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Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans, with an estimated prevalence of 1:200-1:250, based on unbiased genetic screening in Western populations. The vast majority of FH can be explained by mutations in three key genes; LDLR (receptor not synthesized or not functional), APOB (ligand not properly recognizing LDLR), and PCSK9 (gain of function mutations causing excessive elimination of LDLR). Causal mutations in these genes lead to lifelong elevations in low-density lipoprotein-cholesterol, xanthomatosis, and premature atherosclerotic cardiovascular disease. Several large scale patient registries have proliferated around the world and provide real-world data on prevalence and current treatment patterns. In this way, they have highlighted major gaps in the identification, treatment, and follow-up of patients with FH. Regrettably, these registries reveal a consistent and sobering message - patients with FH either remain undiagnosed or receive delayed diagnosis, there are low rates of LDL-C goal attainment even with combination lipid-lowering therapy, and rates of atherosclerotic cardiovascular disease are remarkably higher than the general population. Currently, there are well-developed FH registries in the Netherlands, United Kingdom, Spain, France, Norway, Brazil, Canada, and the United States. Notably absent from this list is the entirety of the Asian continent. As collaborating U.S. investigators who have clinical and research experience with FH and FH registries, we encourage the clinical research leadership of Thailand to design and launch a national FH Registry and genetic biorepository. Besides serving as a tool to advance the science of FH, particularly as it relates to the Thai population, this effort will undoubtedly raise awareness and lead to more efficient diagnosis and treatment, the true role of a registry. The opportunity for Thailand is enormous.
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2. C. M. Angina pectoris in hereditary xanthomatosis. Arch InternMed 1939;64:675-700.
3. Khachadurian AK. The inheritance of essential familialhypercholesterolemia. Am J Med 1964;37:402-7.
4. Goldstein JL, Brown MS. The LDL receptor locus and thegenetics of familial hypercholesterolemia. Annu Rev Genet1979;13:259-89.
5. Goldstein JL, Brown MS. Binding and Degradation of LowDensity Lipoproteins by Cultured Human Fibroblasts:Comparisonof cells from a normal subject and from a patientwith homozygous familial hypercholesterolemia. J Biol Chem1974;249:5153-62.
6. Yamamoto T, Davis CG, Brown MS et al. The human LDLreceptor: a cysteine-rich protein with multiple Alu sequencesin its mRNA. Cell 1984;39:27-38.
7. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia:new insights in pathogenesis and treatment. J ClinInvest 2003;111:1795-803.
8. Tavori H, Fan D, Blakemore JL, et al. Serum proproteinconvertase subtilisin/kexin type 9 and cell surfacelow-density lipoprotein receptor: evidence for a reciprocalregulation. Circulation 2013;127:2403-13.
9. Norata GD, Tavori H, Pirillo A, et al. Biology of proproteinconvertase subtilisin kexin 9: beyond low-density lipoproteincholesterol lowering. Cardiovasc Res 2016;112:429-42.
10. Austin MA, Hutter CM, Zimmern RL, et al. Genetic causes ofmonogenic heterozygous familial hypercholesterolemia: a HuGEprevalence review. Am J Epidemiol 2004;160:407-20.
11. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia:current perspectives on diagnosis and treatment.Atherosclerosis 2012;223:262-8.
12. Jeenduang N, Ruangpracha A, Promptmas C, et al. Twonovel D151Y and M391T LDLR mutations causing LDLRtransport defects in Thai patients with familial hypercholesterolemia.Clin Chim Acta 2010;411:1656-61.
13. Mata N, Alonso R, Badimon L et al. Clinical characteristicsand evaluation of LDL-cholesterol treatment of the Spanishfamilial hypercholesterolemia longitudinal chort study (SAFEHEART).Lipids Health Dis 2011;10:94.
14. Perez de Isla L, Alonso R, Mata N, et al. Coronary heartdisease, peripheral arterial disease, and stroke in familialhypercholesterolaemia: insights from the SAFEHEARTregistry (Spanish familial hypercholesterolaemia cohortstudy). Arterioscler Thromb Vasc Biol 2016;36:2004-10.
15. deGoma EM, Ahmad ZS, O’Brien EC, et al. Treatment Gapsin Adults With Heterozygous Familial Hypercholesterolemiain the United States: Data From the CASCADE-FH Registry.Circ Cardiovasc Genet 2016;9:240-9.
16. Rosinger A, Carroll MD, Lacher D, et al. Trends in TotalCholesterol, Triglycerides, and Low-Density Lipoprotein inUS Adults, 1999-2014. JAMA Cardiol 2017;2:339-41.
17. Gidding SS, Champagne MA, de Ferranti SD, et al. Theagenda for familial hypercholesterolemia: A scientific statementfrom the American Heart Association. Circulation2015;132:2167-92.
18. Humphries SE, Norbury G, Leigh S, et al. What is the clinicalutility of DNA testing in patients with familial hypercholesterolaemia?Curr Opin Lipidol 2008;19:362-8.
19. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance onthe care of familial hypercholesterolaemia from the InternationalFH Foundation. Eur J Prev Cardiol 2015;22:849-54.
20. Wierzbicki AS, Humphries SE, Minhas R, Guideline DevelopmentG. Familial hypercholesterolaemia: summary of NICEguidance. BMJ 2008;337:a1095.
21. Talmud PJ, Shah S, Whittall R, et al. Use of low-densitylipoprotein cholesterol gene score to distinguish patients withpolygenic and monogenic familial hypercholesterolaemia: acase-control study. Lancet 2013;381:1293-301.
22. Motazacker MM, Pirruccello J, Huijgen R, et al. Advances ingenetics show the need for extending screening strategies forautosomal dominant hypercholesterolaemia. Eur Heart J2012;33:1360-6.
23. Khera AV, Won HH, Peloso GM, et al. Diagnostic yield andclinical utility of sequencing familial hypercholesterolemiagenes in patients with severe hypercholesterolemia. J Am CollCardiol 2016;67:2578-89.
24. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifiesrare LDLR and APOA5 alleles conferring risk for myocardialinfarction. Nature 2015;518:102-6.
25. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomaldominant hypercholesterolaemia in the Netherlands: prevalence,genotype-phenotype relationship, and clinical outcome. EurHeart J 2015;36:560-5.
26. De Backer G, Besseling J, Chapman J, et al. Prevalence andmanagement of familial hypercholesterolaemia in coronarypatients: An analysis of EUROASPIRE IV, a study of theEuropean Society of Cardiology. Atherosclerosis2015;241:169-75.
27. Kaufman TM, Duell PB, Purnell JQ, et al. Application ofPCSK9 inhibitors in practice: challenges and opportunities.Circ Res 2017;121:499-501.
28. Perez de Isla L, Alonso R, Watts GF, et al. Attainment ofLDL-cholesterol treatment goals in patients with familialhypercholesterolemia: 5-year SAFEHEART registry follow-up.J Am Coll Cardiol 2016;67:1278-85.
29. Mundal L, Veierod MB, Halvorsen T, et al. Cardiovasculardisease in patients with genotyped familial hypercholesterolemiain Norway during 1994-2009, a registry study. Eur JPrev Cardiol 2016;23:1962-1969.
30. Mundal L, Igland J, Ose L, et al. Cardiovascular diseasemortality in patients with genetically verified familial hypercholesterolemiain Norway during 1992-2013. Eur J PrevCardiol 2017;24:137-144.
31. Silva PR, Jannes CE, Marsiglia JD, et al. Predictors ofcardiovascular events after one year of molecular screeningfor Familial hypercholesterolemia. Atherosclerosis2016;250:144-50.
32. Soutar AK, Naoumova RP. Mechanisms of disease: geneticcauses of familial hypercholesterolemia. Nat Clin PractCardiovasc Med 2007;4:214-25.
33. Alonso R, Andres E, Mata N, et al. Lipoprotein(a) levels infamilial hypercholesterolemia: an important predictor ofcardiovascular disease independent of the type of LDL receptormutation. J Am Coll Cardiol 2014;63:1982-9.
34. Marks D, Wonderling D, Thorogood M, et al. Cost effectivenessanalysis of different approaches of screening for familialhypercholesterolaemia. BMJ 2002;324:1303.
35. Ademi Z, Watts GF, Pang J, et al. Cascade screening basedon genetic testing is cost-effective: evidence for theimplementation of models of care for familial hypercholesterolemia.J Clin Lipidol 2014;8:390-400.
36. Nherera L, Marks D, Minhas R, et al. Probabilistic costeffectivenessanalysis of cascade screening for familialhypercholesterolaemia using alternative diagnostic andidentification strategies. Heart 2011;97:1175-81.
37. Huijgen R, Kindt I, Defesche JC, et al. Cardiovascular risk inrelation to functionality of sequence variants in the genecoding for the low-density lipoprotein receptor: a study among29,365 individuals tested for 64 specific low-density lipoproteinreceptorsequence variants. Eur Heart J 2012;33:2325-30.
38. Wonderling D, Umans-Eckenhausen MA, Marks D, et al.Cost-effectiveness analysis of the genetic screening programfor familial hypercholesterolemia in The Netherlands. SeminVasc Med 2004;4:97-104.
39. Starr B, Hadfield SG, Hutten BA, et al. Development ofsensitive and specific age- and gender-specific low-densitylipoprotein cholesterol cutoffs for diagnosis of first-degreerelatives with familial hypercholesterolaemia in cascadetesting. Clin Chem Lab Med 2008;46:791-803.
40. Umans-Eckenhausen MA, Defesche JC, van Dam MJ, et al.Long-term compliance with lipid-lowering medication aftergenetic screening for familial hypercholesterolemia. ArchIntern Med 2003;163:65-8.