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SHJ Vol 5, No 1                                M Ibrahim, Putting PCSK9 Inhibitors into practice
                (Table 1)  Examples of polymorphisms of PCSK9 that influence circulating levels of LDL-C

             Mutation                                                 Effect on PCSK9 activity
                  S127R                                              - Gain of function (resulting in fewer LDL
                  P216L                                              receptors & higher LDL cholesterol)
                  D374Y
                  D374Y+N157K (double mutation in one patient)
                  C(-161)T+I474V
                  Y142X                                              - Loos of function (resulting in more LDL
                  C679X                                              receptors & lower LDL cholesterol)
                  R46L
                  L108R
                  D35Y

                    •  3.2%  of  White  subjects  in  the ARIC    subjects with loss-of-function PCSK9
                    study  had  the  R46L  loss  of  function     mutations  appeared  to  be  generally  healthy,
                    mutation  of  PCSK9,  which  reduced          with   no    apparent   adverse   pathological
                    mean LDL cholesterol by 15% and the           consequences  arising  from  their  PCSK9
                    risk  of  coronary  heart  disease  by  47%   mutation. Loss of function PCSK9 variants also
                    (adjusted  HR  0.50  [95%CI  0.32  to         did not appear to influence markers of glucose
                    0.79]; p=0.003) vs. non-carriers (19).        homeostasis, such as fasting plasma glucose or
                                                                  insulin levels, or risk for type-2 diabetes (21).
                    • 2.6% of 45,699 subjects  pooled from        These  observations  have  fueled  considerable
                    three observational  studies  in  Denmark     interest  among  researchers  in  cardiovascular
                    had the R46L loss of function mutation        medicine  in  the  prospect  of  pharmacological
                    of  PCSK9;  a  reduction  in  LDL             inhibition  of  PCSK9  as  a  therapeutic  strategy
                    cholesterol  of  11–16%  was  associated      for  the  management  of  dyslipidemia  and
                    with  a  30%  reduction  in  the  risk  of    cardiovascular  risk.  PCSK9  inhibitors  are  the
                    ischemic  heart  disease  for  carriers  vs.   latest  in  a  series  of  new  discoveries  of
                    non-carriers.8  The  improvement  in          biological  therapies  to  address  unmet  clinical
                    cardiovascular outcomes was larger than       needs in chronic, non- communicable diseases.
                    predicted  by  the  reduction  in  LDL
                    cholesterol, which the authors attributed     A  series  of  experiments  from  different
                    to  the  PCSK9  genotype  being  a  better    laboratories  subsequently  showed  that  high
                    predictor  of  lower  lifetime  LDL           levels  of  PCSK9  stopped  the  low  density
                    cholesterol   levels   than   a   point       lipoprotein  (LDL)  receptors  from  functioning.
                    measurement  of  LDL  cholesterol  made       Three  years  later  after  the  French  researchers
                    in adulthood (20).                            identified PCSK9 protein; the results of a large
                                                                  community  study  mapping  LDL  cholesterol
            These  findings  confirm  the  observations           (LDL-C)  levels  and  the  incidence  of  coronary
            described above that lifetime exposure to lower       heart  disease  against  mutations  in  the  PCSK9
            LDL      cholesterol    markedly      improves        gene  were  released  (22).  Those  with  genetic
            cardiovascular  outcomes,  and  extend  this          variations  linked  to  reduced  PCSK9  function
            concept specifically to the actions of PCSK9 on       were found to have significantly lower LDL-C
            levels of LDL cholesterol. Moreover, the              levels and lower risk of coronary heart disease.

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