By combing through the DNA of more than 100,000 people, researchers at Broad Institute, Massachusetts General Hospital, and elsewhere have identified rare, protective genetic mutations that lower the levels of LDL cholesterol \u2014 the so-called \u201cbad\u201d cholesterol \u2014 in the blood. The researchers\u2019 findings reveal that these naturally occurring mutations also reduce a person\u2019s risk of coronary heart disease by about 50 percent. Remarkably, the mutations disrupt a gene called Niemann-Pick C1-Like 1 (NPC1L1) \u2014 the molecular target of the FDA-approved drug ezetimibe, often used as a treatment for high LDL.<\/p>\n
\u201cProtective mutations like the one we\u2019ve just identified for heart disease are a treasure trove for understanding human biology,\u201d said Sekar Kathiresan, a senior author of the study, Broad associate member, and director of preventive cardiology at Massachusetts General Hospital. \u201cThey can teach us about the underlying causes of disease and point to important drug targets.\u201d<\/p>\n
Over the past several years, evidence has been mounting that certain loss-of-function mutations \u2014 mutations that reduce or completely eliminate a gene\u2019s ability to work \u2014 can, at the same time, protect against disease. With this latest discovery, the list now stands at four genes that have been found to offer protective effects against either heart or metabolic disease. (The genes PCSK9, AP0C3, and now NPC1L1 have been found to protect against heart disease, and SLC30A8 has been shown to protect against type 2 diabetes.)<\/p>\n
The scientific community is interested in these protective mutations not only because of what they can reveal about the biological basis of disease, but also for their ability to suggest potential paths toward new therapeutics. From a pharmaceutical perspective, it is much more feasible to develop a drug that disables, rather than activates, a gene.<\/p>\n
Kathiresan\u2019s long-standing interest in the genetics of blood cholesterol and heart disease first led him to uncover rare mutations in the NPC1L1 gene in just a handful of patients. He wondered if other patients carried similar mutations, so he set off on a massive hunt.<\/p>\n
With the combined expertise of Broad Institute\u2019s Genomics Platform, led by Stacey Gabriel, and major support from the National Human Genome Research Institute, Kathiresan and his colleagues sequenced the exomes (the protein-coding portions of the genome) of over 20,000 people of European, African, or South Asian ancestry. They discovered 15 distinct mutations in NPC1L1, all of which serve to inactivate or dampen gene activity. Roughly 1 in 650 people carries one of these inactivating NPC1L1 mutations.<\/p>\n
\u201cWhen it comes to rare variant studies, there is simply no substitute for extremely large sample sizes,\u201d said co-author Gabriel, director of Broad Institute\u2019s Genomics Platform. \u201cThis has become crystal clear through our work on NPC1L1 as well as several other similar projects here at the Broad. We now know the right path to get statistically robust results, and that\u2019s the path we are on.\u201d<\/p>\n
After defining the mutational landscape of NPC1L1 in the initial study group of 20,000 people, Kathiresan and his colleagues correlated those mutations with LDL levels. The researchers examined the genomes of another 91,000 people and found that those with inactivating mutations in NPC1L1 tended to have lower LDL levels than those without such mutations. The reductions averaged about 12mg\/dL, a 10 percent drop that is similar to what is seen in patients receiving ezetimibe therapy.<\/p>\n
Individuals who carry inactivating NPC1L1 mutations also have a lower risk of coronary heart disease \u2014 roughly half the risk compared to those individuals without those mutations.\nBroad Institute<\/link>\n","protected":false},"excerpt":{"rendered":"
By combing through the DNA of more than 100,000 people, researchers at Broad Institute, Massachusetts General Hospital, and elsewhere have identified rare, protective genetic mutations that lower the levels of LDL cholesterol \u2014 the so-called \u201cbad\u201d cholesterol \u2014 in the blood. The researchers\u2019 findings reveal that these naturally occurring mutations also reduce a person\u2019s risk […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[35],"tags":[],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1513"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=1513"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1513\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=1513"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=1513"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=1513"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}