Exploring genetic regulation of immunoglobulin A

Increased levels of the antibody immunoglobulin A (IgA) are correlated with the manifestation of several diseases as well as African ancestry, according to findings published in Nature Communications. The findings provide new insights into the genetic regulation of IgA levels and its potential role in human disease.

"This study, which has found common IgA regulation across ancestral backgrounds, provides insights into the regulation of the human immune system broadly and helps to open doors to understanding how changes in immune system regulatory processes can impact other major organ systems," said Theresa Walunas, Ph.D., associate professor of Medicine in the Division of General Internal Medicine and a co-author of the study.

IgA is an antibody produced by mucous membranes mainly in the respiratory and digestive tracts and is also found in many bodily fluids. Its purpose is multifaceted, playing a key role in detecting food allergies, contributing to the development of different autoimmune and inflammatory diseases, and helping signal the body's immune system to fight off infection.

Increased IgA levels have been shown to contribute to the manifestation of multiple diseases, including kidney disease and diabetes. IgA levels can be increased by a combination of genetic and environmental factors, including age and sex, but previous work has neglected to include more diverse populations when studying the genetic regulation of IgA levels in individuals.

In the current study, investigators performed a genome-wide analysis of serum IgA levels in more than 40,000 participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) representing different ancestral backgrounds, revealing more than identified 20 genome-wide significant loci, or significant positions of genes on the patient's chromosome, and 11 of which were novel.

These loci encode genes were also enriched in immune-related pathways, and 13 candidate genes demonstrated IgA abnormalities when genetically manipulated in mouse models.

Further analysis using clinical annotations derived from the Electronic Medical Records and Genomics (eMERGE) Network of 12 medical centers with electronic health records linked to genome-wide genotype data, including Northwestern University, revealed positive genetic correlations of serum IgA levels with IgA nephropathy (a rare type of kidney disease), type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease and several infections.

African ancestry was also consistently associated with higher serum IgA levels and a greater frequency of IgA-increasing alleles—a set of copied genes with one inherited from each parent—compared to other ancestries.

"The Nortwestern eMERGE team is continuing this work in eMERGE4, where we are working to develop more ancestry-spanning multi-gene analyses and testing how patients and clinicians can use this information to guide care decisions. We're currently enrolling people who are interested in participating in this research" said Walunas, who is also an associate professor of Microbiology-Immunology, of Preventive Medicine in the Division of Health and Biomedical Informatics, and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.