Initial findings of BIPMed were presented during FAPESP Week

Data from a study involving carriers of dystonia demonstrate the importance of gathering genetic data on reference populations in Brazil.

By Karina Toledo, in Michigan  |  Agência FAPESP – In an effort to kick start implementation of precision medicine in Brazil, members of five of the 17 FAPESP-funded Research, Innovation and Dissemination Centers (RIDCs) met in mid-2015 to establish the Brazilian Initiative on Precision Medicine (BIPMed).

The initial findings of this partnership were presented March 28 during FAPESP Week Michigan-Ohio by one of the project founders, Iscia Lopes-Cendes, a professor at the School of Medical Sciences of the University of Campinas (FCM-Unicamp).

Included in the initiative are the Center for Computational Engineering and Sciences (CCES), the Center for Cell-Based Therapy (CTC), the Obesity and Comorbidities Research Center (OCRC) and the Center for Research on Inflammatory Diseases (CRID), lead by the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN).

"The first product launched under the scope of the BIPMed was a public genetic database, the first of its kind in Latin America, that can be accessed at http://bipmed.iqm.unicamp.br/," said Lopes-Cendes.

According to her, the database has already received information from 29 people from the region of Campinas in upstate São Paulo who underwent sequencing of the whole exome, the part of the genome that holds the protein-encoding genes, where disease causing mutations are most likely to occur.

By analyzing data from the 29 exomes currently in the database, the group has found 209 genetic variants that have not been described in any other database in the world, but it is still not known whether or not these genomic variations are related to diseases.

"We already have exome sequencing data from 250 other people ready to be included and analyzed. It is important to stress that we are not talking about patients, but rather about a reference population of people who are healthy, as far as we know. We recruit these volunteers from among those who accompany the patients receiving medical care at the Hospital de Clínicas at Unicamp and it is therefore constitutes a representative sampling of the genetic structure of the patient cohort in the BRAINN studies,” Lopes-Cendes explained.

Also included in the database was information about the presence of more than a million molecular markers of single-nucleotide polymorphisms (SNPs) in 200 individuals of the reference population.

"These SNPs are genetic variations that can be found in any part of the genome, not just in the protein-encoding part. The difference is that instead of sequencing the whole genome, we use a microarray technique with specific probes. SNPs are common molecular markers, found in at least 5% of the population that may or may not be related to the development of diseases,” Lopes-Cendes explained.

As explained by the researcher, these genomic variations that occur outside the protein-encoding region do not usually cause disease, but serve to provide an idea of the genetic structure of the population.

An example of the clinical importance of this knowledge was presented by Lopes-Cendes during FAPESP Week Michigan-Ohio as well as published in the article in the journal Acta Neurologica Scandinavica.

In the study, the team from BRAINN analyzed data from 76 patients receiving medical care at the Hospital de Clínicas at Unicamp who carried a neurological disorder known as dystonia. The disease is characterized by involuntary contractions in one or more muscles that can be painful and intense. Unlike Parkinson’s disease, dystonia can affect people of any age.

"We initially studied the clinical characteristics of our patients and confirmed that they constituted a representative sampling from around the world, in other words, they presented the same conditions as dystonia patients from other countries. We then investigated the two genetic mutations most commonly associated with the disease on the TOR1A and THAP1 genes," the researcher said.

According to Lopes-Cendes, there is an international recommendation to investigate the presence of these two mutations in all carriers of dystonia symptoms in order to establish the diagnosis and identify other family members who may carry the disease.

"However, the study results showed that the TOR1A mutation was not even found in our sampling, while an alteration in the THAP1 gene was found at a much lower frequency than that described in the literature. This indicates that international recommendations are not necessarily valid for Brazil, which has a population whose genetic structure is much more heterogeneous as a result of crossbreeding. That is why it is important to have a genetic database that is representative of our population,” said Lopes-Cendes.

According to her, the group’s studies show that other genetic variants described in international studies as the cause of serious disease were often found in the reference population included in the BIPMed database.

"To make sure that a mutation does in fact cause disease, it cannot be found in healthy individuals. But this analysis is only possible if we have data from a representative population of that individual. If we only look at international databases, we could get false results,” she added.