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


      • 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.


      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.


      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.


      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).


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hovingh G.K.
        • Davidson M.H.
        • Kastelein J.J.P.
        • O'Connor A.M.
        Diagnosis and treatment of familial hypercholesterolaemia.
        Eur. Heart J. 2013; 34: 962-971
        • Huijgen R.
        • Hutten B.A.
        • Kindt I.
        • Vissers M.N.
        • Kastelein J.J.P.
        Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26 406 individuals tested for genetic FH.
        Circ. Cardiovasc. Genet. 2012; 5: 354-359
        • Starr B.
        • Hadfield S.G.
        • Hutten B.A.
        • Lansberg P.J.
        • Leren T.P.
        • Damgaard D.
        • et al.
        Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.
        Clin. Chem. Lab. Med. 2008; 46: 791-803
        • Huijgen R.
        • Kindt I.
        • Verhoeven S.B.J.
        • Sijbrands E.J.G.
        • Vissers M.N.
        • Kastelein J.J.P.
        • et al.
        Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal.
        PLoS One. 2010; 5: e9220
        • Garcia-Garcia A.-B.
        • Ivorra C.
        • Martinez-Hervas S.
        • Blesa S.
        • Fuentes M.J.
        • Puig O.
        • et al.
        Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family.
        Atherosclerosis. 2011; 218: 423-430
        • Huijgen R.
        • Vissers M.N.
        • Kindt I.
        • Trip M.D.
        • de Groot E.
        • Kastelein J.J.P.
        • et al.
        Assessment of carotid atherosclerosis in normocholesterolemic individuals with proven mutations in the low-density lipoprotein receptor or apolipoprotein B genes.
        Circ. Cardiovasc. Genet. 2011; 4: 413-417
        • Leigh S.
        LDLR Database.
        2007 (accessed August 21, 2015)
        • Alonso R.
        • Mata N.
        • Castillo S.
        • Fuentes F.
        • Saenz P.
        • Muñiz O.
        • et al.
        Cardiovascular disease in familial hypercholesterolaemia: influence of low-density lipoprotein receptor mutation type and classic risk factors.
        Atherosclerosis. 2008; 200: 315-321
        • Bertolini S.
        • Cantafora A.
        • Averna M.
        • Cortese C.
        • Motti C.
        • Martini S.
        • et al.
        Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: e41-e52
        • Bertolini S.
        • Pisciotta L.
        • Rabacchi C.
        • Cefalù A.B.
        • Noto D.
        • Fasano T.
        • et al.
        Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.
        Atherosclerosis. 2013; 227: 342-348
        • McPherson R.
        • Frohlich J.
        • Fodor G.
        • Genest J.
        Canadian cardiovascular society position statement – recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease.
        Can. J. Cardiol. 2006; 22: 913-927
        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • Ginsberg H.N.
        • Masana L.
        • Descamps O.S.
        • et al.
        Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease.
        Eur. Heart J. 2013; 34: 3478a-3490a
        • Marks D.
        • Wonderling D.
        • Thorogood M.
        • Lambert H.
        • Humphries S.E.
        • Neil H.A.W.
        Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia.
        BMJ. 2002; 324: 1303
        • Nherera L.
        • Marks D.
        • Minhas R.
        • Thorogood M.
        • Humphries S.E.
        Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies.
        Heart. 2011; 97: 1175-1181
        • Talmud P.J.
        • Shah S.
        • Whittall R.
        • Futema M.
        • Howard P.
        • Cooper J.A.
        • et al.
        Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.
        Lancet. 2013; 381: 1293-1301
        • Huijgen R.
        • Kindt I.
        • Fouchier S.W.
        • Defesche J.C.
        • Hutten B. a
        • Kastelein J.J.P.
        • et al.
        Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.
        Hum. Mutat. 2010; 31: 752-760
        • Huijgen R.
        • Kindt I.
        • Defesche J.C.
        • Kastelein J.J.P.
        Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.
        Eur. Heart J. 2012; 33: 2325-2330
        • Cobbaert C.
        • Boerma G.J.
        • Lindemans J.
        Evaluation of the cholestech L.D.X. desktop analyser for cholesterol, HDL-cholesterol, and triacylglycerols in heparinized venous blood.
        Eur. J. Clin. Chem. Clin. Biochem. 1994; 32: 391-394
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499-502
        • Besseling J.
        • Kindt I.
        • Hof M.
        • Kastelein J.J.P.
        • Hutten B.A.
        • Hovingh G.K.
        Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14, 000 mutation carriers.
        Atherosclerosis. 2014; 233: 219-223
        • Fouchier S.W.
        • Defesche J.C.
        • Umans-Eckenhausen M.W.
        • Kastelein J.P.
        The molecular basis of familial hypercholesterolemia in The Netherlands.
        Hum. Genet. 2001; 109: 602-615
        • Lombardi M.P.
        • Redeker E.J.
        • Defesche J.C.
        • Kamerling S.W.
        • Trip M.D.
        • Mannens M.M.
        • et al.
        Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.
        Clin. Genet. 2000; 57: 116-124
        • Harrel F.E.
        The “Hmisc” Package, Version 3.14-4.
        2014 (accessed July 23, 2014)
        • Huijgen R.
        • Sjouke B.
        • Vis K.
        • de Randamie J.S.E.
        • Defesche J.C.
        • Kastelein J.J.P.
        • et al.
        Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.
        Hum. Mutat. 2012; 33: 448-455
        • Luna Saavedra Y.G.
        • Dufour R.
        • Davignon J.
        • Baass A.
        PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort study.
        Arterioscler. Thromb. Vasc. Biol. 2014; 34: 2700-2705
        • Napolitano C.
        • Novelli V.
        • Francis M.D.
        • Priori S.G.
        Genetic modulators of the phenotype in the long QT syndrome: state of the art and clinical impact.
        Curr. Opin. Genet. Dev. 2015; 33: 17-24