Recently in Genetics Category

An international group of researchers has unlocked another door to understanding the cause of facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy.* Reporting electronically in Science, Lemmers and colleagues add to the long-known genetics of the autosomal dominant disease.

In 1992, it was discovered that the molecular defect in FSHD localizes to the distal portion of the long arm of chromosome 4 (specifically 4q35), in which a dormant repetitive element, D4Z4, is truncated. Only individuals with 1-10 D4Z4 repeats can acquire FSHD (normal individuals have 11-100 repeats). It was further learned that the number of D4Z4 repeats in people with FSHD correlates inversely with the age of onset and disease severity; however, it was also observed that clinical manifestations among family members with the same deletion can differ. (For a free review of FSHD and its genetics, circa 2008, go here.)

The Science authors showed that, somehow, the truncated D4T4 area in FSHD patients changes the chromosomal configuration, which allows for the transcription of an internal homeobox gene, DUX4. But FSHD patients also carry specific single nucleotide polymorphisms (SNPs) distal to the D4Z4 region that encode for a transcript-stablizing poly-A tail. Therefore, in people with FSHD, the transcribed DUX4 gene, which might otherwise be chewed up, is stabilized by being polyadenylated.

What the product of the polyadenylated DUX4 transcript is and what it does remain to be discovered.

* Affecting 1 in 20,000.

Just as an astronomical white count is not an entity unto itself but a marker of a serious underlying disorder, like leukemia, so a big lie on a CV is an indicator of a grave underlying problem, like sociopathy.

Faculty members at the Duke Institute for Genome Sciences and Policy are learning this lesson the hard way thanks to the failure of someone at Duke to perform the basic HR duty of vetting Anil Potti's curriculum vitae 7 years ago. Potti, who was hired in 2003 as a physician-researcher by Duke, falsely claimed that he was a Rhodes Scholar on scientific grant proposals, according to a recent expose by Paul Goldberg in The Cancer Letter. That's a big lie and one suggesting that other big lies are possible, if not probable. Taking this very cue, Goldberg then questioned the integrity of Potti's research at Duke and found that 2 biostatisticians at M. D. Anderson discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.

Consequently the biggest victim of Duke's remote HR lapse: cancer patients who enrolled in clinical trials, which were based on Potti's questionable work. According to the NYT, these trials have now been suspended (after stuttering efforts by Duke officials to reopen them, reported Goldberg). News coverage can also be found at NPR's Shots blog.

For yucks or groans, I performed a quick PubMed search: "A Potti" is the coauthor of 48 articles that were published within the last 5 years. Potti's articles appeared in, for example, PNAS, JAMA, JCO, PLoS One, Lancet Oncology, Nature Medicine, and the NEJM.

Photo of Anil Potti from Duke Institute for Genome Sciences and Policy.

10/24/10 addendum: As the AP reported yesterday, Lancet Oncology editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers on a 2007 article in the journal. (The article validated the use of gene signatures to predict the response of breast cancers to neoadjuvant [perioperative] chemotherapy.) After the damning report from biostatisticians at M. D. Anderson about Potti's alleged errors in another article, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.

The editor also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models. Collingridge expressed his own concerns about the Lancet Oncology article given recent developments surrounding Potti. The journal has contacted the Duke coauthors—Anil Potti, Chaitanya Acharya, Sayan Mukherjee, and Joseph Nevins—and awaits their responses. 

Hospitalizations are reduced by the upfront use of a genetic test for "warfarin sensitivity," according to new results from a comparative-effectiveness study. The Medco- and Mayo-sponsored trial of the anticoagulant (the dosing of which has caused more than one headache in physicians and patients during the last 70 years) compared hospitalization rates among warfarin-treated subjects who underwent genetic testing and those who didn't. The trial results were presented this morning at the ongoing meeting of the American College of Cardiology in Atlanta; data are also available at the company's web site.

In the study, the dose of newly initiated warfarin therapy in nearly 900 adult patients* was adjusted on the basis of Medco's genetic test (performed on blood or cheek swabs). During a 6-month period, the hospitalization rate in this group was 31% lower than that of a historical control group (N = 2688) who had not undergone genetic testing (ITT analysis: ~18% vs ~25%). The hospitalization rate for bleeding or thromboembolism was 28% lower in the genotyped group.

Results from the per-protocol analysis were even more impressive. The rate of all-cause hospitalization and the rate of hospitalization for bleeding or thromboembolism were 33% and 43% lower, respectively, in the genotyped group.

The genetic test, which is available from several companies,** assesses the function of 2 genes, CYP2DC and VKORC1. The former encodes a well-known P450 enzyme that metabolizes warfarin; the latter encodes an enzyme that activates vitamin K (which counteracts the anticoagulant properties of warfarin). The cost of a warfarin sensitivity test is quoted in the press at a range of $250-$400. The FDA first approved use of the genetic test (Verigene; Nanosphere) to inform warfarin dosing in 2007.

According to Medco, about 30 million warfarin prescriptions are written and 2 million patients start warfarin treatment each year. Warfarin is the leading cause of ED visits, hospitalizations, and drug-related deaths. One third of the variability in response to the drug is ascribed to the genetically determined function of CYP2C9 and VKORC1.

Last week, the FDA added a boxed warning to the PI for the antiplatelet drug clopidogrel (Plavix; BMS/sanofi), which may be less effective in patients with reduced function of the CYP2C19 enzyme. (To become active, clopidogrel, a prodrug, must be converted by CYP2C19.) The FDA advised that 2%-14% of Americans are "poor metabolizers" of clopidogrel. CYP2C19 testing is also commercially available through a number of companies.

ITT = intent to treat; PI = package insert.

* Patients were recruited through 29 Medco-managed prescription benefit plans.

** For example, Ambry Diagnostics and Arup Laboratories.

Image of warfarin (Coumadin) bottles from NIGMS/NIH.

Fred Hassan, former CEO of the former Schering-Plough, believes that genomics will breathe new life into the pharmaceutical industry. His cheerleading prediction for how the study of the human genome will invigorate the flagging drug business, personalize healthcare, and extend lives is available at the HuffPo.

It's not an original thought, but Hassan (like the rest of us) recognizes that we're probably on the cusp of finally realizing tailored or boutique-style medicine. One case in point is the apparent, relative benefit and safety of the anti-amyloid bapineuzumab (JNJ; Wyeth) in individuals with Alzheimer disease who don't carry the ApoE4 allele.

In a more tangible way, genomics is informing the development of vaccines and the control of infectious diseases. In a recent PLoS review article ("The Key Role of Genomics in Modern Vaccine and Drug Design for Emerging Infectious Diseases"), Novartis employees describe how knowledge of pathogen and host genomes can be used to identify and select vaccine targets in a process known as reverse vaccinology.

As proof of this concept, the authors describe how whole-genome sequencing led to the identification of vaccine-candidate antigens against Neisseria meningitidis serogroup B. An 18-month analysis of the bacterial genome ultimately led to the identification of 570 genes that likely encoded surface-exposed or secreted proteins—more vaccine-candidate antigens than those discovered during 40 years of conventional analysis. Further antigen screening resulted in the development of a "multi-component" recombinant vaccine (Novartis's MenB vaccine), which is in phase 2/3 development.

A "potentially significant" mutation of the 2009 H1N1 virus has been detected in 3 severe cases (including 2 fatalities) of pandemic flu in Norway; however, the mutated virus is nothing new, according to the World Health Organization. The spontaneous mutation—which does not confer resistance to the antiviral drugs oseltamivir (Tamiflu; Roche) or zanamivir (Relenza; GSK)—was detected as early as April and has been found sporadically in both severe and mild flu cases in other countries,* reports WHO.

The 2009 H1N1 mutation has not been described or labeled explicitly in news reports. But according to a quoted Norwegian health official, the mutation "makes it possible for the virus to fasten itself or infect deeper into the bronchioles, and therefore provide for a more serious progress of the disease." This description suggests that the mutation lies in the gene encoding the viral binding protein, hemagglutinin.

WHO maintains that the current pandemic flu vaccine does produce immunity against the mutated virus.

* Namely Brazil, China, Japan, the Ukraine, and the United States.

Depiction of H1N1 virus from Wikipedia.

Although the gene responsible for Huntington's disease (HD), a dominantly inherited neurodegenerative disorder, was detected more than 10 years ago, the mechanism of its brain-specific pathology has remained elusive. Now investigators at Johns Hopkins reveal, in an elegant series of cell-line experiments, how the genetic disorder preferentially affects the corpus striatum, despite the fact that the mutant protein is found in cells throughout the body. Their findings are available in the journal Science. 

But first some necessary background...

HD is characterized by the expansion of a 3-nucleotide repeat section in the gene that encodes for the protein huntingtin (Htt). Neurotoxicity in HD is related to the cellular solubility of the mutant form of Htt, or mHtt. Protein aggregates of mHtt appear to be neuroprotective, whereas soluble mHtt is associated with cytotoxicity. It is also important to note that the mutant protein is sumoylated—meaning that it is covalently bound to a small ubiquitin-like modifier (SUMO)—which reduces neuroprotective protein aggregation.

Investigating Rhes protein...

The Hopkins investigators chose to examine the relationship between mHtt and the protein Rhes, because the latter is very selectively expressed in the corpus striatum. By using striatal (mouse) cell lines that overexpressed Rhes or that were Rhes deficient, investigators determined that Rhes binds "robustly" to endogenous Htt—but much more so to mHtt than to wild-type Htt. Moreover, overexpression of Rhes, in particular, profoundly affected the survival of cells that expressed mHtt (but not those expressing wild-type Htt). Specifically they found that the cytotoxic effect of overexpressed Rhes was concentration dependent. And in a final set of experiments, investigators determined that overexpressed Rhes augments the sumoylation of mHtt, thereby causing the disaggregation of mHtt and cell death.

So...it appears that striatal Rhes promotes localized neuronal degeneration in HD by enhancing the sumoylation of mHtt. Drugs that block the interaction between Rhes and mHtt may have therapeutic potential in HD, the authors conclude.

Public-domain photo of American folk legend Woody Guthrie, who died of complications due to HD in 1967.

A newly discovered arenavirus, which caused fatal hemorrhagic fever in 1 Zambian and 3 South Africans* last year, has been named Lujo virus. The name is derived from the first 2 letters of the cities where victims manifested their illnesses: Lusaka, Zambia, and Johannesburg, South Africa. Lujo virus is the first Old World arenavirus discovered in 3 decades that is known to cause hemorrhagic fever, according to a new report in PLoS Pathogens.

A case of nonfatal hemorrhagic fever due to Lujo virus also occurred in a South African nurse, who cared for one of last year's deceased victims. The nurse evidently responded to ribavirin treatment and has completely recovered. Human-to-human transmission of Lujo virus is believed to be through contact with infected body fluids. How the index case acquired infection is unknown, but disease-causing arenaviruses are typically transmitted from rodent vectors.

* A Zambian safari employee (index case), a South African paramedic, a South African nurse, and a South African hospital employee.

Photo of house mouse (Mus musculus), which is the rodent vector for the Old World arenavirus, lymphocytic choriomeningitis virus, from Wikipedia.

In August, the FBI announced that USAMRIID scientist Bruce Ivins was the sole perpetrator of the "anthrax letter attacks" of 2001.

Pulmonary anthrax from inhaled letter spores killed 5 people, including 2 postal workers.

• Robert Stevens, 63, a photoeditor at a Florida tabloid office, died October 6, 2001.
• Thomas Morris, Jr., 55, a mail handler at the Brentwood mail facility in Washington, DC, died October 21, 2001.
• Joseph Curseen, 47, an employee at the Brentwood mail facility in Washington, DC, died October 22, 2001.
• Xinh Thi "Kathy" Nguyen, 61, a Vietnamese immigrant and New York City hospital worker, died October 31, 2001.*
• Ottilie Lundgren, a 94-year-old Connecticut resident, died November 21, 2001.*

Attention was directed to Ivins when DNA-sequence variations in the letter spores led to the identification of a specific flask at USAMIRIID, which contained the same mix of Bacillus anthracis spores. Ivins, a B. anthracis microbiologist, had been the primary custodian of the flask since 1997.

Other circumstantial evidence against Ivins:

• USAMRIID, in Fort Detrick, MD, is the only relevant lab in the geographic area where the "federal eagle" envelopes used in the attacks were distributed and sold.
• According to USAMRIID lab records, Ivins worked alone in late-night shifts during September 14-16, 2001, and from September 28 to October 5, 2001, before the rounds of Post/Brokow and Leahy/Daschle letters were respectively mailed.
• Ivins submitted "unusable" and false B. anthracis spores to the FBI for testing. The initial, unusable sample that was submitted to the FBI in 2002 was destroyed by the agency; however, Paul Keim's lab at Northern Arizona University preserved a portion of this initial sample, which was later found to contain mutations identical to the letter spores. In 2004, the FBI seized the USAMRIID flask, which subsequently indicated a genetic match to the B. anthracis in the letters.

Faced with impending prosecution by the DoJ, Ivins killed himself on August 1 July 29 by taking an overdose of Tylenol with codeine. (01/07/09 addendum: News reports now indicate that Ivins took a fatal overdose of acetaminophen, citing police records.)

Relevant background reading at the Pathophilia blog is available at these links:

• DoJ Evidence Against Ivins Compelling
• Genetic Gumshoeing in the Anthrax Letter Attacks
• Despite FBI Anthrax Briefing, Media and Blogging Arguably Egg on "Grassy Knollers"
• How the Smoking-Gun "Anthrax" Flask at USAMRIID Became a Smoking Gun

Also USA Today, believe it or don't, provided some of the most comprehensive news coverage of the bioterrorism investigation.

USAMRIID = US Army Medical Research Institute of Infectious Diseases.

* It remains unknown exactly how Nguyen and Lundgren were exposed to the B. anthracis letter spores.

Public domain photograph of Daschle "anthrax" letter from Wikipedia.

Three Generations, No Imbeciles: Eugenics, the Supreme Court, and

Buck v. Bell

By Paul A. Lombardo

365 pages

If generations of illegitimacy and limited intellect can be used to justify mass sterilization, then count on wiping out most of the southeastern United States, white or black or otherwise. But the consequence would not be merely the intended elimination of welfare-sucking trash—if such an outcome could be predicted. Say goodbye to the works of Tennessee Williams, Faulkner, Capote, and any other writer whose work draws on the freewheeling peccadilloes or horrors, depending on your viewpoint, of the extended Southern family. And say goodbye to anybody like yours truly, whose ancestral history in The Volunteer State contains its share of illiteracy, illegitimacy, and "imbecility" (thank you, US Census Bureau).

But unintended consequences were not considered by proponents of eugenics and sterilization laws in the early 20th century. In their conceit to claim an understanding of inheritance and Darwinian theory, eugenicists believed that the road to public health and lower taxes was paved with the legally mandated sterilization of society's feebleminded and promiscuous citizens—which, in their minds, meant men and women (but mostly women) of the lower classes.

At the center of this sorry time in American history is the legal case of Buck v. Bell, the end-result of Virginia's carefully crafted sterilization law, enacted in 1924. In comprehensive fashion, Georgia lawyer Paul Lombardo lays out this sad case, which was argued before the US Supreme Court, in Three Generations, No Imbeciles, the most detailed account to date of Buck v. Bell and its aftermath.

The Buck in this case was Carrie Buck, a young pregnant woman committed to the Virginia Colony for Epileptics and Feebleminded in 1924 under dubious circumstances. Carrie's mother, Emma, was already a member of the Colony under allegations of mental deficiency and moral turpitude, and Carrie's soon-to-be daughter would be placed in the foster care of the couple who arranged for Carrie's residence at the Colony. Among the 15 of so residents at the state institution selected as candidates by the Colony's Board for sterilization, on the basis of the newly enacted Virginia law, Carrie was chosen as the hapless test case. The argument for Carrie's sterilization would rest on flimsy evidence that 3 generations of the Buck family—including Carrie's infant daughter—constituted inherited imbecility.

Lombardo describes Carrie's legal defense, both at the state and federal levels, as a charade. Buck's anemic appeal before members of the Supreme Court, most of whom sympathized with the eugenics movement, led to a terse ruling in 1927, written by associate justice Oliver Wendell Holmes, Jr, which upheld the Virginia law. In his 3-page opinion, Holmes wrote the famous, cutting phrase, "Three generations of imbeciles are enough," which in fact had no foundation in the Buck family.

On the basis of the Supreme Court decision in Buck v. Bell, many other states (which already had sterilization laws in place) proceeded in relatively unfettered mode to conduct mass sterilization on their less fortunate citizens, and Lombardo writes that the US eugenics movement, bolstered by Buck v. Bell, informed a like-minded program in Socialist Germany, with known consequences.

Remarkably the Supreme Court decision of Buck v. Bell remains intact, although enduring sterilization laws in most states were repealed at the height of the civil-rights movement. (Laws in Washington state and Mississippi remain.) And while the general conceit of today's Americans may be that the constitutionality of legal sterilization won't be tested again before the high court, Lombardo reminds us that the same incentives to improve public health and lower tax burdens exist today and are manifest in selective reproduction methods and judge-mandated orders to not procreate.

For the first time, a predominant form of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in the United States, USA300, has emerged as a major clone of MRSA in another country. In the latest issue of the NEJM, investigators from Colombia and Texas report their identification of USA300 isolates in a series of Colombian MRSA outbreaks, beginning in 2005. The researchers also discovered, in more than 2 dozen Colombian cases, a clone of vancomycin-resistant Enterococcus faecalis (VREF) that had been seen only in Houston.

The NEJM correspondence suggests that, although USA300 has been discovered as a predominant form of MRSA only in Colombia, the clone (not yet genetically identified) may well be a major cause of outbreaks in other Latin American countries.

Photo of spontaneously draining, cutaneous MRSA abscess on hip of prison inmate from the CDC. (Clarification: The photo, not the prison inmate, is from the CDC...at least as far as I know.)