Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism, known to increase levels of total and low-density lipoprotein (LDL) cholesterol in plasma. FH is caused by various mutations, with the majority of known mutations affecting the LDL receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin 9 (Rader et al., 2003; Austin et al., 2004). Without treatment, the lifelong increased LDL-cholesterol levels result in a high risk of premature atherosclerotic cardiovascular disease and death (Nordestgaard et al., 2013a). The diagnosis of FH is confirmed either by applying one of the several clinical criteria, the most common being Dutch Lipid Clinical Network Criteria (DLCN), Simon Broome (SB), and Making Early Diagnosis Prevents Early Death (MEDPED), or by genetic screening.

In a general population setting, FH has recently been estimated to affect 1:313 individuals worldwide, making FH one of the most common genetic disorders in the world (Beheshti et al., 2020). In a Danish study investigating the general population, the estimated prevalence was 1:137 (Benn et al., 2012), suggesting that, in a general population setting, FH is underdiagnosed, emphasizing the importance of efficient FH screening to identify individuals at risk (Beheshti et al., 2020). Identification of subgroups at high risk of FH may facilitate a targeted screening worldwide.

Recent studies have shown that the prevalence of FH varies between countries because of founder effects, use of different diagnostic criteria, and differences in screening for the disease (Beheshti et al., 2020), (Hu et al., 2020)^. However, no previous study summarized differences in the prevalence of FH among ethnic groups (Harada et al., 2018).

We performed a systematic review and meta-analysis to examine the prevalence of FH among different ethnicities.

Of the 267 screened publications, a total of 13 studies, comprising 1,175,249 individuals, were included (Figure 1). Characteristics of the included studies are shown in Table 1. Five studies reported FH prevalence among more than one ethnicity, whereas the remaining eight studies reported FH prevalence in one specific ethnicity (Table 1). The included studies originated from North America (four studies from the United States), Asia (four studies from China, Malaysia, Japan, and Korea), Europe (two studies from Denmark and Germany), South America (Brazil), and South Africa (Cape Town).

Studies included in the meta-analysis utilized both clinical and genetic screening to estimate FH prevalence. Seven studies applied the DLCN (or modified versions), one study applied the MEDPED, two studies applied genetic screening, and the remaining three studies applied another clinical screening method. Studies included were published between 2002 and 2019.

Eleven studies reported the prevalence of FH in general populations, including information on ethnicity, while two studies estimated the FH prevalence across ethnicity in patient cohorts (Table 1).

The following studies estimated the FH prevalence in more than one ethnicity: NHANES, the ELSA-Brasil study, Cape Town Experience, MyHEBAT FH study, and the YOUNG-MI Registry. NHANES represented the ethnicities: non-Hispanic black (considered as black individuals), non-Hispanic white (considered as white individuals), other race/multiracial (considered as mixed/other individuals), Mexican American, and other Hispanics (considered as Latino). The ELSA-Brasil study reported on the following ethnicities: black, white, Asian, and brown, whereas the MyHEBAT study represented Malay, Chinese, and Indian individuals (all considered Asian) and other individuals (de Ferranti et al., 2016; Harada et al., 2018; Chua et al., 2021).

The two patient cohort studies reported on the following ethnicities: black, white, Asian, and colored (considered as mixed race/other) in the Cape Town Experience; and black, Hispanic/Latino (considered as Latino), white, Asian, and mixed/other (considered as mixed race/other) in the YOUNG -MI Registry (Firth and Marais, 2008; Singh et al., 2019).

The remaining eight studies included only one ethnicity: the Copenhagen City Heart Study and the Copenhagen General Population Study with 100% white individuals, the Life-Child cohort reported all as being Caucasian, My Code Cohort as 98.4% Caucasian, and the Alina Health ambulatory as 90% white (Tybjaerg-Hansen et al., 2005; Abul-Husn et al., 2016; Benn et al., 2016; Dathan-Stumpf et al., 2016; Knickelbine et al., 2016). These individuals were all considered white. Individuals included in the Jiangsu Nutrition Study, Kumamoto Health Care, and Korean Metabolic Syndrome Mortality Study were considered Asian (Ohta et al., 2002; Wijesekera et al., 2014; Jung et al., 2018).

In the current study, we estimated the overall FH prevalence to 1:303 in the general population. This is very similar to recent estimations presented in larger studies of 1:313 (Beheshti et al., 2020) and 1:311 (Hu et al., 2020). The pooled prevalence by ethnicity ranged from 0.25% (1:400) to 0.52% (1:192), showing an increase in prevalence from Asian to white to brown to black, suggesting that prevalence differs among ethnicities and that some ethnic groups have a higher risk of FH.

Studies included in the meta-analysis utilized both clinical and genetic screening to estimate FH prevalence. Seven studies applied the DLCN (or a modified version), one study the MEDPED, two studies genetic screening, and the remaining three studies another clinical screening method. The use of clinical screening has several advantages. It may be preferable in areas with limited access to genetic testing and healthcare facilities and may easily be applied in large general population studies, as information about premature coronary artery disease, family history, and clinical measurements is readily obtainable. However, the use of clinical screening may result in an overestimation of FH prevalence, as individuals with other types of dyslipidemias or high lipoprotein (a) may score high in the diagnostic criteria without having genetic FH, resulting in false positives (Hu et al., 2020) although these individuals are at high risk of cardiovascular disease. Similarly, common confounding cardiovascular risk factors such as obesity, diabetes, hypothyroidism, and a high alcohol intake may all cause dyslipidemia, also resulting in false-positive cases and an overestimation of FH prevalence (Nordestgaard et al., 2013b). Differences in these common cardiovascular risk factors together with differences in access to appropriate health care may also explain the differences in the prevalence of FH observed in the present study, although we cannot present data to support this.

As also shown in other studies, the prevalence of FH is significantly higher among patients with premature coronary artery disease and elevated cholesterol concentrations compared to the prevalence observed in general population studies (Beheshti et al., 2020; Hu et al., 2020). In the daily clinic cascade, testing of first-degree relatives is recommended, and it has been suggested that an approach combining contact to relatives through index cases (indirect testing) and direct contact from health care professionals to the relatives (direct testing) may improve the proportion of tested individuals. We did not have information on screening strategy in the patient cohorts included in the present review. However, the choice of strategy may have biased prevalence estimates among ethnicities within the single study (Leonardi-Bee et al., 2021).

The clinical criteria used in FH studies are designed primarily to detect FH in Western populations, and the DLCN, SB, and MEDPED might be less applicable in other populations. This may affect the validity of estimated prevalence in these countries and impact the diagnostic validity in different populations and among ethnicities (Hu et al., 2020).

Genetic screening is considered the most accurate method for diagnosing FH, as the detection of an established disease-causing mutation equals a definite FH diagnosis (Cuchel et al., 2014). Genetic screening is most often applied in patient cohorts to verify the cause of dyslipidemia or establish the presence of a mutation in cascade screening. However, genetic screening is not without limitations. It is time-consuming, is costly, and requires access to health facilities, making it less applicable in less affluent parts of the world (Hu et al., 2020). Moreover, studies using genetic screening report low prevalence estimates of FH, which may be due to not all FH-causing mutations having been identified or included in diagnostic testing panels for FH. Some individuals may present with a polygenic rather than a monogenic cause of FH, which is not always detected (Nordestgaard et al., 2013b; Talmud et al., 2013). In addition, genetic screening often requires evidence from functional studies for further classification of the associated variant as pathogenic or likely pathogenic (Chora et al., 2018). Furthermore, functional characterization of the variant is important for choosing the most effective treatment strategy (Di Costanzo et al., 2021).

In the present study, the estimated prevalence is the highest among black individuals: 0.52% (1:192). However, white individuals had an estimated prevalence of 0.31% (1:323), which is close to the overall estimate. In contrast to this, the prevalence by ethnicity reported in the patient cohort the Cape Town Experience (Firth and Marais, 2008), where 32% of the FH patients were white and 4.9% were black, suggest a bias in access to study participation, potential dissimilarities, or bias in screening strategies.

To successfully investigate differences in prevalence of FH among different ethnicities, a definition of ethnicity was needed. In the included studies, the ancestry of the individuals was either described through race or ethnicity. In four out of five studies representing more than one ethnicity, both terms were used (de Ferranti et al., 2016; Harada et al., 2018). The two concepts are both related to the ancestry of individuals, as race is often described as the distinctive physical trait of an individual, that is, the biology, while the ethnicity is more individual or subjective and is acquired through a cultural identification of the individual. Both terms are considered social concepts, meaning that there are no links between genes and ethnicity. In the present study, the categories of ethnicities were given and limited by the studies included.

The major limitations of the present study are the limited availability of data on prevalence among ethnicities and heterogeneity in diagnostic criteria used. A very limited number of studies reported data on the distribution of FH across ethnicities. White and black individuals were included in most studies, while the inclusion of other ethnicities was limited, potentially introducing bias of estimates of prevalence among less represented ethnicities. Only one study reported FH prevalence among Latino and brown individuals, respectively, and a pooled prevalence could not be estimated for these subgroups.

The 13 studies included used different diagnostic criteria, which might bias and contribute to the heterogeneity of the estimated pooled prevalence. Four out of seven studies applying DLCN used a modified version of the screening method (Wijesekera et al., 2014; Benn et al., 2016; de Ferranti et al., 2016; Harada et al., 2018). The modifications made were due to a lack of data, such as missing information on xanthomas and corneal arcus, or insufficient information on family history. These limitations might have led to an underestimation of the FH prevalence in these studies (Wijesekera et al., 2014; Benn et al., 2016; de Ferranti et al., 2016; Harada et al., 2018). However, minor modifications of the criteria were accepted, and the given studies were still considered eligible for inclusion.

The studies included represent different cohorts, with variations in sex distribution and mean age. These differences might further contribute to between-study heterogeneity. Two out of the 11 general population studies examined the FH prevalence in pediatric cohorts (Ohta et al., 2002; Abul-Husn et al., 2016). Clinical screening of FH among children may have to be interpreted differently compared to the results presented in studies examining adult populations. Children might present with lower LDL-cholesterol levels than adults, and a family history of premature myocardial infarction may not be available, as the parents of younger children may be too young to have signs of myocardial infarction. These factors may contribute to underestimating FH prevalence (Pang et al., 2016). However, the prevalence estimated in the two pediatric cohorts was similar to other FH prevalence estimates presented within the ethnic group.

Another limitation might be the variations in the representation of men and women within the different study cohorts. The YOUNG-MI Registry cohort consisted of 80.9% men compared to 19.1% women (Singh et al., 2019). This underrepresentation of women might affect the estimated FH prevalence, especially when clinical screening methods, such as DLCN, are applied. The DLCN includes own myocardial infarction as a criterion, and as women in general have myocardial infarction at an older age compared to men, an underestimation of FH prevalence may be seen in cohorts with less women compared to men. This could also explain the differences seen among the two included patient studies, as the estimated FH prevalence in the YOUNG-MI Registry is significantly lower than the FH prevalence measured in the Cape Town Experience (Firth and Marais, 2008).

Robust examination of prevalence by ethnicity requires large studies with sufficient data on both FH prevalence in the entire study cohort and among ethnicities. In the present study, study cohorts originating from different countries have been included. For future studies, the ideal setting would be to investigate the prevalence of FH by ethnicity within one country, representing an admixed and diverse society but within the same healthcare system and using the same clinical FH criteria. Focus on aligning sex and age to minimize study heterogeneity may also be important. This set-up would reduce potential bias and give an opportunity to further explore potential differences in FH prevalence according to ethnicity and potential inequalities in access to and participation in screening programs, helping to guide targeted screening and prevention.

In this systematic review and meta-analysis, we found that FH prevalence varies across different ethnicities, ranging from 0.25% (1:400) to 0.52% (1:192), with the highest prevalence seen among black and brown individuals and the lowest prevalence estimated among Asian individuals. There is a need for studies investigating FH prevalence according to ethnicity to establish potential benefits of intensified FH screening in certain population subgroups and further explore potential biases and inequalities in current FH diagnostic criteria and screening programs.