriers.

Their results were robust when restricted to individuals who might be presumed not to have undergone CF genetic testing (mothers of CF cases during the time period prior to the pregnancy) and also when they removed individuals in whom CF genetic testing might have been performed due to occurrence of a disease that suggested underlying CF. They also performed simulations to determine whether false discovery might explain their results and found this unlikely to be the case. Their results have important implications not only for how CF is conceptualized, but also for the potential burden of disease associated with the CF gene at the population level. The study also raises important ethical questions related to how we use the ever-increasing volume of electronic clinical records linked to genetic (or genomic) data.

In Miller et al.’s (6) study, the relative elevations in risk of CF-linked disease states are lower in carriers than in individuals with CF, but as Miller et al. (6) note, the high prevalence of CFTR mutation heterozygosity in the general population means that any elevation in risk has important implications for burden of disease. To understand this, we need to explore the concept of attributable risk or the etiological fraction of disease due to a particular cause (in this case either CF carrier state or CF disease). Epidemiologists typically consider two different types of attributable risk: attributable risk percent among exposed individuals (AR%) and population- attributable risk percent (PAR%) (9). AR% represents the fraction of disease in exposed individuals that is due to their exposure, as opposed to background risk.

For example, in the study of Miller et al. (6), the OR for acute pancreatitis in CF carriers is 2.5. Assuming the disease is rare, such that the OR approximates a relative risk (9), and confronted with a CF carrier with acute pancreatitis, we would say that the AR% for this individual is (OR − 1)/OR, which is (2.5 − 1)/2.5 or 60% (9). This approach acknowledges that there is baseline risk of acute pancreatitis even in the absence of CF carrier state and considers only risk to the individual. The OR for acute pancreatitis is much higher in those with CF [around 13 in Miller et al. (6)], so the AR% for CF in an individual with CF and pancreatitis would be (13 − 1)/13 or 92%.

By contrast, PAR% considers both prevalence of exposure in the population and relative elevation of risk and serves as an estimate of total population-level disease burden that could be modified by eliminating risk. Again, assuming OR approximates a relative risk, we can estimate PAR% as [pe(OR − 1)]/[pe(OR − 1) + 1], where pe is the prevalence of exposure (9). If prevalence of mutated CFTR heterozygosity in the population is 3% (3), the PAR% for pancreatitis is ∼4%. In 1990, it was estimated that there were 30,000 individuals with CF living in the United States (10), at a time when the US population was 250 million persons. Thus, the prevalence of CF would have been ∼12/1,000,000 at that time. Based on this prevalence, the PAR% for CF is only 0.1% or 1/40th of that attributable to CF carrier state. I explore this idea further in Fig. 1.

Bar graph illustrating the difference in attributable risk percent (Left) and population-attributable risk percent (Right) for individuals heterozygous (light gray) and homozygous (dark gray) for mutated CFTR alleles, for selected CF-linked diseases. It can be seen that attributable risk for a given disease is higher in those with cystic fibrosis than in CF gene carriers. However, because of the higher prevalence of CFTR heterozygosity than homozygosity, the PAR% for these diseases is higher (generally, far higher) for CF gene carriers than for those with cystic fibrosis. An exception is bronchiectasis, where an extraordinarily high odds ratio in those with cystic fibrosis (∼920) results in similar PAR% estimates (12% for CF carriers vs. 9% for individuals with cystic fibrosis). Data for this bar graph are derived from Miller et al. (6). Prevalence estimates are as noted in the text.

In addition to forcing us to rethink the relationship between CF heterozygosity and burden of disease, Miller et al.’s (6) study should flag the emerging likelihood that common genetic variants will be linked to elevated risk of disease occurrence, as genetic testing data, and genomic sequencing data, become more widely available. Are we at risk for pathologizing widespread and important genetic variation within human populations? Will existing legislation that forbids stigmatization by insurers and employers, based on genetic information, prove sufficiently robust to protect carriers (11)? Could fear of stigma result in a decline in preconception genetic testing and undermine efforts to prevent CF? These questions are critically important for, but transcend, CF. The rapid growth in availability of genetic and genomic information means that we will come to see disease pathways more clearly, and differently, in the near future. We need a firm ethical footing to be able to handle this new knowledge.


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