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For most people, PCSK9 is produced within the cells of the liver and other organs, and then migrates to the cell surface and into the bloodstream. In contrast, the variant causes PCSK9 to get stuck within the cells that produce it. Typically, when proteins fail to migrate out of the cell, they cause cellular stress. Yet, strangely, the Q152H variant does not lead to cellular stress. Instead, this small genetic variation has a significant protective effect against cardiovascular, liver, and kidney diseases.[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column width=”1\/2″][vc_column_text]Those who possess the Q152H variant among the three French-Canadian families are living well into their 90s \u2013 their plasma LDL-cholesterol levels and their risk of cardiovascular diseases are both low, and their liver function is normal.<\/p>\n
The variant was first discovered by Dr. Michel Chr\u00e9tien of the Institut de Recherches Cliniques de Montr\u00e9al (IRCM), who published his findings in 2011. However, until now the underlying mechanisms that confer these health benefits were unknown.<\/p>\n
Dr. Richard Austin and Dr. Paul Lebeau, vascular biologists at St. Joe\u2019s, teamed up with Dr. Chr\u00e9tien, an endocrinologist.[\/vc_column_text][\/vc_column][vc_column width=”1\/2″][vc_video link=”https:\/\/youtu.be\/WrPF1qq8ANk” el_width=”80″ align=”center”][vc_column_text]<\/p>\n
[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text]\u201cThese are exciting findings \u2014 what we\u2019ve found may represent a kind of fountain of youth,\u201d said Dr. Austin, a medical professor and one of the senior authors of a study on the variant. \u201cNow we want to see whether we can come up with a gene therapy approach to overexpress this specific mutant gene variant in the liver, and thereby offer an innovative treatment for a number of diseases that normally lead to early death.\u201d[\/vc_column_text][\/vc_column][\/vc_row][vc_row full_width=”stretch_row_content” full_height=”yes” parallax=”true” parallax_image=”1115″][vc_column][vc_empty_space height=”750″][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text css_animation=”slideInRight” css=”.vc_custom_1658957710929{background-color: #ffffff !important;}”]<\/p>\n
Study co-author Jae Hyun Byun (left) and Dr. Richard Austin (right) discussing their research in the lab<\/em><\/strong><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column width=”2\/3″][vc_column_text]\u201cThese results from Dr. Austin\u2019s group are particularly gratifying since they experimentally explain that this gene mutation, known to lower cardiovascular accidents, also protects against liver injury and dysfunction, even in individuals who are in their late 80s and mid-90s,\u201d said Dr. Chr\u00e9tien, also an emeritus scientist at the Ottawa Hospital Research Institute.<\/p>\n Since the research was first published in the Journal of Clinical Investigation <\/em>in early 2021, Dr. Austin and his team have continued to study the Q152H variant at St. Joe\u2019s.<\/p>\n \u201cPCSK9 is predominantly expressed in the liver and circulates throughout the body,\u201d said Dr. Austin. \u201cHowever, we have also found that the Q152H variant protects other organs, including the kidneys, which also express PCSK9.\u201d[\/vc_column_text][\/vc_column][vc_column width=”1\/3″][vc_single_image image=”185″ img_size=”150×150″ alignment=”center” css_animation=”none”][vc_column_text]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text]Now, working with a Toronto-based company called The Centre for Phenogenomics, researchers are developing a mouse model using state-of-the-art CRISPR-Cas9 gene editing technology. The mouse model will possess the same genetic variant \u2013 Q152H \u2013 that has been shown to protect against disease, thereby allowing scientists to further study PCSK9.[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”1336″ img_size=”medium” alignment=”center” css_animation=”none”][vc_column_text]<\/p>\n [\/vc_column_text][vc_separator][vc_empty_space height=”16″][vc_column_text]The article “The loss-of-function PCSK9Q152H\u00a0<\/sup>variant increases ER chaperones GRP78 and GRP94 and protects against liver injury“<\/em>\u00a0by Paul Lebeau and his collaborators was published in the\u00a0Journal of Clinical Investigation<\/em>\u00a0on January 4, 2021.<\/p>\n The study was funded in part by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada, the Fondation J-Louis L\u00e9vesque, the Richard and Edith Strauss Foundation, the Fondation Notre-Dame de Zeitoun, and the Aclon Foundation.[\/vc_column_text][vc_empty_space height=”16″][vc_separator][vc_empty_space height=”32″][vc_icon icon_fontawesome=”fas fa-book-reader” color=”custom” size=”xl” align=”center” custom_color=”#008b77″ link=”url:%2F2021%2Four-stories%2F|title:Our%20Stories”][vc_column_text]<\/p>\nKidney Research Pillar<\/h6>\n
St. Joe’s gratefully acknowledges Amgen Canada’s support of research conducted in our Kidney Pillar and within the Austin Laboratory.<\/h6>\n