New genetic clues for arthritis

Arthritic hands


Current treatments relieve the symptoms but not for all patients, and there is no cure

An international team of researchers has found more than 40 new areas in DNA that increase the risk of rheumatoid arthritis.

The work is the largest genetic study ever carried out, involving nearly 30,000 patients.

The investigators believe new drugs could be developed to target these areas that could one day provide a cure for the disease.

The findings are published in the Journal Nature.

“Start Quote

What this offers in the future is an opportunity to use genetics to discover new medicines for complex diseases like rheumatoid arthritis and to treat or even cure the disease”

Prof Robert PlengeHarvard Medical School

The research team compared the DNA of arthritis patients with those without the disease and found 42 ‘faulty’ areas that were linked with the disease. The hope is that drugs can be developed to compensate for these faults.

The lead researcher Professor Robert Plenge of Harvard Medical School found that one of these areas produced a weakness that was treated by an existing drug that was developed by trial and error, rather than specifically made to correct the genetic problem.

This finding, he says, shows such discoveries could be used to design new drugs.

“What this offers in the future is an opportunity to use genetics to discover new medicines for complex diseases like rheumatoid arthritis to treat or even cure the disease,” he said.

Complex diseases

Some have argued identifying genetic weak areas for complex diseases – known as single nucleotide polymorphisms (SNPs) – is not useful. There is little or no evidence, they argue, that “silencing the SNPs” with drugs will relieve any symptoms.

But Dr Plenge says the fact that he has found an established drug that treats the symptoms that arise from a particular SNP for rheumatoid arthritis validates this genetic approach.

“Start Quote

There are already therapies that have been designed in the cancer field that might open up new opportunities for retargeting drugs”

Prof Jane WorthingtonDirector, Centre for Genetics

“It offers tremendous potential. This approach could be used to identify drug targets for complex diseases, nut just rheumatoid arthritis, but diabetes, Alzheimer’s and coronary heart disease”

Fast track

The study also found SNPs in the rheumatoid arthritis patients that also occur in patients with types of blood cancer.

According to Prof Jane Worthington, director of the centre for genetics in Manchester, this observation suggests that drugs that are being used to treat the cancer could be effective against rheumatoid arthritis and so should be fast tracked into clinical trials.

“There are already therapies that have been designed in the cancer field that might open up new opportunities for retargeting drugs,” she told BBC News.

“It might allow us a straightforward way to add therapies we have to treat patients with rheumatoid arthritis”.

Genetic Test for Autism Refuted.

A team of Australian scientists claimed to have developed a genetic test that predicts a person’s risk of developing autism spectrum disorder (ASD) with 72 percent accuracy. Writing in Molecular Psychiatry, the team led by Stan Skafidis and Carlos Pantelis from the University of Melbourne said that their panel of 237 genetic markers could “correctly classify ASD from non-ASD individuals” and “may provide a tool for screening at birth or during infancy to provide an index of at-risk status.”

But a new study, led by Benjamin Neale from Massachusetts General Hospital, suggests that those claims were overblown. Neale’s team replicated the Australian group’s research in a larger sample, and found that the proposed panel of markers did not accurately predict ASDs.

“The claims in the original manuscript were quite bold. If they were true, it really would have been quite a major advance for the field, with serious ramifications for patients and other risk populations,” said Neale. “I think it’s important to ensure that this kind of work is of the highest quality.”

“This is a convincing refutation that calls into question the original results on specific technical grounds, rather than simply a non-replication that leaves a puzzling discrepancy between the two studies,” said Leonid Kruglyak, a geneticist from the University of California, Los Angeles, who was not involved in either study.

In 2012, Skafidis’s team compared the genes of 732 European people with ASD from the Autism Genetic Resource Exchange database, with those of 123 neurotypical people from a different cohort. They searched for single nucleotide polymorphisms (SNPs) that were linked to ASD, especially those in genes with roles in relevant cellular pathways.

They eventually settled on 237 SNPs in 146 genes, which they used to create a classifier for predicting ASD risk. When they tested the classifier on 243 cases and 42 controls from the same databases, it correctly predicted ASD with an accuracy of 85.6 percent.

The team then tested the classifier on an independent group of people—525 with ASD taken from the Simons Foundation Autism Research Initiative and 2,620 controls from the Wellcome Trust Birth Cohort. It identified the ASD cases with an accuracy of 71.7 percent.

But to other geneticists, these results seemed too good to be true. They implied that this small set of SNPs can explain around 11 percent of the variation in ASD risk—an unprecedented figure for any psychiatric condition. If the set truly had such strong effects, genome-wide association studies (GWAS) should have identified those SNPs by now—and they had not. It will likely take a sample of hundreds of thousands of people to find SNPs with such predictive power, as has been the case for other traits like height. “The magnitude of the study you need is dramatically larger than what was presented,” said Neale.

Neale wrote to Skafidis’s team asking for the full list of 237 SNPs, but did not receive it. (Skafidis told The Scientist that they offered the code that they used to generate their results, which should have been even better.) As such, they focused on the 30 most important SNPs, which were detailed in the published paper.

By comparing 5,417 cases and 5,417 controls from the Psychiatric Genomics Consortium, Neale’s team found that none of the 30 SNPs were significantly associated with ASD risk. The researchers also combined the SNPs into a classifier, using methods detailed in the original paper, and tested it on 4,623 cases and 4,623 controls from the same group. Again, the set failed to predict ASDs any better than chance. Finally, they also showed that the cellular pathways which the Australian team identified are not significantly associated with ASDs. The team’s results were published as a letter to the editor on 22 October, also in Molecular Psychiatry.

Several factors could explain the differences between the two studies. The Melbourne team initially tested the accuracy of their risk classifier on the same group of people whom they used to identify their SNP set. This is bad practice. “To appropriately assess the accuracy of a classifier, the sample which is used to develop it must be fully distinct from the sample on which it is tested,” said Kruglyak.

The Australian researchers also drew their cases and controls from separate populations with subtly different ethnic compositions. The SNPs they identified could have reflected reflect random ancestral differences between the two groups, rather than meaningful differences in ASD risk. Daniel Geschwind from the University of California, Los Angeles, made the same argument in a letter regarding Skafidis’s paper, which was published in the same journal this April.

Kruglyak added a third possible explanation: “batch effects, in which cases and controls are genotyped at different times and on different technology platforms,” he proposed. This problem also plagued a similar recently-retracted paper, which identified a panel of SNPs that could supposedly predict longevity.

But Skafidis said that Neale’s team may have come to different conclusions because the group did not use the full set of SNPs, nor the code that was provided. His team has submitted a response to the new study, which is in revision with Molecular Psychiatry (and does list the full set of 237 SNPs).

Meanwhile, Neale emphasized that other research into the genetics of autism are yielding stronger results. Several studies have identified loss-of-function mutations, and differences in the number of copies of certain genes, that are linked to ASD risk. Promising GWAS results have been presented at conferences and are making their way into published papers. “Autism genetics shouldn’t be tarnished by science that hasn’t been robustly proven,” he said. “There are successes beginning to emerge, and that’s really exciting and important.”

Gene Variant Linked With Reduced Lung Cancer Risk.

A variant in a gene involved with inflammation and the immune response is linked with a decreased risk of lung cancer. That is the finding of an analysis published early online in CANCER, a peer-reviewed journal of the American Cancer Society. The results add to the growing body of literature implicating these processes in the development of lung cancer.

Meredith Shiels, PhD, MHS and Anil Chaturvedi, PhD, of the National Cancer Institute in Rockville, MD, and their colleagues analyzed 1,429 variants in inflammation- and immunity-related genes from 378 patients with lung cancer and 450 healthy controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. The investigators observed a significant link between lung cancer and 81 single nucleotide polymorphisms (SNPs) located in 44 genes.

They then compared these results with observed or imputed data from four recently completed genome-wide association studies (GWAS) that included 5,739 lung cancer cases and 5,848 controls. Of the 81 SNPs, one in particular — named rs4648127 and located within the NFKB1 gene — was associated with lung cancer in both analyses. This SNP was linked with an estimated 44 percent reduced risk of lung cancer in the cancer screening trial and a 21 percent reduced risk in the combined GWAS analysis.

The NF-κB, or nuclear factor kappa B, protein that is produced in part from the NFKB1 gene is known to play an important role in immunity and inflammation by regulating gene expression, cell death, and cell proliferation. Also, previous research has shown that immunity and inflammation may affect the development of lung cancer. “Our study provides further evidence that inflammation may be associated with lung cancer risk,” said Dr. Shiels. She added that future studies should further examine the NFKB1 gene and its relationship with lung cancer risk.



Gastric Cancer with Epstein-Barr Virus Is Less Deadly.

EBV tumor positivity was associated with lower tumor stage and longer survival.


In a small but significant percentage (9%) of gastric cancers, tumor cells contain Epstein-Barr virus (EBV). To assess whether EBV positivity is associated with cancer outcomes, investigators pooled data on 4599 patients with invasive gastric cancer from 13 case series.

Median follow-up was 3.0 years. The prevalence of EBV-positive cancer was 8.2%. In multivariate analysis, EBV positivity was associated with lower tumor stage (odds ratio, 0.79 per unit change in stage; 95% confidence interval, 0.69–0.91). In unadjusted regression analysis, higher tumor stage was associated with higher mortality, with hazard ratios of 3.1 for stage II, 8.1 for stage III, and 13.2 for stage IV when compared with stage I. Median survival was higher in patients with EBV-positive tumors than in patients with EBV-negative tumors (8.5 years vs. 5.3 years; P=0.0006). After adjusting for stage and other potential confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI, 0.61–0.86). Heterogeneity among studies was low.

Comment: Findings from this large study support previous data showing a better prognosis for gastric cancers that contain Epstein-Barr virus. However, because these results are from a pooled analysis of case series rather than a meta-analysis of published studies, it is possible that inclusion of other case series could affect the results. In addition, results are limited by the lack of data on treatment. Nevertheless, by focusing on these studies, the investigators were able to evaluate a relatively homogeneous dataset, minimizing confounding between series. As the authors note, the mechanism for improved outcomes with EBV positivity requires additional study, as does the possibility that EBV-positive gastric cancer might represent a distinct disease entity.


Source:Journal Watch Gastroenterology

Study reveals how inherited risk factors in ‘junk DNA’ affect breast cancer predisposition.

Novel method provides insights in biology of breast cancer

In light of recent large population studies, it’s known that some people carry inherited DNA changes that increase their lifetime risk of diseases, including breast and prostate cancer. To the surprise of scientists, scores of these “risk alleles” have been found in vast regions of the genome – sometimes called “junk DNA” or “dark matter” – that don’t carry the genetic code for proteins, so how they influence an individual’s cancer risk isn’t known.

In a new study, scientists at Dana-Farber Cancer Institute have shown that several such alleles affect DNA segments known as “enhancers” and turn on or off genes involved in breast cancer. Interestingly, four of the genes the research team pinpointed hadn’t previously been implicated in breast cancer. The scientists, led by Matthew Freedman, MD, PhD, reported their findings in the Jan. 31 issue of Cell.

“We can use this tool to show that the DNA variation that influences risk controls the expression of a nearby gene involved in cancer,” said Freedman, of Dana-Farber’s Center for Cancer Genome Discovery and Center Functional Cancer Epigenetics and the Broad Institute. Freedman explained that knowing this link gives scientists new insights into the biology of breast cancer. “If you can identify which pathway or gene is involved in the risk of developing cancer, primary cancer prevention efforts can be more rationally designed.”

In the past several years, investigations called genome-wide association studies (GWAS) have helped define the genetic root causes of many diseases, including cancer. These studies have identified large numbers of relatively common polymorphisms, or places in the human genome where the genetic code differs among individuals, that are associated with inherited, increased risks of cancer.

About 70 such variants – also known as single-nucleotide polymorphisms, or SNPs – have been identified in prostate cancer and an equal number in breast cancer. Although these risk alleles are common in the population, each one increases cancer risk by only a modest amount, according to Freedman. Some individuals may inherit enough risk variants, however, to make a significant difference that someday might prompt physicians to recommend preventive measures.

Freedman said that because the segments of DNA containing the variants lie in uncharted regions of the genome, “it has been a challenge to connect these variants to genes that influence cancer risk.” Clues to their function came in 2012, when reports based on a public database called ENCODE suggested that many of these SNPs are located within regions that regulate the activity of genes.

The Dana-Farber scientists tapped this information and another large publicly funded database, The Cancer Genome Atlas, which contains thoroughly analyzed samples of tumors and the corresponding normal tissue from cancer patients. They studied data on increased gene activity in tumor samples from 407 breast cancer patients. At the same time, they examined data on normal blood samples from those same patients, which revealed the number of breast cancer risk alleles the patients had been born with.

Sophisticated computational methods then linked the risk alleles’ promoter functions to six overactive genes within the breast cancers: two of the genes had already been implicated in breast cancer, but four were identified for the first time, the scientists reported. “Our data showed that the expression of these genes was under genetic control [of the DNA variants],” Freedman said.

He said that this study, the largest of its kind, “is just the beginning” of further work to understand how these variants affect the biology of breast cancer development.

First author of the report is Qiyuan Li, PhD, a postdoctoral fellow in the Freedman lab.

The research was supported in part by grants from the National Institutes of Health (U19CA148537 and R01 CA131341), the Mayer Foundation, the H.L. Snyder Medical Foundation, the Kohlberg Foundation, and the A. David Mazzone Awards Program.

At Dana-Farber/Brigham and Women’s Cancer Center, breast cancer is treated through the Susan F. Smith Center for Women’s Cancers Breast Oncology Program.

Source: Dana-Farber Cancer Institute.


Association between low vitamin D, clinical outcomes varied.

Previous studies have suggested that low 25-hydroxyvitamin D concentration could be a modifiable risk factor associated with chronic disease. However, recent data derived from four cohort studies now suggest genetic variants might modify the association between low 25-hydroxyvitamin D and adverse health outcomes such as hip fractures, incident myocardial infarction, incident cancer or death from any cause.

Gregory P. Levin, PhD, of the University of Washington in Seattle, and colleagues examined 141 single nucleotide polymorphisms (SNPs) from a discovery cohort of 1,514 patients from the Cardiovascular Health Study (CHS). From 1992 to 1993, 2,312 patients underwent serum 25-(OH)D measurements and were followed for 11 years.

Besides the CHS, researchers used replication meta-analyses in the US Health, Aging, and Body Composition study (Health ABC; n=922) with follow-up in 1998-1999 through 2005. They also used the Italian Invecchiare in Chianti study (InCHIANTI; n=835) with follow-up in 1998-2000 through 2006; and the Swedish Uppsala Longitudinal Study of Adult Men (ULSAM; n=970) with follow-up in 1991-1995 through 2008.

Levin and colleagues found that interactions between 5 SNPs and low 25-(OH)D were identified in the CHS discovery cohort and one SNP associated with a variant in the VDR gene replicated from the Health ABC study.

Of the patients examined from the CHS, researchers discovered that low 25-(OH)D was linked to hip fractures, incident MI, incident cancer or death from any cause (composite outcomes) in patients with one minor allele at rs7968585 (HR=1.40; 95% CI, 1.12-1.74) and in patients with two minor alleles at rs7968585 (HR=1.82; 95% CI, 1.31-2.54). However, researchers wrote there was no evidence of an association in patients with no minor alleles (HR=0.93; 95% CI, 0.70-1.24).

“These results suggest that individuals with specific 25-(OH)D metabolism genotypes may be particularly susceptible to, or protected from, the potential adverse health effects of low vitamin D,” the researchers wrote.

Source: Endocrine Today.