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• W4200563792 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 42, No. 1Response by Björnsson et al to Letter Regarding Article, “Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBResponse by Björnsson et al to Letter Regarding Article, “Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland” Eythór Björnsson, Gudmundur Thorgeirsson, Anna Helgadóttir, Daníel F. Gudbjartsson, Hilma Hólm, Unnur Thorsteinsdóttir, Patrick Sulem and Kári Stefánsson Eythór BjörnssonEythór Björnsson deCODE genetics, Reykjavík, Iceland. Search for more papers by this author , Gudmundur ThorgeirssonGudmundur Thorgeirsson deCODE genetics, Reykjavík, Iceland. Search for more papers by this author , Anna HelgadóttirAnna Helgadóttir deCODE genetics, Reykjavík, Iceland. Search for more papers by this author , Daníel F. GudbjartssonDaníel F. Gudbjartsson deCODE genetics, Reykjavík, Iceland. Search for more papers by this author , Hilma HólmHilma Hólm deCODE genetics, Reykjavík, Iceland. Search for more papers by this author , Unnur ThorsteinsdóttirUnnur Thorsteinsdóttir deCODE genetics, Reykjavík, Iceland. Search for more papers by this author , Patrick SulemPatrick Sulem deCODE genetics, Reykjavík, Iceland. Search for more papers by this author and Kári StefánssonKári Stefánsson deCODE genetics, Reykjavík, Iceland. Search for more papers by this author Originally published22 Dec 2021https://doi.org/10.1161/ATVBAHA.121.317201Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:e46–e47In Response:We thank Tromp et al for their interest in our article.1 As the authors mention, we found that the clinical familial hypercholesterolemia (FH) phenotype (defined as probable or definite FH using modified Dutch lipid clinic network criteria) was explained by monogenic FH in only about 5% of cases. Tromp et al wonder whether this finding may be related to overestimation of the prevalence of clinical FH in our study due to: (1) the use of highest documented level of LDL-C (low-density lipoprotein cholesterol), (2) contribution of lipoprotein(a), and (3) the use of an accurate family history informed by genealogy and information from electronic health records.Despite the namesake, the clinical FH phenotype as defined by the Dutch lipid clinic network criteria or other phenotypic scoring systems is not specific for a monogenic cause.2 Various other factors contribute to this phenotype, including polygenic and nongenetic causes of hypercholesterolemia as well as primary lipid disorders other than FH (including elevated lipoprotein(a)).3 Therefore, one would expect the clinical FH phenotype to be considerably more common than monogenic FH, consistent with our findings.We used the highest documented level of LDL-C for each individual in an attempt to best reflect an untreated level. We agree that in some cases the highest LDL-C level may capture a transient or persistent elevation due various factors, including secondary causes of hypercholesterolemia.4 Given the complexities of reliably differentiating primary from secondary causes of hypercholesterolemia using data from electronic health records, however, we did not attempt to differentiate these in our study. Thus, secondary causes of hypercholesterolemia may have contributed to the prevalence of the clinical FH phenotype in our study.We agree that lipoprotein(a) may contribute to the clinical FH phenotype. Among those with available measurements in our sample, we found extremely high molar concentration of lipoprotein(a) (>200 nmol/L) in 9.3% (n=58 out of 622) of individuals with clinical FH, compared with 4.4% (n=1683 out of 38 426) of those without clinical FH. Thus, it is reasonable to assume that about 9% of clinical FH in our study may be explained, at least in part, by extremely high levels of lipoprotein(a). Importantly, the cardiovascular risk of these individuals is likely underestimated by their LDL-C level due to the particularly high atherogenic potential of lipoprotein(a).5We informed the Dutch lipid clinic network criteria using a genealogy-based family history that is not subject to recall bias. This is a strength of our study as an accurate family history is more likely to lead to appropriate identification of the clinical FH phenotype, whereas lack thereof may result in underdiagnosis. As Tromp et al mention, family history of hypercholesterolemia or premature cardiovascular disease has poor specificity for monogenic FH.It is important to understand that the clinical FH phenotype is a high-risk hypercholesterolemia phenotype of heterogeneous etiology. As we1 and others6 have shown, monogenic FH appears to be a relatively uncommon cause of the clinical FH phenotype in the general population. More common causes include polygenic hypercholesterolemia as well as other inherited or aquired (secondary) lipoprotein disorders. Severely elevated lipoprotein(a) may contribute to the clinical FH phenotype, emphasizing the need for recognition of this risk factor. As Tromp et al highlight, these are important points to consider in the identification and management of patients with a phenotype suggestive of FH.Disclosures Recent (E. Björnsson) and current (G. Thorgeirsson, A. Helgadóttir, D.F. Gudbjartsson, H. Hólm, U. Thorsteinsdóttir, and K. Stefánsson) report employment at deCODE genetics, a subsidiary of Amgen, Inc.FootnotesFor Disclosures, see page e47.References1. Björnsson E, Thorgeirsson G, Helgadóttir A, Thorleifsson G, Sveinbjörnsson G, Kristmundsdóttir S, Jónsson H, Jónasdóttir A, Jónasdóttir Á, Sigurðsson Á, et al.. Large-scale screening for monogenic and clinically defined familial hypercholesterolemia in Iceland.Arterioscler Thromb Vasc Biol. 2021; 41:2616–2628. doi: 10.1161/ATVBAHA.120.315904LinkGoogle Scholar2. Chan DC, Pang J, Hooper AJ, Bell DA, Bates TR, Burnett JR, Watts GF. A comparative analysis of phenotypic predictors of mutations in familial hypercholesterolemia.J Clin Endocrinol Metab. 2018; 103:1704–1714. doi: 10.1210/jc.2017-02622CrossrefMedlineGoogle Scholar3. Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS. Familial hypercholesterolaemia.Nat Rev Dis Primers. 2017; 3:17093. doi: 10.1038/nrdp.2017.93CrossrefMedlineGoogle Scholar4. Vodnala D, Rubenfire M, Brook RD. Secondary causes of dyslipidemia.Am J Cardiol. 2012; 110:823–825. doi: 10.1016/j.amjcard.2012.04.062CrossrefMedlineGoogle Scholar5. Gudbjartsson DF, Thorgeirsson G, Sulem P, Helgadottir A, Gylfason A, Saemundsdottir J, Bjornsson E, Norddahl GL, Jonasdottir A, Jonasdottir A, et al.. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes.J Am Coll Cardiol. 2019; 74:2982–2994. doi: 10.1016/j.jacc.2019.10.019CrossrefMedlineGoogle Scholar6. Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O’Dushlaine C, Leader JB, Lester Kirchner H, Lindbuchler DM, et al.. Genetic identification of familial hypercholesterolemia within a single U.S. health care system.Science. 2016; 354:aaf7000. doi: 10.1126/science.aaf7000CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 2022Vol 42, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.121.317201PMID: 34936471 Originally publishedDecember 22, 2021 PDF download Advertisement SubjectsGeneticsLipids and Cholesterol" @default.
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