Big data study reveals molecular links

Why do people infected with the human immunodeficiency virus (HIV) often suffer from cardiovascular, liver, and other comorbidities? Researchers at the Center for Individualized Infection Medicine (CiiM) investigated this question as part of the 2000HIV study, a multi-omics cohort coordinated by several research centers in the Netherlands.

They identified various molecules and mechanisms that could be linked to the development of these comorbidities. The scientists are making the extensive results of their study freely available. They hope that they will be used for new research approaches and lead to a better understanding of the underlying causes and to helpful therapies.

The researchers published their study results in the journal Nature Medicine. The CiiM is a joint institution of the Helmholtz Center for Infection Research (HZI) and Hannover Medical School (MHH).

“People with HIV often suffer from non-AIDS-related comorbidities such as cardiovascular disease, liver disease, or cancer. They are more prone to chronic inflammation in the body, which causes them to age faster and have a lower life expectancy than other people,” says Prof. Yang Li, head of the department of Computational Biology for Individualized Medicine and Director of CiiM.

“With our big data study, we wanted to find out which molecular players are behind these disease-causing processes.”

The study was based on extensive multi-omics data sets from over 1,300 people with HIV, which were collected as part of a large-scale cohort study (2000HIV Study) conducted in the Netherlands.

“This multi-omics data treasure trove, comprising a wide variety of data such as gene data, protein data, and metabolic data, provided us with unique insights into different levels of molecular biology,” says Javier Botey-Bataller, a scientist in the CiiM department Computational Biology for Individualized Medicine and one of the two lead authors of the study.

His CiiM colleague Nienke van Unen, co-first author, adds, “We analyzed another important molecular data level—the strength of the immune response. This reflects the fitness of the immune system in the face of challenges from pathogens.”

The researchers correlated the multi-omics data with the study participants’ existing comorbidities—including cardiovascular disease, narrowing of the carotid artery due to plaques, and chronic obstructive pulmonary disease (COPD)—and searched for abnormalities, for example, in genes or molecular signaling pathways.

“We were actually able to uncover a whole range of previously hidden molecular patterns and players associated with the respective comorbidities,” says Botey-Bataller. In addition, the researchers identified molecules that have the potential to predict the strength of the immune response.

“An excessive immune response can lead to inflammation, which is the main cause of comorbidities in people with HIV. Therefore, the intensity of the immune response is a very important parameter,” explains Botey-Bataller.

“Our study has enabled us to draw up a kind of molecular map that can be used to guide further research projects, for example to investigate the significance of certain genes or proteins in this context.” The data and analysis results of the study are available online and can be used for further research projects.

Yang Li said, “Our study is the first in the field of research into comorbidities in HIV to use a multi-omics approach. Individual molecular biological levels already reveal a great deal. However, it was only by comparing the different molecular biological levels that we were able to uncover completely new players and connections that can be used as starting points for the development of novel therapies in the future.”

In the course of their investigations, the researchers made another interesting discovery: They found that a specific variant of the NLRP12 gene, which is involved in regulating cellular inflammatory processes, causes particularly high inflammation levels.

“This was the case in study participants who were infected with HIV, but also in a comparison cohort where participants did not have HIV,” explains Nienke van Unen.

“People with this gene variant therefore seem to be generally more susceptible to high inflammation levels and associated diseases.”