Variation in the Prevalence of Familial Hypercholesterolemia Around the World


Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C), cholesterol deposition in the skin and tendons, and premature coronary heart disease.1 In 1938, Müller linked xanthomas, elevated cholesterol, and coronary heart disease to an in-born error of metabolism from a single gene defect.2 In 1963, Khachadurian described the homozygous (HoFH) and heterozygous (HeFH) phenotype in FH patients in Lebanon and elucidated the inheritance pattern as autosomal co-dominant.3 Building on this work in 1973, Goldstein and Brown characterized the low-density lipoprotein receptor (LDLR) and related the phenotype of FH to defects in the LDLR.4 And in 1983, Russell and colleagues cloned the LDLR gene, which allowed for molecular-level analysis of receptor mutations.5

The earliest manifestation of HeFH is hypercholesterolemia. Arcus corneae and tendon xanthomas appear at the end of the second decade, and clinical symptoms of coronary heart disease appear by the fourth decade. Plasma cholesterol levels average 350 mg/dL.1 Individuals with HoFH have marked hypercholesterolemia at birth. Cutaneous and tendon xanthomas, arcus corneae, and generalized atherosclerosis develop during childhood. They can develop aortic valve and supravalvar stenosis, and death by myocardial infarction typically occurs in the second decade. Plasma cholesterol levels range from 600-1,200 mg/dL.1

LDLR mutations account for greater than 90% of FH cases.4 There are over 1,700 allelic variants of the LDLR.6 There are also rare forms of FH that result from mutations in genes for apolipoprotein B-100 (ApoB), proprotein convertase subtilisin/kexin type 9 (PCSK9),8 and the low-density lipoprotein receptor adaptor protein 1 (LDLRAP1), which causes a rare form of autosomal recessive FH.9

Frequency of Phenotype

The prevalence of HeFH has been estimated to be about 1:500, and 1:1 million for HoFH making it the most common monogenic disorder encountered in clinical practice.1 These prevalence estimates were based on the frequency of FH in survivors of myocardial infarction and their relatives in the U.S.10 Researchers have found similar frequencies in the United Kingdom, Japan, Norway, Hungary, and Finland.11,12,13

However, there is evidence that the actual prevalence is much higher. One theory to explain the high frequency of FH in some populations is the founder effect, which is the loss of genetic variability in a population that occurs when a new population is formed through the migration of a small number of individuals who carry a higher proportion of FH mutations by chance. When the population expands there would be a higher proportion of affected individuals who share the specific genetic variant introduced by the founders.11

Regional Variation in the Frequency of FH


In the 1960s, Khachadurian3 and colleagues described the inheritance pattern of FH due to the high prevalence in many large families in Lebanon.14 Epidemiological surveys of individuals with clinical FH suggest the frequency of HeFH is ten-fold higher and an HoFH prevalence of 1:100,000.15 Molecular studies have shown that a nonsense mutation in the LDLR also known as the "Lebanese allele"16 is common in this population. However, other gene variants also contribute to the prevalence of FH.17 The high prevalence in Lebanon is attributed to the founder effect from early settlements groups, as well as high rates of consanguinity.

South African Afrikaners

In the 1970s, Seftel et al. recognized high rates of FH among the Afrikaans-speaking people of South Africa.18 They descended from Dutch, French, and German immigrants in the late 17th and early 18th centuries. The population prevalence of HeFH in inhabitants of rural southwestern Cape towns was 1:71.19 Three mutations in the LDLR account for the majority of cases of FH. A point mutation in the 3' end of exon 4 accounts for 65% of mutations and is called FH Afrikaner-1. There are also two other mutations, one in exon 9--FH Afrikaner-2, and exon 4--FH Afrikaner-3, which in total account for 90% of cases.20 All three of these mutations have been detected in lower frequencies in the Netherlands, which is consistent with the founder effect.21

South African Jews

Ashkenazi Jews in South Africa also have high rates of FH. They are descendants of an estimated 40,000 Jews who arrived in South Africa between 1880 and 1910. They were immigrants from a small geographical area in Lithuania.22 The prevalence of HeFH among Johannesburg's Jews is 1:67.22 The majority had a common mutant allele, a 3-base pair deletion in exon 4 of the LDLR gene23 called FH-Piscataway. This same mutation has been found in other groups of Ashkenazi Jews around the world who originated from Lithuania.23 A founder effect is unlikely to have manifested with this large starting population, which suggests the high prevalence of FH stems from a founder mutation in Lithuania.

South African Indians

The third group in South Africa with a high incidence of FH is a minority group of South African Indians who were traders and came from the Gujarat province of India between 1860 and 1911. The frequency of FH in Indians of Gujarat origin is >1:100.24 The allele FH-Zambia which is a proline to leucine switch on position 664 of the LDLR has been detected in unrelated Indian families all originating in the Gujarat province of India.24 Two other LDLR mutations causing FH have been identified: FH Durban-1, a point mutation in ligand-binding repeat 2, and FH Durban-2, a point mutation in ligand-binding repeat 3 of the LDLR.25

French Canadians

The settlement of present-day Québec began in the early 17th century around Québec City. During that period 8,527 immigrants arrived from France and settled in the St. Lawrence Valley. The prevalence of HeFH in the province of Québec in 1980 was 1:270. There are higher concentrations in Northeastern Québec with a minimal estimated frequency of FH of 1:154 and even as high as 1:81 on the North shore of the St. Lawrence River.26 Five mutations in the LDLR gene account for 76% of FH cases.26 One of those mutations, a >10 kb deletion at 5' end of the gene involving the promoter and exon 1, is present in 60% of FH patients at one lipid clinic in Montréal.26


In Finland, four different mutations in the LDLR gene were shown to account for approximately 75% of HeFH cases.13,27 Molecular genetic studies of the prevalence of HeFH among the general population indicate a prevalence of 1:600.13 However, the prevalence of FH is 1:441 in the North Karelia province with the FH-North Karelia allele accounting for 85% of the cases of heterozygous FH. In one commune in the eastern part of the country, the prevalence is as high as 1:143.27 In the 17th century settlers from the west arrived in the North Karelia province and presumably one of the original settlers carried the FH-North Karelia allele.27


Tunisia has known several different civilizations over the centuries including the Romans, Carthaginians, Turks, Arabs, and French. Today, the population consists of people of Berber or Arab origin with some minorities such as Italians and Jews. In 1992, Slimane et al. estimated the prevalence of HoFH at 1:125,000 and HeFH 1:165.28 Of these patients, 60% were born of consanguineous marriages. Specific genes associated with this population have not been studied.


While most estimates of the frequency of FH are based on hospitalized patients and patient registries, the Copenhagen General Population Study is the first estimate of FH in 69,016 people from the Danish general population using phenotypic assessment and common mutations in the Danish population. Using the Dutch Lipid Clinical Network Criteria,29 the prevalence of definite and probable FH was 1:137. In addition, only half of those with FH were on cholesterol lowering therapy. This study reflects the high prevalence of FH in a population not subject to the founder effect, and the underdiagnosis and undertreatment of FH in that community.30


The prevalence of FH in some populations is higher than common estimates due to the founder effect. However, even in the absence of the founder effect, high prevalences exist.30 Therefore, there are an estimated 14 to 34 million individuals with FH worldwide,31 and less than 1% of these cases have been diagnosed. Of the individuals with known FH less than half are receiving appropriate treatment.30

Early detection and treatment probably would reduce premature morbidity and mortality of this disease. Cascade screening of family members of known index cases is the most cost-effective approach for identification of new FH cases.32 However, it relies on clinical signs to develop and be recognized. Alternatively, universal screening of children offers the opportunity to cast a wider diagnostic net and intervene before the development of atherosclerosis.

Once diagnosed, individuals with FH can be treated with lifestyle measures, lipid-lowering therapies, and possibly novel therapies including PCSK9 monoclonal antibodies, anti-sense oligonucleotides targeting ApoB, and microsomal triglyceride transfer protein inhibitors to change the clinical course of the disease.31


  1. Goldstein JL, Hobbs HH, Brown MS. Familial Hypercholesterolemia. In: Eds Scriver CR, Sly WS, Childs B, et al. The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill Professional; 2000: 2863–22913.
  2. Müller C. Angina pectoris in hereditary xanthomatosis. Arch Intern Med 1939;64:675-700.
  3. Khachadurian AK. The inheritance of essential familial hypercholesterolemia. Am J Med 1964;37:402-7.
  4. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34-47.
  5. Russell DW, Yamamoto T, Schneider WJ, Slaughter CJ, Brown MS, Goldstein JL. cDNA cloning of the bovine low density lipoprotein receptor: feedback regulation of a receptor mRNA. Proc Natl Acad Sci U S A 1983;80:7501-5.
  6. Fokkema IFAC, Den Dunnen JT, Taschner PEM. LOVD: easy creation of a locus-specific sequence variation database using an "LSDB-in-a-Box" approach. Hum Mutat 2005;26:63-8.
  7. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A 1987;84:6919-23.
  8. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6.
  9. Garcia CK, Wilund K, Arca M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 2001;292:1394-8.
  10. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973;52:1544-68.
  11. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004;160:407-20.
  12. Patterson D, Slack J. Lipid abnormalities in male and female survivors of myocardial infarction and their first-degree relatives. Lancet 1972;1:393-9.
  13. Lahtinen AM, Havulinna AS, Jula A, Salomaa V, Kontula K. Prevalence and clinical correlates of familial hypercholesterolemia founder mutations in the general population. Atherosclerosis 2015;238:64-69.
  14. Slack J. Inheritance of familial hypercholesterolemia. Atheroscler Rev 1979;5:35-66.
  15. Fahed AC, Safa RM, Haddad FF, Bitar FF, Andary RR, Arabi MT, Azar ST, Nemer G. Homozygous familial hypercholesterolemia in Lebanon: a genotype/phenotype correlation. Mol Genet Metab 2011 Feb;102:181-8.
  16. Lehrman MA, Schneider WJ, Brown MS, et al. The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. J Biol Chem 1987;262:401-10.
  17. Abifadel M, Rabès JP, Jambart S, et al. The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modified gene. Hum Mutat 2009;30:E682-91.
  18. Seftel HC, Baker SG, Sandler MP, et al. A host of hypercholesterolaemic homozygotes in South Africa. Br Med J 1980;281:633-6.
  19. Steyn K, Weight MJ, Dando BR, Christopher KJ, Rossouw JE. The use of low density lipoprotein receptor activity of lymphocytes to determine the prevalence of familial hypercholesterolaemia in a rural South African community. J Med Genet 1989;26:32-6.
  20. Kotze MJ, Warnich L, Langenhoven E, du Plessis L, Retief AE. An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics. J Med Genet 1990;27:298-302.
  21. Defesche JC, van Diermen DE, Lansberg PJ, et al. South African founder mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia in the Dutch population. Hum Genet 1993;92:567-70.
  22. Seftel HC, Baker SG, Jenkins T, Mendelsohn D. Prevalence of familial hypercholes terolemia in Johannesburg Jews. Am J Med Genet 1989;34:545-7.
  23. Meiner V, Landsberger D, Berkman N, et al. A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews. Am J Hum Genet 1991;49:443-9.
  24. Rubinsztein DC, Coetzee GA, Marais AD, et al. Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin. J Lipid Res 1992;33:1647-55.
  25. Rubinsztein DC, Jialal I, Leitersdorf E, Coetzee GA, van der Westhuyzen DR. Identification of two new LDL-receptor mutations causing homozygous familial hypercholesterolemia in a South African of Indian origin. Biochim Biophys Acta 1993;1182:75-82.
  26. Moorjani S, Roy M, Gagné C, et al. Homozygous familial hypercholesterolemia among French Canadians in Québec. Arteriosclerosis 1989;9:211-6.
  27. Vuorio AF, Turtola H, Piilahti KM, Repo P, Kanninen T, Kontula K. Familial hypercholesterolemia in the Finnish North Karelia. Arterioscler Thromb Vasc Biol 1997;17:3127-38.
  28. Slimane MN, Pousse H, Maatoug F, Hammami M, Ben Farhat MH. Phenotypic expression of familial hypercholesterolaemia in central and southern Tunisia. Atherosclerosis. 1993;104:153-8.
  29. WHO Human Genetics Programme. Familial hypercholesterolaemia (FH): report of a second WHO consultation, Geneva, 4 September 1998. WHO. 1999.
  30. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97:3956-64.
  31. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a.
  32. Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus case finding for familial hypercho lesterolaemia: a systematic review and cost-effectiveness analysis. Health Technol Assess 2000;4:1-123.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia

Keywords: Alleles, Antibodies, Monoclonal, Aortic Valve, Apolipoprotein B-100, Apolipoproteins B, Arcus Senilis, Atherosclerosis, Base Pairing, Cholesterol, Cholesterol, LDL, Consanguinity, Constriction, Pathologic, Coronary Disease, Exons, Hypercholesterolemia, Hyperlipoproteinemia Type II, Inheritance Patterns, Leucine, Life Style, Lipoproteins, LDL, Minority Groups, Myocardial Infarction, Oligonucleotides, Antisense, Phenotype, Point Mutation, Proline, Proprotein Convertases, Receptors, LDL, Registries, Tendons, Xanthomatosis, Dyslipidemias

< Back to Listings