NEW YORK — Researchers have analyzed the genetic regulation of the human blood plasma proteome and have applied their findings to study gout.
The proteome is often dysregulated in disease and specific proteins could present targets for drug therapy. But, as researchers from Johns Hopkins University School of Medicine noted, many proteomic studies have largely relied on samples from individuals of European ancestry.
As they reported in Nature Genetics on Monday, they instead analyzed over 4,500 plasma proteins in more than 7,000 European-American and nearly 2,000 African-American individuals from the Atherosclerosis Risk in Communities (ARIC) cohort, looking for correlations between protein levels and genetic variants. They identified thousands of proteins associated with common variants, some of which overlapped between the ancestry groups. The researchers further applied their findings to conduct proteome-wide association studies, one of which suggested a potential gout therapy.
"Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits," senior author Nilanjan Chatterjee from Johns Hopkins and colleagues wrote in their paper.
The researchers analyzed 4,657 plasma proteins in 7,213 European-American and 1,871 African-American individuals from the ARIC cohort in conjunction with genome-wide SNP data. They identified 2,004 plasma proteins in the European-American and 1,618 in the African-American individuals that were associated with common variants located in cis regions of the corresponding gene. Between the two subsets of the ARIC cohort, 1,447 proteins overlapped.
Ten percent of the cis-protein quantitative trait loci (pQTLs) identified in the European-Americans were nonexistent or rare in the African-American samples, while about a third of the cis-pQTLs identified in the African-American subset were nonexistent or rare in the European-Americans. This, the researchers noted, underscores the value of including diverse ancestry data to identify ancestry-specific cis-pQTLs.
Through fine-mapping, the researchers homed in on potential causal variants linked to the set of overlapping proteins. For instance, they zeroed in on a region of chromosome 16p13.3 that corresponds to the hemoglobin subunit zeta protein (HBZ), which is involved in oxygen transport and metal-binding mechanisms and has been implicated in thalassemia. One variant, rs2541645, appeared to be a causal variant in both populations. That same variant is also a strong eQTL for HBZ expression in Genotype-Tissue Expression project data and has been linked to various erythrocyte-related outcomes in UK Biobank data, further suggesting it could be a regulatory variant.
The researchers also noted that the analysis of data from the African-American subset led to a smaller set of two variants, as compared to seven among the European-American subset.
Using this data and an Elastic Net machine learning method, they developed protein imputation models for cis-heritable plasma proteins. The accuracy of the models was higher for the European-American subset than for the African-American one. Additionally, a cross-ancestry analysis found that the models trained using the European-American population performed worse in the African-American subset than the European-American one, further highlighting the advantages of including diverse ancestries in genetic studies, according to the researchers.
With these models, they conducted two proteome-wide association studies — of serum urate and of gout — that implicated several proteins in the conditions. In particular, the gout PWAS identified a link to the interleukin-1 receptor antagonist protein (IL1RN), which binds to the cell surface interleukin-1 receptor to inhibit the proinflammatory effect of interleukin-1 signaling.
This finding suggested that the drug anakinra, a recombinant and slightly modified version of the IL1RN protein that is used to treat rheumatoid arthritis, could also potentially be harnessed to treat gout flares. Studies examining its use in gout are ongoing, they noted.