Category Archives: Immunology

Flower Could Revolutionise Leukemia Treatment

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From the Daily Mail

Baby's Breath

“Scientists unveiled a major medical breakthrough that could revolutionise the treatment of leukaemia patients and save thousands of lives.

Experts have discovered that an extract from the white flower commonly known as Baby’s Breath can boost the efficiency of anti-cancer drugs by a staggering million times.

They found that molecules called saponins, extracted from the Gypsophila Paniculata plant, appear to break down the membrane of cancer cells.”



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Alzheimers memory problems are caused by amyloid beta oligomers,not amyloid plagues

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AD-3

This is a single Alzheimer's disease plaque - the green shows fibrils and the red shows other assembly states of beta-amyloid;Image by Zerd via Flickr

Using a new mouse model of Alzheimer’s disease, researchers at Mount Sinai School of Medicine have found that Alzheimer’s pathology originates in Amyloid-Beta (Abeta) oligomers in the brain, rather than the amyloid plaques previously thought by many researchers to cause the disease.[2]

Alzheimer disease (AD) is the leading cause of dementia, affecting more than 26 million people worldwide.Clinically, the disease is characterized by progressive memory loss and a decline in cognitive abilities.[1]

Several symptomatic treatments are in use for AD; however, no disease-modifying therapies are currently available.[1]

The search for an Alzheimer drug is hindered by lack of understanding of the disease and also by the lack of suitable tests to measure efficacy of trial drugs.Currently the only way to measure efficacy in Alzheimer drug clinical trials is to use psychological tests which measure how well a patient is doing to how they were a year ago.There is quite a lot of variability in Alzheimer’s patients as to how they are doing mentally and there can be large variations in results.[3] Thus,in order to  to account for these variations the trials need to be conducted over many years.Imaging and immunoassays such as the ELISA assay are also used to see if the drug is working as expected.However these techniques alone are not enough as they measure physical processes such as antibody drugs binding to the target plagues which indicates if the drug is doing its intended while the mental tests discussed above tend to be quite variable in their own right which makes attributing changes in cognitive function to the drug challenging.

The study, which was supported by the  “Oligomer Research Consortium” of the Cure Alzheimer Fund and a MERIT Award from the Veterans Administration, appears in the journal Annals of Neurology.

Amyloids are insoluble fibrous protein aggregates sharing specific structural traits.Abnormal accumulation of amyloid in organs may lead to amyloidosis,something any fans of the TV show ‘House’ will be all too familiar with,and may play a role in various other neurodegenerative diseases such as Alzheimer’s.

Amyloid beta(Aβ or Abeta) is a peptide of 39–43 amino acids which appears to be the main constituent of amyloid plaques in the brains of Alzheimer’s disease patients and which also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy. These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,[1] a protein fold that is shared by other peptides such as the prions associated with protein misfolding diseases.

“The buildup of amyloid plaques was described over 100 years ago and has received the bulk of the attention in Alzheimer’s pathology,” said lead author Sam Gandy, MD, PhD, Professor of Neurology and Psychiatry, and Associate Director of the Alzheimer’s Disease Research Center, Mount Sinai School of Medicine. “But there has been a longstanding debate over whether plaques are toxic, protective, or inert.” [2,4]

Several research groups had previously proposed that rather than plaques, floating clumps of amyloid (called oligomers) are the key components that impede brain cell function in Alzheimer’s patients. To study this, the Mount Sinai team developed a mouse that forms only these oligomers, and never any plaques, throughout their lives.

In this case,oligomers refer to protein complexes composed of two or more subunits.Protein complexes are a form of quaternary structure with proteins in the complex being  linked by non-covalent protein-protein interactions.Different protein complexes have different degrees of stability over time and  complex formation often serves to activate or inhibit one or more of the complex members. In this way protein complex formation can be similar to phosphorylation. A method that is commonly used for identifying the members of protein complexes is immunoprecipitation.

The researchers found that the mice that never develop plaques were just as impaired by the disease as mice with both plaques and oligomers. Moreover, when a gene that converted oligomers into plaques was added to the mice, the mice were no more impaired than they had been before.

“These findings may enable the development of neuroimaging agents and drugs that visualize or detoxify oligomers,” said Dr. Gandy. “New neuroimaging agents that could monitor changes in Abeta oligomer presence would be a major advance. Innovative neuroimaging agents that will allow visualization of brain oligomer accumulation, in tandem with careful clinical observations, could lead to breakthroughs in managing, slowing, stopping or even preventing Alzheimer’s.[2]

“This is especially important in light of research reported in March showing that 70 weeks of infusion of the Abeta immunotherapeutic Bapineuzumab® ,a much anticipated humanized monoclonal antibody developed by Elan to bind to the plaques, cleared away 25 percent of the Abeta plaque, yet no clinical benefit was evident.” [2]

###

The Mount Sinai team included Michelle Ehrlich, MD, Professor of Pediatrics, Neurology, and Genetics and Genomic Sciences, and John Steele, a Mount Sinai graduate student, who performed the key analyses of the behavioral data. Dr. Charles Glabe, an oligomer expert and a member of the Cure Alzheimer Fund research consortium, is also a co-author of the paper. Dr Gandy is also a neurologist at the James J Peters Veterans Affairs Medical Center, an affiliate of Mount Sinai School of Medicine.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of few medical schools embedded in a hospital in the United States. It has more than 3,400 faculty in 32 departments and 15 institutes, and ranks among the top 20 medical schools both in National Institute of Health funding and by U.S. News & World Report. The school received the 2009 Spencer Foreman Award for Outstanding Community Service from the Association of American Medical

Colleges.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2009, U.S. News & World Report ranked The Mount Sinai Hospital among the nation’s top 20 hospitals based on reputation, patient safety, and other

patient-care factors. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and about 530,000 outpatient visits took place.

References

1.  http://www.medscape.com/viewarticle/717219

2.http://www.eurekalert.org/pub_releases/2010-04/tmsh-amp042710.php

3.http://health.nytimes.com/ref/health/healthguide/esn-alzheimers-qa.html

4.http://www.sciencedaily.com/releases/2009/11/091123114813.htm

Further Reading

Active and passive Immunotherapy for Neurodegenerative Disorders (pdf)

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A15416&rendertype=figure&id=A15420

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Golden Bullet for Cancer?

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Gold

Gold;Image via Wikipedia

A good article on a form of nanoparticle called nanocages,which I hadn’t even heard of until I read this article on Science Daily!This technology looks promising as it achieved good results despite the fact that it had not been optimized.However it still has a way to go in terms of achieving more precise targeting to tumor cells.

“ScienceDaily (Mar. 16, 2010) — In a lecture he delivered in 1906, the German physician Paul Ehrlich coined the term Zuberkugel, or “magic bullet,” as shorthand for a highly targeted medical treatment.Magic bullets, also called silver bullets, because of the folkloric belief that only silver bullets can kill supernatural creatures, remain the goal of drug development efforts today.A team of scientists at Washington University in St. Louis is currently working on a magic bullet for cancer, a disease whose treatments are notoriously indiscriminate and nonspecific. But their bullets are gold rather than silver. Literally.….”

“We saw significant changes in tumor metabolism and histology,” says Welch, “which is remarkable given that the work was exploratory, the laser ‘dose’ had not been maximized, and the tumors were ‘passively’ rather than ‘actively’ targeted.”“

Read the rest of the article on Science Daily by clicking here.

More Information on Nanocages:

Video on gold nanoparticles:

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Reveiw on Targeting of Drugs and Nanoparticles to Tumors

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Nice review in the Journal of Cell Biology on the targeting of drugs and nanoparticles to tumors.

Excerpt:

“The concept of targeted drug delivery is attractive because it recapitulates some of the advantages of topical application of drugs: high local concentration and low systemic exposure. In practice, this approach has met with some success but has not provided the hoped-for “silver bullets.” However, recent developments in the field have rekindled interest in the targeting approach. We call this mode of drug delivery “synaphic” targeting; it is also referred to as pathotropic or active targeting. Cancer stands out as a disease most likely to benefit from targeted drug delivery….”

To read the rest of the review click here.

More Information:

Video introducing  nanotechnology:

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Personalised Approach To Tackling Breast Cancer Studied

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Invasive ductal carcinoma of the breast. H&E s...

Invasive ductal carcinoma of the breast. H&E stain Image via Wikipedia

Introduction

Improving quality of life and potentially keeping the cancer under control for a longer period of time are goals of a new clinical trial at the cancer center’s TGen Clinical Research Services, a partnership of Scottsdale Healthcare and the Translational Genomics Research Institute (TGen).

“Many are living with refractory (cancer that has not responded to treatmnent), or advanced, breast cancer that has not responded or continues to grow despite standard treatments,” explains Nurse Practitioner Gayle Jameson, principal investigator.

The pilot study is supported by the Side-Out Foundation, a group founded by volleyball enthusiasts to help wage war on breast cancer.Women or men with advanced breast cancer that has progressed through three prior treatments are eligible for the trial, available in the western U.S. only.The new study, managed by TGen Drug Development (TD2), is open to a total of 25 patients at only two sites, the Virginia G. Piper Cancer Center at Scottsdale Healthcare and Fairfax Northern Virginia Hematology Oncology.

Approach

Biopsied tissue will be analyzed for unique characteristics and abnormal genes in cancer cells, which are then targeted for treatment with FDA-approved anticancer medications. “We may discover that a tumor has a gene mutation that responds to a drug not typically used in a ‘one-size-fits-all’ approach,” explains Jameson.

“What we are doing here is precisely matching a treatment to a specific type of cancer cell mutation and abnormal protein signaling pathways that may activate cancer cell growth. The patient would then be treated with one or more medications based on the information provided by the analyses.”

Researchers call the Side-Out study the “next generation of breast cancer treatment,” expanding on what was learned about molecular profiling in an earlier clinical trial at the Virginia G. Piper Cancer Center.

Results of the earlier trial, known as the Bisgrove Study, showed that molecular profiling can identify specific treatments that help keep cancer in check for significantly longer periods, and in some cases even shrinking tumors. Clinical trials at the cancer center are administered by the Scottsdale Healthcare Research Institute.

Disscussion

This is a great step forword in the whole area of personalised medicine which identifies charactertistiscs of disease that are specific to different people.These characteritics can then be targeted more accuratly using the correct medication.Although this is approach is used to some degree in many treatments e.g. identifying hormone receptive breat cancers from those that are not ,this takes that approach to a whole new level.

About TGen

The Translational Genomics Research Institute (TGen) is a non-profit 501(c)(3) organization focused on developing earlier diagnostics and smarter treatments.

Translational genomics research is a relatively new field employing innovative advances arising from the Human Genome Project and applying them to the development of diagnostics, prognostics and therapies for cancer, neurological disorders, diabetes and other complex diseases.

References:

http://www.tgen.org/index.cfm

Retrieved March 14, 2010, from http://www.sciencedaily.com­ /releases/2010/03/100311151722.htm

Other Interesting Articles:

A look at the treatment benefits of differentiating between characteristics of recurrent breat cancer from those of the original cancer :http://www.sciencedaily.com/releases/2009/03/090318211238.htm

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The Danger of Assumptions

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Esophageal cancer affecting the lower esophage...
Image via Wikipedia

In all science, error precedes the truth, and it is better it should go first than last.  ~Hugh Walpole

Everyone knows as a scientist your expected to be constantly busy asking questions and challenging assumptions.However this is to some degree unfeasible,you cant distrust everything or it will take a very long time to get any work done.

However,some researchers got a shock recently when it was announced that three frequently used human esophageal adenocarcinoma cell lines used for cancer research were in fact anything but, according to a brief communication published online January 14 in the Journal of the National Cancer Institute. Two of the cell lines have been used in 11 U.S. patents and were part of more than 100 published studies.

The 13 established esophageal adenocarcinoma cell lines (or 14 if another suspect one is in fact authentic) are important because of the limited availability of patient samples and the fact that there are no animal models of the disease. New drugs can be tested on these cells to see if they have an effect before they are tested on real patients and important biochemical pathways can also be elucidated.

Read the rest of this article on scientificblogging.com.

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Ebola-Overview and Recent Discoveries

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Transmission Electron Micrograph of the Ebola ...

Transmission Electron Micrograph of the Ebola Virus. Hemorrhagic Fever, RNA Virus.Image via WikipediaEbola

Introduction to Ebola

Ebola haemorrhagic fever (EHF) is a viral haemorrhagic fever and one of the most virulent viral diseases known to humankind.The Ebola virus was first identified in the western equatorial province of Sudan and in a nearby region of Zaire (now Democratic Republic of the Congo) in 1976 after significant epidemics in Nzara, southern Sudan and Yambuku, northern Zaire.

Species of Ebola

The Ebola virus belongs to the Filoviridae family (filovirus) and has five distinct species: Bundibugyo, Côte d’Ivoire, Reston, Sudan and Zaïre. Bundibugyo, Sudan and Zaïre species have all been associated with large outbreaks of Ebola haemorrhagic fever (EHF) in Africa causing death in 25-90% of all clinically ill cases, however Côte d’Ivoire and Reston have not.(4,5)Human infection with the Ebola Reston subtype, found in the Western Pacific, has only caused asymptomatic illness, meaning that those who contract the disease do not get sick (clinically ill).

Symptoms

Ebola has an incubation period (time between exposure and first symptoms appearing) of two to twenty one days.It is is characterized by the sudden onset of fever, intense weakness, muscle pain, headache and sore throat. This is often followed by vomiting, diarrhoea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding. Laboratory findings show low counts of white blood cells and platelets as well as elevated liver enzymes. (5)

Transmission

The Ebola virus is transmitted by direct contact with the blood, body fluids and tissues of those who are infected with it. Transmission of the Ebola virus has also occurred by handling sick or dead infected wild animals (chimpanzees, gorillas, monkeys, forest antelope, fruit bats).

Treatment

Severe cases require intensive supportive care, as patients are frequently dehydrated and in need of intravenous fluids or oral re-hydration with solutions containing electrolytes.No specific treatment or vaccine is yet available for Ebola hemorrhagic fever. Several potential vaccines are being tested but it could be several years before any is available.(5)

Natural Reservoir of Ebola

The natural reservoir of the Ebola virus is unknown despite extensive studies but it seems to reside in the rain forests of the African continent and in areas of the Western Pacific.(5)A natural reservoir or nidus is the long-term host of the pathogen (infectous agent) of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so asymptomatic(no apparent symptoms) and non-lethal.Different hypotheses have been developed to explain the origin of Ebola outbreaks. Laboratory observation has shown that bats experimentally infected with Ebola do not die, and this has raised speculation that these mammals may play a role in maintaining the virus in the tropical forest.Extensive ecological studies are currently under way in the Republic of the Congo and Gabon to identify the Ebola’s natural reservoir.(5)

Life Cycle

Pathogeneis Schematic

  • Virus attaches to host receptors though the GP (glycoprotein) surface peplomer and is endocytosed into vesicles in the host cell.
  • Fusion of virus membrane with the vesicle membrane occurs; nucleocapsid is released into the cytoplasm.
  • The encapsidated, negative-sense genomic ssRNA is used as a template for the synthesis ( 3′ – 5′) of polyadenylated, monocistronic mRNAs.
  • Translation of the mRNA into viral proteins occurs using the host cell’s machinery.
  • Post-translational processing of viral proteins occurs. GP0 (glycoprotein precursor) is cleaved to GP1 and GP2, which are heavily glycosylated. These two molecules assemble, first into heterodimers, and then into trimers to give the surface peplomers. SGP (secreted glycoprotein) precursor is cleaved to SGP and delta peptide, both of which are released from the cell.
  • As viral protein levels rise, a switch occurs from translation to replication. Using the negative-sense genomic RNA as a template, a complementary +ssRNA is synthesized; this is then used as a template for the synthesis of new genomic (-)ssRNA, which is rapidly encapsidated.
  • The newly-formed nucleocapsides and envelope proteins associate at the host cell’s plasma membrane; budding occurs, and the virions are released. (7)

New Discovery

Researchers at Iowa State University have uncovered how the deadly Zaire Ebola virus decoys cells and eventually kills them.A research team led by Gaya Amarasinghe, an assistant professor of biochemistry, biophysics and molecular biology, had previously solved the structure of a critical part of an Ebola protein known as VP35 (Yiral protein 35), which is involved suppression of the hosts immune system.The results of that research were published in the journal Proceedings of the National Academy of Sciences of the United States of America last January.Amarasinghe and his research team now know how VP35 is able to do it.The current research is published in the current issue of the journal Nature Structural and Molecular Biology and is available as an advanced online publication.(1,2,3)

Mechanism of Ebola Immune Evasion

When most viruses invade a cell, they start to make RNA in order to replicate.When the healthy host cell senses the replicating RNA, the host cell starts to activate anti-viral defenses that halt replication and eventually help clear the viral infections.What Amarasinghe and his group have discovered is that Ebola virus encoded VP35 protein actually masks the replicating viral ribonucleic acid (RNA) by binding itself to short double stranded RNA(dsRNA) which results in the cell not realizing it has an invading virus.Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses.(6)

Conserved basic residues in VP35 IID (Interferon Inhibitory Domain)recognize the dsRNA backbone, whereas the dsRNA blunt ends are ‘end-capped’ by a pocket of hydrophobic residues that mimic RIG-I (retinoic acid inducible gene I)–like receptor recognition of blunt-end dsRNA.(1,2)One of the reasons Ebola, in particular the strain isolated from Zaire, is so deadly is that the host cells don’t have any immune response when the virus enters the cell, said Amarasinghe.(1,2)

“The question with Ebola has always been ‘Why can’t host cells mount an immune response against the Ebola virus, like they do against other viruses?’” said Gaya. (2)

“The answer is, ‘If the cell doesn’t know that there’s an infection, it cannot build up any response.’ So our work really gets at the mechanism Ebola infection and immune evasion.(2)

Research

The collaborative approach taken by Amarasinghe enabled him to team up with virologist Christopher Basler at the Mt. Sinai School of Medicine, New York City, to investigate how the structural findings match up with how these proteins function inside the cell.”Our initial structure that we solved in 2008 was key to expanding our knowledge, but the structure was just part of the equation, and when we put it together with the functional studies, everything made sense,” Amarasinghe said.In his current research, Amarasinghe focused on a specific part of the

Phylogenetic tree comparing full-length genomes of ebolavirus and marburgvirus by Bayesian analysis. Posterior probabilities greater than 0.5 and maximum likelihood bootstrap values greater than 50 are indicated at the nodes.

Zaire Ebola VP35 protein that he thought looked unusual.As testing results came in, he found that the suspect region of the protein was binding with, or neutralizing, the part of the host cell that triggers the immune system in the cell. (2)

“The interesting thing about the Ebola virus is that it doesn’t let cells even get started to defend themselves,” he said. “This hides the (viral) RNA from being recognized by the host cell. This is a powerful immune evasion mechanism.” (2)

Other Research Findings

It has also been found that the Ebola virus  disables a cellular protein called tetherin that normally can block the spread of virus from cell to cell.Ebola Glycoprotein (GP) possesses the ability to counteract tetherin, which is both IFN (interferon)-induced in many primary cells and constitutively expressed on the primary targets of Ebola virus infection, particularly monocytes and dendritic cells.Tetherin,also known as Bst-2 or CD317, is one of the immune system’s responses to a viral infection. If working properly, tetherin stops the infected cell from releasing the newly made virus, thus shutting down spread to other cells.(8)Thus when it is antagonized it can no longer block the spread of the virus to other cells.

Ebola also possesses several strategies to antagonize IFN production and signaling. Ebola VP35 prevents IFN production by blocking activation of IFN regulatory factor 3, and VP24 (Viral Protein 24)inhibits IFN responsiveness by blocking the nuclear accumulation of tyrosine-phosphorylated STAT1(signal transducer and activator of transcription 1) . These proteins likely suppress de novo IFN-induced synthesis of viral restriction factors, but constitutive (always on) expression in various cell types remains a restrictive barrier to viral infection. (6,8)

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Further Information

Amarasinghe, along with Daisy Leung, associate scientist; Mina Farahbakhsh, undergraduate student; Eshwar Ramanan, graduate student; Luke Helgeson, undergraduate student; and Richard Honzatko, professor; all from Iowa State’s biochemistry, biophysics and molecular biology department, together with Kathleen Prins, graduate student, and Basler, associate professor; from Mount Sinai School of Medicine; JoAnn Tufariello; assistant clinical professor of the Albert Einstein College of Medicine, New York City; Dominika Borek, instructor; and Zbyszek Otwinowski from the University of Texas Southwestern Medical Center, Dallas; and Jay Nix from the Berkeley National Laboratory, Calif., co-authored this study.

Work in the Amarasinghe laboratory was funded in part by the Roy J. Carver Charitable Trust, National Institutes of Health, and the Midwest Regional Center for Excellence for Biodefense and Emerging Infectious Disease Research. X-ray crystallographic data were collected at the Advanced Light Source beamline 4.2.2., and the Advanced Photon Source Structural Biology Center Sector 19 beamlines.

Sources

1.Leung,Daisy W, Prins,Kathleen C ,Borek,Dominika M , et al (2010)’Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35′ Nature Structural & Molecular Biology [17 January 2010]  doi:10.1038/nsmb.1765

2.http://www.eurekalert.org/pub_releases/2010-01/isu-isu011910.php

References

3.Daisy W. Leunga,Nathaniel D. Gindera,D. Bruce Fultona,Jay Nixb,Christopher F. Baslerc,Richard B. Honzatkoa andGaya K. Amarasinghea1 Structure of the Ebola VP35 interferon inhibitory domain [January 2, 2009], doi: 10.1073/pnas.0807854106

4.WHO ‘Ebola Hemorrhagic Fever’ :http://www.who.int/csr/disease/ebola/en/

5.http://www.who.int/mediacentre/factsheets/fs103/en/index.html

6.Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling.http://www.ncbi.nlm.nih.gov/pubmed/16698997

7.http://biomarker.cdc.go.kr:8080/pathogen/pathogen_view_en.jsp?pclass=2&id=44

8.Rachel L. KaletskyJoseph R. Francica et al (2008)Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein,PNAS,doi: 10.1073/pnas.0811014106

Further Reading

http://www.rcsb.org/pdb/explore/explore.do?structureId=3FKE

http://esciencenews.com/articles/2009/01/27/penn.study.identifies.how.ebola.virus.avoids.immune.system

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Ebola.htm

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Cancer Initiating Stem Cells Supress Immune Response to Brain Tumor and the Role of STAT3 Pathway in Immunosuppression

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Glioblastoma (histology slide)

Glioblastoma (histology slide);Image via Wikipedia

Cancer-initiating cells that launch glioblastoma multiforme, the most lethal type of brain tumor, also suppress an immune system attack on the disease, scientists from The University of Texas M. D. Anderson Cancer Center report in a paper featured on the cover of the Jan. 15 issue of Clinical Cancer Research.(1)

See the rest of my article on http://www.scientificblogging.com/biochem_geek/blog/cancer_initiating_stem_cells_supress_immune_response_brain_tumor

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C-Reactive Protein (CRP) Gene Variants Not Assscoiated With An Increased Risk of Cancer

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A picture of CRP from 1B09.

A picture of CRP from 1B09.pdb made using pymol;Image via Wikipedia

Introduction

Gene variants associated with increased circulating levels of C-reactive protein, a marker of inflammation, are not associated with an increased risk of cancer, according to a brief new communication published online on January the 7th in the Journal of the National Cancer Institute.(1)

Research

The scientists,Stig E. Bojesen, M.D., Ph.D., of the Department of Clinical Biochemistry, Herlev Hospital, and Copenhagen University Hospital in Denmark, and their colleagues used a Mendelian randomization design (for more information on this see my blog post on Mendelian Randomization) to test whether four common C-reactive protein (CRP) polymorphisms were associated with increased circulating plasma CRP levels and to determine whether this increase was associated with cancer. The study population consisted of 10,215 participants in a prospective study and 36,403 participants in a cross-sectional study of the adult general population of Denmark, all of whom where genotyped for CRP single-nucleotide polymorphisms (SNPs).(1)

C-Reactive Protein

Human C-reactive protein (CRP) (a) is the classical acute phase reactant, the circulating concentration of which rises rapidly and extensively in a cytokine-mediated response to tissue injury, infection and inflammation. CRP, named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae was the first acute-phase protein to be described.(b)The protein resembles an antibody and performs several functions associated with host defence: it promotes agglutination, bacterial capsular swelling and phagocytosis, and activates the classical complement pathway through its calcium-dependent binding to phosphocholine which is expressed on the surface of dead or dying cells (and some bacteria). It is a member of the pentraxin family of proteins.(c)

Research Results

It was found that variants in the CRP gene  were associated with altered plasma levels of CRP but did not find an association between these gene variants and an increased risk of cancer. The authors write that “…although we may be able to exclude CRP per se as a cause of cancer, we cannot exclude the possibility that inflammation could lead to cancer. Also, our results do not invalidate the potential clinical use of slightly increased plasma CRP levels to predict the risk of certain cancer subtypes.”(1)

Research on C-Reactive Protein and Diabetes

Previously Eric Brunner of the Royal Free and University College London Medical School, London, and colleagues, examined the association between levels of C-reactive protein and the risk of type 2 diabetes in a paper published online in PLOS medicine in 2008.(1)

Results

Previous research had suggested that raised levels of this marker are linked with an increased risk of diabetes but it was not clear whether C-reactive protein actually caused the condition.Brunner and colleagues used Mendelian randomization to account for the effect of other variables (such as obesity, blood pressure, and socio-economic position) which might play a role in the development of diabetes.The researchers showed that levels of C-reactive protein in the blood are not likely to cause diabetes but noted that inflammation may play a causal role via upstream effectors rather than the downstream CRP.(2)

Sources:

1. Allin KH, Nordestgaard BG, Zacho J, Tybjærg-Hansen A, Bojesen SE.(2010)

‘C-Reactive Protein and the Risk of Cancer:A Mendelian Randomization Study’,available: http://jnci.oxfordjournals.org/cgi/content/abstract/djp459v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=snps+in+c+reactive+protein&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

2. Brunner EJ, Kivimäki M, Witte DR, Lawlor DA, Smith GD, et al. (2008) Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream. PLoS Med 5(8): e155. doi:10.1371/journal.pmed.0050155

3. Keavney B (2008) More Evidence Against a Causal Association between C-Reactive Protein and Diabetes. PLoS Med 5(8): e174. doi:10.1371/journal.pmed.0050174

References:

a. HUMAN C-REACTIVE PROTEIN COMPLEXED WITH PHOSPHOCHOLINE http://www.rcsb.org/pdb/explore/explore.do?structureId=1B09

b.Mark B. Pepys and Gideon M. Hirschfield (2003) C-Reactive protein:a critical update ,J. Clin. Invest. 111(12): 1805-1812 (2003). doi:10.1172/JCI18921.

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