Chronic pain is a pain that lasts for more than six months and is often compared to an “undead cancer”. Currently, the prevalence of chronic pain is as high as 20% in Europe and the United States, and it has attracted great attention worldwide. The World Congress on Pain has recognized pain as the “fifth vital sign of human beings” after breathing, pulse, temperature and blood pressure, and there is no good treatment for it. In this study, researchers identified genetic variants associated with pain sensitivity by exome sequencing. First, they administered the Quantitative Sensory Test (QST) to 2,500 subjects to determine and quantify the degree of pain sensitivity. From these, 200 of the most pain-sensitive and 200 of the least pain-sensitive subjects were then selected for the study, and their exons were sequenced to identify the occurrence of low-frequency gene mutations. The final sequencing results revealed that the two groups with extreme pain response differed significantly in the pattern of rare mutations in 138 genes, including GZMM. By performing functional analysis of the metabolic pathways of these genes, the researchers identified for the first time that the angiotensin II metabolic pathway plays an important role in pain regulation and also provides new targets for the development of pain treatment drugs. Angiotensin II, a peptide hormone that regulates blood pressure, has been used as an important target in a variety of cardiovascular diseases and has led to the development of many targeted drugs, such as numerous angiotensin-converting enzyme inhibitors and angiotensin receptor blocker class drugs. FranceWilliams, a senior lecturer at the School of Bipolar Research and Epigenetics at King’s College London, said, “The study’s new findings make it possible to use drugs currently used to treat hypertension for the treatment of pain.” Xin Jin, head of the project at UWM, said, “There is growing evidence that rare variants overlooked in genome-wide association analysis (GWAS) make a considerable contribution to complex diseases and phenotypes. The success of this project demonstrates that next-generation sequencing (NGS) technology makes it possible for us to study this in depth, and the use of this technology in various complex disease and phenotype studies will lead to a wealth of new discoveries.”