Proteome-wide Mendelian randomization identifies causal plasma proteins in prostate cancer development

Area of Science:

• Genetics
• Oncology
• Biochemistry

Background:

• The causes of prostate cancer are not fully understood.
• The association between plasma protein levels and prostate cancer risk remains unclear.

Purpose of the Study:

• To investigate the causal relationship between plasma protein levels and prostate cancer risk.
• To identify specific plasma proteins that may influence prostate cancer development.

Main Methods:

• Mendelian randomization analyses were conducted using cis-protein quantitative trait loci (cis-pQTL) variants.
• Data from the PRACTICAL consortium were analyzed, with findings replicated in the FinnGen consortium.
• Causal effects of plasma proteins and circulating gene expression on prostate cancer risk were assessed.

Main Results:

• Four plasma proteins (CREB3L4, HDGF, SERPINA3, GNPNAT1) were positively correlated with increased prostate cancer risk.
• Five plasma proteins (TNFRSF6B, GSK3A, EIF4B, CLIC1, SMAD2) were associated with decreased prostate cancer risk.
• Causal effects of CREB3L4, HDGF, SERPINA3, TNFRSF6B, EIF4B, and SMAD2 were confirmed in replication and meta-analyses.

Conclusions:

• Plasma levels of SMAD2 and CREB3L4 are significantly associated with prostate cancer risk.
• These proteins may play crucial roles in prostate cancer etiology.
• Further research into SMAD2 and CREB3L4 could inform prostate cancer prevention and treatment strategies.