Researchers find strong genetic risk factor for type 2 diabetes in Latin American patients

Researchers find strong genetic risk factor for type 2 diabetes in Latin American patients -

Broad Institute researchers and collaborators Harness exome sequencing in the study of 4000 Latin Americans; reveal variant of the strong effect of gene that could guide treatment

In the largest study of its kind published to date, an international team of researchers in Mexico and the US have discovered a strong genetic risk factor for type 2 diabetes that affects mainly Latin American patients, but rarely elsewhere. Further work characterized a gene called HNF1A, responsible for a rare hereditary form of diabetes which against a class of widely available and inexpensive drugs is very effective. The discovery provides important new clues about the genetics of type 2 diabetes populations in Latin American populations, and suggests the possibility of treatments tailored depending on the genetic makeup of patients. The study appears in the June 11 issue of Journal of the American Medical Association ( JAMA ).

"We have identified a genetic risk factor that is present in about 2 percent of Mexicans with type 2 diabetes, and its effects are considerable - increase the risk of developing the disease five times a person, "said corresponding author Jose Florez, associate member of the broad Institute, associate Professor of medicine at Harvard medical school and a physician assistant in the Unit of diabetes and human genetics research Centre at the General Hospital Massachusetts. "It is a striking finding, which really underscores the power of the genetic approach."

Although type 2 diabetes is a major public health problem worldwide, countries of America Latin bear a disproportionate burden. in Mexico, for example, it is estimated that the disease affects more than 14 percent of adults, which is about twice the rate among Europeans and white Americans. a number of factors are thought to drive this increased prevalence, including environmental influences and genetic.

Several large-scale genomic studies have been conducted to identify genetic risk factors that contribute to type 2 diabetes to date, more than 70 genomic regions have been implicated in the disease. However, most of these studies have focused on European populations, leaving a significant portion of the genomic landscape of unexplored disease.

An international research team, known as the type name SIGMA 2 Diabetes Consortium, was formed to investigate the genetics of type 2 diabetes in Mexicans and other Latin American populations. In the current study, the team harnessed exome sequencing, a method that decodes the genetic information in genes coding for proteins - ". Exome" a relatively small part of the genome called Whole exome sequencing has the potential to reveal very rare variations in the genetic code that are often not captured by other approaches, but are more likely to affect protein function.

This work was conducted as part of the Slim Initiative for Genomic Medicine for the Americas (SIGMA), a Mexican-American joint project funded by the Carlos Slim Foundation, the Carlos Slim Health Institute. SIGMA focuses on several key diseases with particular relevance to public health in Mexico and Latin America, including type 2 diabetes and cancer.

For the study JAMA , the researchers analyzed samples from nearly 4,000 participants, both people with type 2 diabetes and healthy controls who were of Latin origin Mexican -américaine or another. Their first results have identified two genes :. SLC16A11, the team previously found to be linked to an increased risk of diabetes (results published late last year in the journal Nature), and type 2 HNF1A

The researchers found a mutation in the gene HNF1A which is present in about 2 percent of Mexicans with type 2 diabetes, but only a tenth as many healthy adults and is associated with a four to five times greater risk of the disease has increased. This variant of the gene not previously associated with the current form of type 2 diabetes, and is most often found in populations of Latin America or other Native American descent.

Although the role of the new variant is the gene itself HNF1A is understood. When its function is completely disabled, a rare inherited form of diabetes known as MODY results. MODY, or Maturity Onset Diabetes of the Young usually emerge earlier as type 2 diabetes, often in the middle twenties, and occurs even in the absence of pre-existing obesity.

However, the HNF1A mutation identified in the current study, called p.E508K, is considered less serious that those responsible for MODY, leaving some residual function of the intact gene. Patients with type 2 diabetes who wear this attenuated form are generally indistinguishable from other patients with type 2 diabetes in terms of age of onset and body weight.

These results, while shedding new light on the genetics of type 2 diabetes populations, raise important questions about potential treatments - namely, whether drugs that preferentially work in patients with MODY work also in patients with type 2 diabetes who carry the variant p.E508K. MODY resulting from HNF1A mutations is often successfully treated with a type of drug known as sulfonylurea because patients with MODY are much more sensitive to this drug that metformin, the first-line drug generally prescribed in diabetes of common type 2.

"This is an exceptional discovery - which helps explain the epidemic type 2 diabetes rates in the populations of Latin America," said Teresa Tusie-Luna, project manager at Instituto Nacional de Ciencias y M-dicas Nutrici-n n Zubir- Salvador and senior researcher at the biomedical research Institute, national University of Mexico. "But we must be aware that if the conclusion is associated with high levels of risk of disease, we still do not know how the mutation behaves and whether there is a specific therapeutic method can be safely applied in the clinic for people who carry the mutation There is much more we need to learn "

This work was made possible by a large multinational consortium which includes: ..

• team based in Boston included researchers from the Broad Institute, Massachusetts General Hospital and Harvard Medical School. It was led by Florez; David Altshuler, deputy director and academic director of the Broad Institute and Harvard Medical School professor at Massachusetts General Hospital; and Daniel MacArthur, group leader in the analysis unit and translational genetics at Massachusetts General Hospital, Assistant Professor at Harvard Medical School and a researcher at the Broad Institute; the analysis was conducted by Karol Estrada, a researcher at the Unit of Analysis and translational genetics at Massachusetts General Hospital and the Broad Institute.

• The team based in Mexico City included researchers from the Instituto Nacional de Ciencias y M -dicas Zubir Nutrici-n-n Salvador, Instituto de Investigaciones Biom-dicas UNAM, led by Teresa Tusi- and Carlos Aguilar; the Instituto Nacional de Medicina Gen-mica (INMEGEN) led by Lorena Orozco; and the Study of Diabetes Mexico led by Clicerio Gonz-lez-Villalpando.

• The Los Angeles-based team included investigators from the Keck School of Medicine of the University of Southern California and was led by Brian Henderson and Christopher Haiman.

• team based in Norway included researchers from the University of Bergen and Haukeland University Hospital, and was conducted by Nj-lstad Pl.