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Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia

      Highlights

      • Levels of LDL-C vary widely among patients with familial hypercholesterolemia.
      • It can be hypothesized that patients identified early in a cascade screening setting express a more severe phenotype.
      • However, we found no association between distance-to-index and LDL-C or CVD risk.
      • These findings lend support for genetic cascade testing in familial hypercholesterolemia.

      Abstract

      Background and aim

      We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family.

      Methods

      We included heterozygous FH patients identified by genetic cascade screening 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 carrier is identified, their first degree relatives are tested as well, and so on. The associations between distance-to-index (expressed as family relationship) and both LDL-C levels and CVD risk, were evaluated using multivariable linear and Cox regression models.

      Results

      Distance-to-index could be determined in 13,374 patients. Mean (±standard error) levels of LDL-C did not differ significantly in 1st, 2nd, 3rd, and 4th or more family members: 5.46 (1.42), 5.17 (1.42), 4.89 (1.37), and 4.58 (1.27) mmol/L, respectively (adjusted p-for-trend: 0.104). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82–1.03).

      Conclusion

      This study was the first to investigate the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a decrease of phenotype severity lends support for genetic cascade testing in FH.

      Keywords

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