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Chronic Infection Genetic Risk Loci Point to Immune, Metabolic Pathways

NEW YORK (GenomeWeb) – Genome-wide association analyses involving hundreds of thousands of individuals of European ancestry suggest that genes contributing to immune and metabolic processes can contribute to chronic inflammation.

As they reported online today in the American Journal of Human Genetics, the researchers performed a meta-analysis of two genome-wide association studies involving more than 200,000 individuals enrolled through the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Inflammation Working Group, searching for sites that coincided with circulating C-reactive protein — a marker for chronic, low-grade inflammation. In the process, they uncovered 58 new and known loci linked to levels of CRP levels circulating in the blood, leading to genes that tended to cluster into immune and liver metabolic pathways.

"Given that inflammation is implicated in the pathogenesis of multiple complex diseases, our insights into the biology of inflammation could contribute to future therapies and interventions," co-corresponding authors Behrooz Alizadeh, an epidemiology researcher at the University of Groningen, and Abbas Dehghan, an epidemiology researcher affiliated with the University of Groningen and Imperial College London, and their colleagues wrote.

For their study, the researchers performed a meta-analysis of a HapMap imputed-genotype GWAS involving 204,402 participants from 78 studies  and a 1000 Genomes imputed-genotype GWAS involving 148,164 participants from 49 studies, searching for variants associated with circulating CRP levels.

In participants from the HapMap GWAS, for example, the team verified ties at 16 of the 18 loci previously implicated in circulating CRP. The meta-analysis of 1000 Genomes GWAS data led to 40 loci, including three dozen sites also identified in the HapMap analysis. Half a dozen more loci turned up in the 1000 Genomes analysis following adjustment for body mass index (BMI).

"Adjusting for BMI in the CRP GWAS abolished the association at only three lead variants, suggesting that the genetic regulation of chronic, low-grade inflammation is largely independent of BMI," the authors reported. "Notably, BMI adjustment resulted in the identification of six variants that were not associated with CRP in the BMI-unadjusted GWAS."

The collection of variants identified in participants from the HapMap-imputed GWAS explained an estimated 6.2 percent of variance in circulating CRP levels, the team noted. That edged up slightly, to 6.5 percent, using the variants linked to circulating CRP in the individuals from the GWAS with imputation from 1000 Genomes data. Only a handful of lead variants showed significantly different ties to the circulating CRP trait in men and women who were profiled. 

From there, the team used conditional analyses and Mendelian randomization analyses to look for additional genetic interactions and other related conditions, respectively, fleshing out the function and potential relevance of CRP-related variants with the help of gene set enrichment information and expression quantitative trait loci data from 44 post-mortem brain samples. 

"The data identified gene sets involved in the biology of the immune system and liver as main regulators of serum amounts of CRP," the authors wrote, noting that their Mendelian randomization analyses "supported causal associations between genetically increased CRP and a protective effect on schizophrenia and increased risk of [bipolar disorder]."