Mini Review - Interventional Cardiology (2023)

Familial hyperlipidemia caused by Apolipoprotein B mutation in the Pediatric Amish population: A mini review

Corresponding Author:
Devyani Chowdhury
Cardiology Care for Children, Lancaster, PA, USA,

Received date: 02-Jun-2023, Manuscript No. FMIC-23-101131; Editor assigned: 05-Jun-2023, PreQC No. FMIC-23-101131 (PQ); Reviewed date: 19-Jun-2023, QC No. FMIC-23-101131;Revised date: 26-Jun-2023, Manuscript No. FMIC-23-101131 (R); Published date: 04-Jul-2023, DOI: 10.37532/1755-5310.2023.15(S17).433


Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disorder that causes increased low density lipoprotein cholesterol (LDL-C) levels and a higher risk of premature atherosclerosis and cardiovascular disease (CVD). Common causes of FH include inherited genetic mutations in the LDLR, APOB, and PCSK9 genes. LDLR, APOB, and PCSK9 mutations account for 79%, 5%, and <1% of cases of FH respectively. Apolipoprotein B (ApoB) is the necessary atherogenic lipoprotein which can serve as a determinant of cardiovascular disease including hypercholesterolemia. A founder variant in Apolipoprotein B (APOB p.R3527Q) causes FH and is found in 12% of the Pennsylvania Amish population. This article provides an overview of ApoB metabolism and clinical manifestations associated with APOB mutations. An understanding of the clinical manifestations caused by APOB p.R3527Q can be beneficial for the clinical diagnosis and treatment of FH in the Amish. Based on previous studies, changes in LDL cholesterol (LDL-C), LDL particles (LDL-P), small dense LDL particles, and ApoB levels can be seen among these patients putting them at an increased risk for atherosclerotic issues, vascular hardening, and changes in endothelial function, particularly among homozygous individuals.


Familial hyperlipidemia; Amish; Apolipoprotein-B


FH: Familial Hypercholesteromia; LDL-(P): Low Density Lipoprotein (Particles); LDL-C: Low Density Lipoprotein-Cholesterol; CVD: Cardiovascular Disease; ApoB: Apolipoprotein B; ApoA-1: Apolipoprotein A-1; HDL-(P): High Density Lipoprotein (Particles); sdLDL-(C): Small dense Lipoprotein (Cholesterol); Lp(a): Lipoprotein(a); CIMT: Carotid Intima-Media Thickness; PWV: Pulse Wave Velocity; NLA: National Lipid Association


Familial hypercholesterolemia

FH is an autosomal dominant genetic disorder which typically causes increased LDL-C levels starting from a very young age and a higher risk of premature atherosclerosis and CVD [1,2]. Symptoms of CVD typically emerge in adulthood, but atherosclerosis begins during childhood [3-5]. Diagnosis for FH can be made through family history, genetic testing, and LDL levels. FH is caused by pathogenic genetic variants in LDLR, APOB, or PCSK9. This review will focus on APOB associated FH.

Amish population and founder effect

The Amish community is an isolated population that has a high prevalence of FH. A founder variant in Apolipoprotein B-100 (rs5742904, NC_000002.12; NM_000384.3; APOB c.10580G>A; p.Arg3527Gln; previously described as p.Arg3500Gln; referenced here as APOB p.R3527Q) has a 12% carrier frequency among the Amish of Lancaster County, Pennsylvania [6]. A founder effect occurs when a small number of "founders" migrate out of a larger population to establish a new smaller population in which outside members cannot marry in, reducing the genetic variation in the new smaller group. The frequency of some genetic variants can become greatly enriched due to founder effects when one of the original founders carries a genetic variant that may be rare in other populations [7]. Such is the case with the APOB p.R3527Q variant which has a minor allele frequency of 6.7% in the Amish and only 0.08% in European populations [8,9].

This founder variant in ApoB is a major determinant of LDL-C levels and coronary artery calcification in the Amish [6]. In previous studies, adults who were heterozygous for APOB p.R3527Q had 58-70 mg/dL higher LDL-C than non-carriers and were about 4.5 times more likely to have detectable coronary artery calcification [6,10]. Other lipid components, such as ApoB, Apolipoprotein A-1 (ApoA-1), LDL and HDL particles (LDL-P and HDL-P), small dense LDL Cholesterol (sdLDL-C), and Lipoprotein(a) may also be elevated and associated with atherosclerosis. Thus, to prevent or delay atherosclerotic complications caused by the APOB p.R3527Q variant in the Amish community, it is necessary to decrease LDL-C levels [11,12].

Lipid physiology

Apolipoprotein B can be found in two forms ApoB-48 and ApoB-100. ApoB-48 functions as part of a chylomicron which is used to transport fats through blood vessels. ApoB-100 protein’s main function is to transport cholesterol through the arterial wall to be broken down in the liver. ApoB-100 is a necessary protein which helps LDLs to attach with their specific cell-surface receptors. A description of the function of Apolipoprotein B. ApoB is a crucial health determinant as high levels of ApoB may indicate a higher risk of cardiac disease due to elevated LDL levels leading to atherosclerotic changes [13]. Normal ApoB levels in adults are considered to be <100 mg/dL. It is widely accepted that an ApoB level of >110 mg/dL is considered high risk for cardiovascular disease.

In addition to LDL-C, other serum lipids are associated with atherosclerosis risk in adults, but their predictive utislity in pediatrics is largely unknown. All pro-atherogenic lipoproteins, including LDL-C, contain one ApoB surface protein, so serum measurements of ApoB or the ratio of ApoB to ApoA-1 (the primary lipoprotein on HDL, a protective lipoprotein) may more accurately reflect the number of atherogenic particles and better predict CVD risk. Some studies support this hypothesis [2,14-19], while others have found ApoB and ApoB:ApoA-1 to be equivalent to LDL-C in predicting CVD risk [2,20-23]. Consistent with this observation, it was found that APOB p.R3527Q heterozygotes had elevations of ApoB and ApoB: ApoA-1 that were strongly correlated with LDL-C, suggesting that in patients with FH, these biomarkers might be interchangeable with predicted CVD risk [2].

Cholesterol content in LDL varies because some particles are large and have an abundance of cholesterol, whereas others are smaller in size and lack cholesterol. LDL particle number (LDL-P) has been shown to be a stronger predictor of CVD risk compared to LDL-C [24-26]. Others have shown its predictive value to be comparable to LDL-C [27]. APOB p.R3527Q heterozygotes had significantly increased LDL-P and LDL-C and LDL-P correlated strongly with LDL-C [2].

Lp(a) consists of a single ApoB with a plasminogen-like protein apolipoprotein(a). Lp(a) levels vary greatly among individuals and do not correlate with LDL-C, non-HDL-C, ApoB, or LDL particle number [28]. Lp(a) has been shown to be predictive of CVD risk in adults, independent of LDL-C, especially in those with elevated LDL-C and FH [11,29-32]. Lp(a) is higher in individuals with FH and it is theorized that severe increases of Lp(a) have an FH-like clinical phenotype [33-35].


Other tests to assess atherosclerosis and vascular stiffness in children

Previous studies in children with FH, have shown higher Carotid Intima-Media Thickness (CIMT) among the affected children as compared to unaffected siblings beginning at 8 to 12 years of age [36]. It is unclear whether children with the APOB p.R3527Q variant have the same increases in CIMT [2]. In a study of 16 Amish young people ages 3-28 years with APOB p.R3527Q variant (13 heterozygotes, 3 homozygotes) and their unaffected age matched siblings, the study did not find a significant increase in CIMT [2]. The interaction of LDL-C and age was significant in the overall cohort, suggesting a cumulative effect of age and LDL-C on CIMT. Pulse Wave Velocity (PWV) is a method used to measure vascular stiffness and while it varies greatly in healthy pediatric subjects [37], it increases with age [38]. PWV has been found to be increased in children with FH [39]. However, in this study of APOB p.R3527Q, PWV did not differ significantly from controls and we found no correlations between PWV and either age or LDL-C [2]. Abnormal flow-mediated dilation is found in children with a family history of cardiovascular events, FH, and familial combined hyperlipidemia in other studies [40]. It is important to note that this study cohort of APOB p.R3527Q had lower LDL-C values than seen in many other forms of FH, which may explain the lack of differences in CIMT and PWV [2]. Taken together, these data suggest that APOB p.R3527Q may be less severe than other forms of FH. Additional studies of larger cohorts will help confirm whether these findings hold true.

Cascade screening

Genetic testing of at-risk family members of individuals with the APOB p.R3527Q variant (also known as cascade screening), can effectively identify individuals with FH so that early screening and treatment of high cholesterol can be undertaken. Even with similar LDL levels, people with FH have a higher risk of CVD than people without FH [41]. Homozygotes have a poor prognosis with mortality usually before the thirty years of age from a cardiovascular event [41]. Thus, wide spread and early screening to identify and treat FH can have significant improvements in disease management [42]. According to the National Heart, Lung, and Blood Institute, it is recommended that universal cholesterol screening occurs for all patients ages 9-11 and 17-21 because of hormonal changes through puberty [43]. Among individuals with a family history of high LDL (or FH), screening should begin at age 2 [43].

Pediatric cholesterol levels

Without genetic testing, heterozygous FH is typically suspected in children with LDL-C above 160 mg/dL and a positive family history or LDL-C above 190 mg/dL [44]. Cholesterol levels normally peak around age 9-11 years, decrease during adolescence, and steadily increase after age 17 years [45-48]. Studies have found that children and adolescents with APOB p.R3527Q have elevated levels of LDL-C compared to age-matched controls, similar to what is observed in adults with the same gene variant [2]. However, some individuals with APOB p.R3527Q may have normal or only slightly elevated LDL-C and may be overlooked using current cholesterol screening guidelines [49]. Other factors that may lead to the variability in LDL-C elevations among APOB p.R3527Q heterozygotes may include lifestyle or other environmental factors. At-risk family members of these individuals with normal or slightly elevated LDL-C could easily be missed, underscoring the necessity of cascade genotyping.

Treatment with statins is recommended for heterozygous FH starting at age 8-10 years after ruling out secondary causes and may occur simultaneously with lifestyle changes [50]. For homozygotes, statin therapy should be started at the time of diagnosis often occuring in infancy [50]. Given the increased cardiovascular risk in homozygotes, immediate therapeutics is recommended to improve atherosclerotic changes that may follow into adulthood [50-51].

Pregnancy and FH challenges

Pregnancy outcomes tend to be favorable in women with FH, however there are some special challenges that need to be considered [52]. This issue is of particular importance in the Amish given their large family sizes. During pregnancy, LDL-C serum levels typically increase for normal fetal growth. Increasing estrogen levels during pregnancy are thought to enhance synthesis of total cholesterol and LDL-C by about 30%–50% [52,53]. According to National Lipid Association (NLA) recommendations, women diagnosed with FH are advised to cease cholesterol reducing medications such as statins during pregnancy. While considered low risk, the use of cholesterol-lowering medications in pregnant women has shown fetal complications [54]. Lipoprotein apheresis is the treatment of choice for high-risk FH patients. Women with homozygous FH or with an established atherosclerotic vessel or aortic disease should be offered therapy with statins during pregnancy if lipoprotein apheresis is not readily available. Given the recommendations for stopping statin therapy during pregnancy, it is advantageous for women to be diagnosed as early as possible to manage their lipids properly before ending statin therapy while pregnant [55].


This review provides an overview of FH caused by APOB p.R3527Q in the Amish community with an emphasis on the pediatric population. Cascade genetic screening can provide early diagnosis of family members that have the variant. This early diagnosis is important given that, while fasting LDL-C is higher on average in children with APOB p.R3527Q, some heterozygous individuals have levels normal or below the threshold for suspecting FH, thus highlighting the value of genetic screening over LDL alone. Data remain conflicting, likely due to small sample sizes, on the extent to which elevations in LDL-C due to APOB p.R3527Q lead to premature cardiovascular disease. While our study in children and young adults with APOB p.R3527Q did not identify significantly increased CIMT or endothelial dysfunction, a study in middle-age adults did find increased coronary artery calcification among those with the variant. Nonetheless, it is prudent to screen for APOB p.R3527Q among Amish individuals, provide careful monitoring and offer treatment for elevated LDL.


This work was supported by the National Institute of Health (Grant number-NIH R01HL163514).

Conflicts of Interest


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