Association between Type 2 Diabetes Loci and Measures of Fatness

Type 2 diabetes (T2D) is a metabolic disorder characterized by disturbances of carbohydrate, fat and protein metabolism and insulin resistance.

The majority of T2D patients are obese and obesity by itself may be a cause of insulin resistance. Our aim was to evaluate whether the recently identified T2D risk alleles are associated with human measures of fatness as characterized with Dual Energy X-ray Absorptiometry (DEXA).

Nine single nucleotide polymorphisms (SNPs) in the CDKN2AB, CDKAL1, FTO, HHEX, IGF2BP2,KCNJ11, PPARG, SLC30A8 and TCF7L2 genes were genotyped.

Linear regression was used to study association between individual SNPs and the combined allelic risk score with body mass index (BMI), fat mass index (FMI), fat percentage (FAT), waist circumference (WC) and waist to hip ratio (WHR).

Significant association was observed between rs8050136 (FTO) and BMI (p = 0.003), FMI (p = 0.007) and WC (p = 0.03); fat percentage was borderline significant (p = 0.053). No other SNPs alone or combined in a risk score demonstrated significant association to the measures of fatness.

From the recently identified T2D risk variants only the risk variant of theFTO gene (rs8050136) showed statistically significant association with BMI, FMI, and WC.

Investigation of TNFA 308G > A and TNFB 252G > A polymorphisms in genetic susceptibility to migraine.

J Neurol. 2009 Dec 25; Ghosh J, Joshi G, Pradhan S, Mittal B look for the association of tumor necrosis factor (TNF) gene polymorphisms (TNFA 308G > A, and TNFB 252G > A) in genetic susceptibility to migraine. The pathogenesis of migraine involves many immune-mediated mechanisms in the vascular endothelium. TNF, being a potent immunomodulator and pro-inflammatory cytokine, is suggested to be involved in inflammatory reactions leading to migraine attacks. A total of 216 normotensive migraine patients, 160 tension type headache (TTH) patients and 216 healthy controls (HC) were recruited in the study. The genetic polymorphisms were investigated through SNP association analysis using a matched case control migraine population. Genotyping of TNFA 308G > A polymorphism and TNFB 252G > A was done using ARMS PCR and PCR-RFLP, respectively. A borderline association was observed in TNFA 308GA genotype in migraine patients versus HC (p = 0.043; OR = 1.763; 95% CI = 1.019-3.051). After sub-grouping migraine into migraine with aura (MA) or without aura, significant difference at genotypic (p = 0.015; OR = 2.293; 95% CI = 1.172-4.487) as well as allelic (p = 0.035; OR = 1.955; 95% CI = 1.047-3.651) level was evident. The difference was even more significant in female MA at genotypic (p = 0.006; OR = 2.901; 95% CI = 1.361-6.181) and allelic level (p = 0.017; OR = 2.318; 95% CI = 1.159-4.635) as well as for A allele carriers in MA [p value = 0.020; OR = 2.205 (1.132-4.295)] and female MA (p value = 0.008; OR = 2.741; CI = 1.297-5.792). No association of TNFB252G > A was observed in migraine patients or any subgroups. We did not find any association of TNFA or TNFB gene polymorphisms with TTH. In conclusion, the TNFA 308G > A polymorphism was found to be associated with MA, particularly in females, whereas we could not find any association of TNFB 252G > A polymorphism in genetic susceptibility to migraine on comparing the migraine patients with HC or TTH patients.

Toward reading your own personal 'Book of Life'

What secrets about your risk for diseases are written in your own personal "Book of Life" - the 30,000 or so genes that make you you?

Advances in DNA-sequencing technology are bringing closer the day when it will be more economical for consumers to get an answer to that question, and others, by ordering up the deciphering of their entire genetic endowment - their "personal genome." With their Book of Life in hand, consumers and their physicians could map out strategies for the prevention, early diagnosis, and more effective treatment of diseases ranging from cancer to rare-genetic disorders.

C&EN Senior Editor Celia Henry Arnaud notes that the first human genome sequence cost more than $2 billion and took about a decade to complete. Technological advances now have cut the time to as little as one week, and some companies are charging individuals $48,000 for the service, a cost that experts expect to drop sharply in the coming years, the article notes.

But the technology also raises important ethical and legal issues, including the possibility of discrimination on the basis of genetic information in the areas of employment and insurance coverage. Many believe that personal genomes are inevitable. "In the future, sequencing will be so cheap and so easy to access that everybody could get sequenced if they want. It'll be iPod pricing," says the CEO of a company that specializes in direct-to-consumer genome sequencing.

Genomes of identical twins reveal epigenetic changes that may play role in lupus

Identical twins look the same and are nearly genetically identical, but environmental factors and the resulting cellular changes could cause disease in one sibling and not the other.

In a study published online in Genome Research (www.genome.org), scientists have studied twins discordant for the autoimmune disease lupus, mapping DNA modifications across the genome and shedding light on epigenetic changes that may play a role in the disease.Because the genetic makeup of monozygotic twins (commonly known as identical twins) is nearly identical, phenotypic traits and heritable diseases are often concordant, manifesting in both siblings.

However, some phenotypes and diseases such as autoimmune disease can arise in only one sibling, suggesting other factors such as environment likely play a role in determining phenotypic differences.Epigenetic modifications, cellular changes that can influence expression of genes, are now widely recognized to influence phenotype and frequently occur in disease. Furthermore, environmental factors such as diet and chemical exposure can change the epigenetic status of genes.

Recent research has identified epigenetic modifications at several aberrantly regulated genes in autoimmune diseases such as systemic lupus erythematosus (SLE), and other studies have suggested that epigenetic differences are associated with phenotypic discordance between identical twins. In this work, researchers from Spain and the United States performed the first genome-wide high-throughput analysis of a specific epigenetic modification, DNA methylation, in the context of autoimmune disease. Taking advantage of the identical genetic background in monozygotic twins, the group directly compared DNA methylation in healthy twins and twins discordant for autoimmune diseases, including SLE, looking for changes that could be related to pathogenesis in one sibling and not the other.n the case of SLE, the group found widespread changes in DNA methylation status at a significant number of genes.

Dr. Esteban Ballestar, senior author of the study, noted that this is the largest number of genes exhibiting DNA methylation changes observed in an autoimmune disease to date, and includes genes previously implicated in SLE pathogenesis. Importantly, Ballestar's team found that a significant number of the novel differentially methylated genes are related to multiple immune system functions and are potentially linked to SLE."Our study suggests that the effect of the environment or differences in lifestyle may leave a molecular mark in key genes for immune function that contributes to the differential onset of the disease in twins," Ballestar said. Most studies of DNA methylation and human disease have been in the context of cancer research, Ballestar noted, and he hopes that this work will attract more researchers to also investigate DNA methylation alterations in autoimmune disease and other disorders for the development of therapies.

Lupus is a chronic inflammatory disease that can affect various parts of the body, especially the skin, joints, blood, and kidneys.

Genetics Times: New research could advance research field critical to personalized medicine

It's the ultimate goal in the treatment of cancer: tailoring a person's therapy based on his or her genetic makeup.

While a lofty goal, scientists are steadily moving forward, rapidly exploiting new technologies. Researchers at Georgetown Lombardi Comprehensive Cancer Center report a significant advance in this field of research using a new chip that looks for hundreds of mutations in dozen of genes.

The goal of personalized medicine is to determine the best treatment and the optimal dose carrying the fewest side-effect, especially as new drugs are discovered and treatment options increase. Variations in our genes encode proteins, which impact how a drug is metabolized or taken in by the cells. This directly impacts the drug's effectiveness and the kinds of side-effects that may be caused by its toxicity.

"Currently, available genotyping tools test only a few genes at a time," explains John F. Deeken, a pharmacogentic researcher at Lombardi. "With a new chip called DMET, as many as 170 genes can be examined for more than a thousand variations. This type of turn-key testing, if validated, could eventually replace highly-specialized, time-consuming and labor-intensive testing -- thus allowing more institutes the opportunity to pursue genotyping and pharmocogenetic research. That alone would be a significant development for our field and for expediting the research many of us believe is the future of medicine."

Such a development is particularly critical for cancer research, both in terms of drug discovery and treatment. Genetic variability among patients in cancer clinical trials is not commonly taken into account, a factor that could skew dosage amounts and doom an otherwise promising new drug. A more simple and faster test could be readily incorporated into treatment trials.

Deeken serves as a consultant to Sanofi-Aventis, the manufacturer of docetaxel, a drug involved in the current reported study. Three other authors are employees of Affymetrix, the manufacturer of the DMET platform. The study was done in part at the National Cancer Institute and supported by funding from the National Institutes of Health.