Abstract 12421: Association Between Distance-to-index And Phenotype In Familial Hypercholesterolemia

Abstract

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder characterized by severely increased levels of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease (CVD). Early identification of patients is warranted, to initiate preventive therapy. Genetic cascade screening has been exploited during the last two decades in the Netherlands. However, since the cascade starts with an FH patient with high clinical suspicion, the FH phenotype might deflate in family members with FH who are identified in subsequent steps of cascade testing. We set out to test this hypothesis. Methods: We analyzed heterozygous FH patients identified by the genetic cascade screening program in the Netherlands from 1994 to 2014. A cascade starts with identification of a genetically proven FH patient (“index patient”) followed by testing in first degree relatives. If a mutation is found in one of them, their first degree relatives are tested as well, and so on. The association between exposure (i.e. distance to the index [1st, 2nd, 3rd or 4th or more degree family member]) and primary outcome (i.e., LDL-C level) was evaluated using linear regression models. Second, we tested whether increasing distance-to-index was associated with decreasing CVD risk by means of Cox proportional hazard models. In all regression analyses we adjusted for potential confounders and family relations. Results: A total of 64,171 persons participated in the screening program, of whom 26,176 had molecularly defined heterozygous FH. Of these, 4,531 (17%) were index patients. The distance-to-index could be determined in 13,392 (61%) of the remaining FH patients. Mean (± standard error) levels of LDL-C modestly decreased with increasing distance-to-index: 211 (56), 199 (54), 189 (52) and 178 (51) mg/dL in 1st, 2nd, 3rd and 4th or more, respectively (p-for-trend: 0.005). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82 - 1.03). Conclusions: To our knowledge, this is the first study ever investigating the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a strong association between distance-to-index LDL-C or and CVD risk in FH lends support for genetic cascade testing.