THE PCSK9 GENE: RELATIONSHIP TO HUMAN HEALTH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 循环中的低密度脂蛋白水平构成了冠状动脉疾病的主要危险因素，而冠状动脉疾病是当今美国最大的死因。LDL-胆固醇的血浆水平因个体而异。虽然这种变化的50%可归因于饮食，运动和其他因素，但这种变化的50%可归因于遗传。 PCSK 9是一种分泌型丝氨酸蛋白酶，在胆固醇稳态中起关键作用。 已在家族DHS 20中确定了导致血浆LDL-胆固醇低的PCSK 9中的选定序列变异（研究编号1287 -355）。 到目前为止，已经鉴定出没有受影响等位基因、一个受影响等位基因和两个受影响等位基因的家庭成员。 虽然LDL-胆固醇的血浆水平根据受影响等位基因的数量而变化，但未观察到生理参数的其他差异。 为确保PCSK 9缺失不会导致其对血浆LDL-胆固醇影响以外的其他生理变化，我们希望对血浆PCSK 9缺失、低水平和正常水平的受试者进行全面的临床评价。该项目的最终目标是确定循环PCSK 9的缺乏是否与表达PCSK 9的器官内外的临床病理学相关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Circulating levels of LDL constitute the major risk factor for coronary artery disease--the largest cause of death in America today. Plasma levels of LDL-cholesterol vary from individual to individual. While 50% of this variation is attributable to diet, exercise and other factors, 50% of this variation is attributable to genetics. PCSK9 is a secreted serine protease that plays a critical role in cholesterol homeostasis. Select sequence variations in PCSK9 that result in low plasma LDL-cholesterol have been identified in family DHS20 (study #1287-355). So far, family members with no affected alleles, one affected allele and both affected alleles have been identified. While plasma level of LDL-cholesterol vary according to the number of affected alleles, no additional differences in physiologic parameters have been observed. To ensure that the absence of PCSK9 does not confer additional physiologic change beyond its effect on plasma LDL-cholesterol, we wish to perform a comprehensive clinical evaluation of subjects with absent, low and normal levels of plasma PCSK9. Ultimately the goal of the project is to determine if the absence of circulating PCSK9 is related to clinical pathology within and beyond the organs in which PCSK9 is expressed.