Background

Proteogenomics, which connects genomic information with actual protein levels in the body, has become a key tool for new drug development. However, previous studies have been biased towards populations of European ancestry. This has limited the prevention and treatment of diseases in non-European populations. Different populations have different genetic characteristics, and there was a risk of missing pathological mechanisms that are only activated in specific groups.

Plasma proteomics, which precisely analyzes proteins in the blood, has also faced technical barriers. Most previous studies relied on affinity-based analysis methods. This method is fast, but there is a risk of measurement errors if the protein structure changes due to genetic mutations. In addition, the concentration difference between the most and least abundant plasma proteins is 10 billion-fold, making analysis very difficult. As a result, it has often failed to identify key disease target proteins with extremely low concentrations.

Key Findings

1,400 Plasma Proteins Captured by Nanoparticles

A joint research team, including the Wellcome Sanger Institute, began analyzing blood samples from approximately 1,400 British South Asians (Bangladeshi and Pakistani ancestry) residing in the UK to address the limitations of existing technologies. The researchers used nanoparticles to filter out high-concentration proteins in the plasma and concentrate low-concentration proteins, introducing a novel nanoparticle-enriched mass spectrometry (NP-MS) method. In this process, they successfully detected more than 5,700 protein groups using the Seer Proteograph XT platform.

895 Genetic Variants Revealed a Proteomic Map

The researchers compared the obtained proteomic data with genomic information to analyze protein quantitative trait loci (pQTLs), which directly affect protein levels. As a result, they identified more than 1,200 significant genetic variant-protein associations, of which 895 were confirmed as cis-protein quantitative trait loci (cis-pQTLs). Notably, about half of the identified variants are new genomic information not observed in European ancestry studies. This demonstrates the importance of diverse studies that include non-European populations for understanding disease.

Filling the Gaps Missed by Existing Platforms

The researchers demonstrated the technical complementarity by comparing the same samples using existing affinity-based analysis methods, SomaLogic 11k and Olink HT platforms. Mass spectrometry-based analysis precisely identifies immunoglobulin variable regions or specific protein fragments that are missed by affinity platforms. As a result, it was confirmed that the protein regions detected by each analysis platform are qualitatively different.

Uncovering a New Autoimmune Mechanism of Graves' Disease

The researchers combined the discovered pQTL data with genome-wide association study (GWAS) results and concluded that 21 proteins are involved in the development of 44 diseases. A representative example is the elucidation of the pathogenesis of Graves' disease, an autoimmune thyroid disease. They revealed that a genetic variant of the IGLV3-21 (Immunoglobulin Lambda Variable 3-21) protein, which has not been clearly elucidated, induces an autoimmune response in B cells and increases the risk of the disease. This is expected to be a useful guide for designing targeted therapies for Graves' disease in the future.

Significance and Prospects

This study has paved the way for addressing the blind spots in precision medicine by analyzing non-European populations, which have been neglected in genomic analysis. It is widely recognized that the study has refined the identification of customized drug targets by identifying unique protein genetic variants in specific populations. It also presented a practical standard for organically combining mass spectrometry and affinity-based analysis to create a complete plasma proteomic map.

Of course, there are still challenges to be solved before it can be applied in clinical practice. Nanoparticle-enriched mass spectrometry has relatively high equipment operating costs and is slower compared to affinity-based platforms. In addition, further validation is required to generalize the results of the 1,400-person cohort to the entire South Asian population worldwide. A follow-up task is a large-scale clinical validation study that includes more non-European populations.