The following is a summary of “Novel Causal Plasma Proteins for Hypothyroidism: A Large-scale Plasma Proteome Mendelian Randomization Analysis,” published in the February 2023 issue of Endocrinology & Metabolism by Yang, et al.

In recent years, several risk proteins for hypothyroidism have been reported. However, many more plasma proteins have yet to be tested for their potential mechanisms and causal effects. Therefore, for a study, researchers sought to identify potential mechanisms and novel causal plasma proteins for hypothyroidism using Mendelian randomization (MR).

Researchers conducted a large-scale plasma proteome MR analysis using protein quantitative trait loci (pQTLs) for 2,297 plasma proteins. The pQTLs were classified into 4 different groups, and MR analyses were conducted within the four groups simultaneously. The significant proteins were discovered and validated in two different cohorts. They also conducted colocalization analysis and enrichment analysis using the proteins found with MR.

Investigators identified 31 proteins in the discovery cohort, among which 13 were validated in the validation cohort. Of the 13 validated proteins, nine were identified as risk factors (ISG15, Fc receptor-like protein 2, tumor necrosis factor ligand superfamily member 14, Rab-2A, FcRL3, thrombomodulin, interferon [IFN]-lambda-1, platelet glycoprotein Ib alpha chain, IL-7RA) for hypothyroidism, whereas others were identified as protective proteins (protein O-glucosyltransferase 1 [POGLUT1], tumor necrosis factor ligand superfamily, 3-hydroxyisobutyryl-CoA hydrolase, transferrin receptor protein 1). Among the significant proteins, POGLUT1 strongly colocalized with expression quantitative trait loci from whole blood (posterior probability of colocalization [PP4] = 0.978) and the thyroid (PP4 = 0.978). Two different trans-pQTLs (rs2111485 PP4 = 0.998; rs35103715 PP4 = 0.998) for IFN-lambda-1 colocalized with hypothyroidism in different chromosomes.

In conclusion, the study identified and validated 13 proteins associated with hypothyroidism using univariable MR. The effect of IFN on hypothyroidism was reinforced and expanded. The study also broadened the understanding of the causal proteins for hypothyroidism and provided insights into the relationships between plasma proteins and hypothyroidism. The proteins identified in the study can potentially be used as early screening biomarkers for hypothyroidism.

Reference: academic.oup.com/jcem/article-abstract/108/2/433/6747484?redirectedFrom=fulltext