Familial Hypercholesterolemia: A Call for Increased Awareness in the Asian Indian Population

Sophia L Wong1,* and Arun K Garg1,2

¹Department of Pathology and Laboratory Medicine, University of British Columbia, Canada

²Department of Laboratory Medicine and Pathology, Fraser Health Authority, Canada

*Corresponding author: Sophia L Wong, Department of Pathology and Laboratory Medicine, University of British Columbia, 855 West 12th Avenue, Vancouver, British Columbia, V5Z 1M9, Canada

Received: May 12, 2014; Accepted: June 14, 2014; Published: June 16, 2014

Abstract

Cardiovascular Disease (CVD) is the leading cause of death in India. Asian Indians have a high prevalence of CVD, with earlier disease onset, more severe clinical phenotype, and worse patient outcomes. Familial Hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism, and affected individuals have a 10- to 20-fold increased risk of premature CVD. Early disease modification through lifestyle changes and lipid-lowering therapies is highly effective and potentially life-saving, yet FH remains poorly diagnosed and inadequately managed.There is an immense need foran increased awareness of FH in the Indian population. Studies to examine the potential contribution of FH to the alarming CVD trends in India are also urgently required.

Keywords: India; Familial hypercholesterolemia; Cardiovascular disease; Coronary heart disease

Introduction

Cardiovascular Disease (CVD) is a major and growing problem in India. It is the leading cause of death for both males and females in all regions of India [1]. In a 2001-2003 report, CVD accounted for 19% of deaths across all ages, and 25% of deaths in the 25 to 69 age category [1]. A more recent report, published by the World Health Organization in 2005, found 28% of all deaths in India to be attributed to CVD [2]. Asian Indians are known to have an increased prevalence of CVD compared to other ethnic groups [3,4]. Alarmingly, the average age of CVD onset is earlier among Asian Indians, who have a more severe disease course and a worse prognosis [3-7]. This has a significant economic impact as many affected are in their prime productive years. In the year 2000, deaths from CVD in the 35 to 64 age groupin India led to a loss of 9.2 million potentially productive years, a figure 570% higher than that of the United States. In the year 2030, the loss is expected to increase to 17.9 million years, or 940% greater than the projected United States percentage [8].

Although the excess cardiovascular risk may be partly explained by conventional and emerging risk actors [5] - particularly the high rate of metabolic syndrome and glucose intolerance in Asian Indians [9,10] - the contribution of monogenic hypercholesterolemic conditions, such as Familial Hypercholesterolemia (FH), to this phenomenon remains unclear. FH (Online Mendelian Inheritance in Man [OMIM] entry 143890) is an inherited disorder of lipoprotein metabolism, and is among the most common autosomal dominant diseases encountered in clinical medicine [11]. FH patients have significantly elevated plasma cholesterol levels since birth, and experience a 10- to 20-fold increased risk of premature Coronary Heart Disease (CHD) if not satisfactorily managed [12,13]. While14 to 34 million people worldwide are estimated to be affected by FH, most (>90%) remain undetected, with an unacceptable diagnostic rate of <1% in many countries [14]. Even though effective therapy is available, FH is often inadequately managed [15].

As one of the most populated countries in the world, India undoubtedly carries a significant burden of the disease. However, the true prevalence of FH in India remains unknown, although it is estimated to affect at least 2.5 million individuals. There is therefore an urgent need to raise awareness of this condition among both health care providers and the general public. It is vital that FH patients be identified in a timely manner and be initiated on lifelong lipid-lowering therapies, so as to attenuate the development of atherosclerotic CVD and to reduce premature morbidity and mortality. This review serves to provide information about FH, and to promote the dissemination of knowledge on FH, to Asian Indian physicians.

Background and prevalence

FH is caused by genetic derangements in the Low-Density Lipoprotein (LDL) clearance pathway, leading to diminished cellular uptake of LDL particles and increased plasma LDL-cholesterol (LDL-C) Concentrations. Although it is dominantly inherited, FH has a strong gene dosage effect. Patients with 1 mutant allele are heterozygotes; those with identical defects in both alleles are homozygotes, while still others with different mutations in the 2 alleles are compound heterozygotes. In most parts of the world, the prevalence of heterozygous FH (HeFH) is between 1 in 300 and 1 in 500 [16]. However, in certain populations, such as the French Canadians [17], the Christian Lebanese [18], the Tunisians [19], as well as the Afrikaners [20], Ashkenazi Jews[21], and Indians [22]of South Africa, HeFH may be much more common - up to 1 in 50 to 100 - due to founder effects [12]. In HeFH patients, the cumulative risk of a fatal or non-fatal CHD by the age of 60 is at least 50% in males and 30% in females [23,24]. By contrast, homozygous FH (HoFH) individuals usually present with the sequelae of severe and widespread atherosclerosis, including sudden death from acute myocardial infarction (MI), in the first 2 decades of life [25]. However, HoFH remains rare, with a reported occurrence of 1 in 1 000 000 [25].

Molecular pefects

In humans, cholesterol is synthesized (or recycled) in the liver, and subsequently packaged into Very Low-Density Lipoprotein (VLDL) particles. VLDL is released into circulation and provides a source of cholesterol for peripheral tissues. It subsequently returns to the liver as LDL, and is taken up via interaction of its surface ligand, apolipoprotein B100 (apoB100), with the LDL receptor and an adaptor protein termed LDL receptor adaptor protein 1 (LDLRAP1). The complex is internalized and transported to lysosomes, where LDL is hydrolyzed and the receptor recycled back to the cell surface [26].

FH has been attributed to mutations in the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), the proprotein convertase subtilisin/kexin type 9gene (PCSK9), and the LDL receptor adaptor protein 1 gene (LDLRAP1). LDLR defects account for the majority (85-90%) of FH cases, although the prevalence is region-dependent [27,28]. More than 1200 variants have been described, with about 79% being pathogenic [29]. The reported mutations affect all functional domains of the LDL receptor, and can be categorized into 5 major classes [30]: class 1, with complete absence of receptor synthesis (null alleles); class 2, with impaired receptor transport between the endoplasmic reticulum and the Golgi apparatus, and thus failure of receptor expression on the cell surface (transport-defective alleles); class 3, with receptors which are unable to bind to LDL particles on the cell surface (binding-defective alleles); class 4, with receptors which, once bound to LDL, fail to cluster in clathrin-coated pits and initiate receptor-mediated endocytosis of LDL (internalization-defective alleles); and class 5, with receptors which, once internalized, do not release LDL in lysosomes and recycle back to the cell surface (recycling-defective alleles).

Mutations in APOB and PCSK9 are less common, and make up approximately 5-6% and 1-2% of FH cases, respectively [27,28]. A single amino acid substitution at position 3500, from arginine to glutamine, in exon 26 is the most common defect in APOB, and is responsible for 5-7% of FH cases in Europe [31,32], although it is less frequently reported in other populations [12]. Because mutations in the APOB allele do not have complete penetrance, affected individuals present with a similar clinical phenotype as classic FH, but with less severe LDL-C elevations. PCSK9 is a serine protease which binds to and targets LDL receptors for lysosomal destruction, thereby preventing their recycling to the cell surface [33]. Gain-of-function mutations in PCSK9 lead to significant hypercholesterolemia, and >20 defects have been described [14].

Only a small number (<30) of genetic mutations have been reported in Asian Indians (Table 1), with the majority affecting LDLR. We did not come across any studies describing APOB or PCSK9 defects in Indian FH patients. India is a highly heterogenous population with diverse ethnic groups, and this may potentially explain the paucity of common FH-causing mutations in Asian Indians [34]. It is possible that region- or community-specific FH mutations do exist, especially in areas which have endured longstanding segregations due to religious or cultural practices [34]. One common genetic aberration is the Pro685Leu mutation (or Pro664Leu, if the historical numbering system is used) in exon 14 of LDLR, which was initially reported by Soutar et al. in a South African Indian [35]. It was later found to account for 50% of FH mutations in Indian immigrants residing in South Africa [36]. This molecular defect has since been described in other Indian FH individuals spanning a wide geographical distribution [32,37-41], most of whom have a common Gujarati ancestral origin [39].

Table 1: Genetic defects reported in Asian Indian patients with familial hypercholesterolemia.



  
    Exon 
    cDNA Modification^a 
    Mutation at 
      Peptide Level^b 
    Patient(s)' Region of Origin in India 
    Patient(s)' Country of Residence 
    Reference 
  
  
    LDLR Gene
  
  
    1
    c.1A>T
    p.Met1Leu    (M-21L)
    N/A
    South Africa
    [93] 
  
  
    3
    c.205A>C
    p.Lys69Gln
    N/A
    India
    [94] 
  
  
    3
    c.232C>T
    p.Arg78Cys    (R57C)
    N/A
    South Africa
    [95] 
  
  
    3
    c.242_243insG
    p.Arg81fsX49 (R60fsX49)
    N/A
    India
    [96] 
  
  
    3
    c.268G>T
    p.Asp90Tyr    (D69Y)
    N/A
    South Africa
    [97] 
  
  
    3
    c.301G>A
    p.Glu101Lys
    N/A
    United Kingdom
    [41] 
  
  
    4

    c.397_398insG
    p.Asp133GlyfsX47 (D112GfsX47)
    N/A
    India
    [96] 
  
  
    4
    c.418G>A
    p.Glu140Lys    (E119K)
    N/A
    South Africa
    [97] 
  
  
    4
    c.649_650insT
    p.Asp217ValfsX110
    N/A
    United Kingdom
    [41] 
  
  
    4
    c.661G>T
    p.Asp221Tyr    (D200Y)
    N/A
    South Africa
    [36] 
  

  
    4
    c.682G>A
    p.Glu228Lys (E207K)
    Maharashtra
    South Africa
    [36] 
  
  
    5
    c.709C>T
    p.Arg237Cys
    N/A
    United Kingdom
    [41] 
  
  
    5
    c.736delG
    p.Gly246GlufsX19 (G225EfsX19)
    N/A
    United Kingdom
    [32] 
  
  
    6
    c.829G>A
    p.Glu277Lys    (E256K)
    N/A
    Malaysia
    [98] 
  
  
    8
    c.1176C>A
    p.Cys392X    (C371X)
    N/A
    South Africa
    [93] 
  
  
    9
    c.1215C>G
    p.Asn405Lys    (N384K)
    Gujarat/Surat
    South Africa
    [36] 
  
  
    9
    c.1217G>C
    p.Arg406Pro    (R385P)
    N/A
    United Kingdom
    [32] 
  
  
    9
    c.1222G>A
    p.Glu408Lys    (E387K)
    Gujarat
    India
    [99] 
  
  
    N/A
    United Kingdom
    [38] 
  
  
    N/A
    South Africa
    [32] 
  
  
    N/A
    United Kingdom
    [41] 
  
  
    9
    c.1241T>G
    p.Leu414Arg    (L393R)
    N/A
    India
    [99] 
  
  
    10
    c.1474G>A
    p.Asp492Asn
    N/A
    United Kingdom
    [41] 
  
  
    11
    c.1681C>T
    p.Gln561X    (Q540X)
    West India
    United Kingdom
    [100] 
  
  
    13
    c.1855T>C
    p.Phe619Leu
    N/A
    United Kingdom
    [41] 
  
  
    14
    c.2054C>T 
    p.Pro685Leu    (P664L)
    Gujarat/Surat
    South Africa
    [37] 
  
  
    Gujarat
    South Africa
    [35] 
  
  
    N/A
    United Kingdom
    [38] 
  
  
    N/A
    United Kingdom
    [39] 
  
  
    Gujarat
    United Kingdom
    [40] 
  
  
    N/A
    United Kingdom
    [32] 
  
  
    N/A
    United Kingdom
    [41] 
  
  
    16
    c.2356A>T
    p.Ser786Cys    (S765C)
    N/A
    South Africa
    [36] 
  
  
    17
    c.2439G>A
    p.Trp813X
    N/A
    United Kingdom
    [41] 
  
  
    7-12
    Deletion of exons 7-12
    -
    N/A
    United Kingdom
    [41] 
  
  
    7-14
    Approx. 11-kb deletion of exons 7-14
    -
    N/A
    United Kingdom
    [101] 
  
  
    Other Genes
  
  
    LDLRAP1,    Exon 1
    c.70_71delGG^c
    p.Gly24ArgfsX9^c
    N/A
    United Kingdom
    [102]



Table 1: Genetic defects reported in Asian Indian patients with familial hypercholesterolemia.

Very rarely, defects in LDLRAP1 (formerly known as ARH) lead to a complete loss of function in the accessory protein essential for LDL endocytosis [42]. Patients have an autosomal recessive hypercholesterolemia, with a clinical picture resembling HoFH [42]. One such case has been described in Asian Indians (Table 1).

Diagnosis

FH should be considered in patients with a personal or family history of marked hypercholesterolemia and/or premature CHD. Up to 20% of patients who present with an acute MI before the age 45 have FH [12]. HeFH individuals, with at least 50% residual function in their LDL clearance pathway, typically have untreated LDL-C levels 2-3 times above normal [26], corresponding to plasma LDL-C concentrations between 5 and 13 mmol/L [43]. In contrast, HoFH patients, with2-30% residual activity, will present with untreated LDL-C concentrations >13 mmol/L, or 4-8 times above average [26,43]. Triglycerides and high-density lipoprotein cholesterol (HDL-C) levels are typically normal and low, respectively [26].

On physical examination, cutaneous stigmata of FH may be observed, and are secondary to the infiltration of lipid-laden histiocytes, and/or deposits of cholesterol, in the tendons (xanthomas), in theeyelids (xanthelasmas), oralong the corneal margin (corneal arcus) [12]. Xanthomas are often found in the extensor tendons of the hands or in the Achilles, but may also occur in the patellar or triceps tendons [12]. Partial or complete corneal arcus is suggestive of FH if observed in a young patient (age <45). In general, physical findings of FH are insensitive but specific markers of the disease [12]; their absence does not exclude FH.

A number of validated algorithms are available to assist in the diagnosis of FH, including the Dutch Lipid Clinic Network (DLCN) Criteria (Table 2)[44], the Simon Broome Register Criteria in the United Kingdom (Table 3)[45], and the Make Early Diagnosis- Prevent Early Death (MEDPED) Criteria in the United States (Table 4)[46]. Due to biological variations, the average of at least 2 fasting LDL-C results should be used to make a diagnosis of FH [47]. Acute illnesses can lower both total cholesterol and LDL-C, and lipid testing should be deferred until at least 8 weeks post-recovery [48].Secondary causes of hypercholesterolemia (such as hypothyroidism, nephrotic syndrome, cholestatic liver disease, and certain medications), as well as familial combined hyperlipidemia, should be ruled out, although these pathologies would not present with the dermatological findings of FH.

Criteria	Score
1. Family History
First-degree relative with known premature coronary and/or vascular disease (men <55 years, women <60 years)	1
First-degree relative with LDL-C >95^th percentile for age and sex	1
First-degree relative with tendon xanthomas and/or corneal arcus	2
Children age <18 years with LDL-C >95^th percentile for age and sex	2
2. Clinical History
Patient with premature coronary artery disease (ages as above)	2
Patient with premature cerebral or peripheral vascular disease (ages as above)	1
3. Physical Examination
Tendon xanthoms	6
Corneal arcus age <45 years	4
4. Laboratory Analysis
LDL-C =8.5 mmol/L	8
LDL-C 6.5-8.4 mmol/L	5
LDL-C 5.0-6.4 mmol/L	3
LDL-C 4.0-4.9 mmol/L	1
5. DNA Analysis
*Functional mutation in a FH-related gene (e.g.LDLR, APOB, or PCSK9)*	8
Diagnosis	Total Score
Definite FH	>8
Probable FH	6-8
Possible FH	3-5
Unlikely FH	<3

Criteria
A. Plasma cholesterol measurement of: i. TC >7.5 mmol/L or LDL-C >4.9 mmol/L in an adult ii. TC >6.7 mmol/L or LDL-C >4.0 mmol/L in a child<16 years
B. Tendon xanthomas in the patient, or in a first-degree relative (parent, sibling, or offspring) or second-degree relative (grandparent, aunt, or uncle)
*C. DNA-based evidence of mutation in a FH-related gene (e.g.LDLR, APOB, or PCSK9)*
D. Family history of coronary artery disease: i. Below age 60 in a first-degree relative ii. Below age 50 in a second-degree relative
E. Family history of hypercholesterolemia: i. TC >7.5 mmol/L in an adult first- or second-degree relative ii. TC >6.7 mmol/L in a child or sibling age <16 years
Diagnosis	Criteria
Definite FH	�A + B�� or�� C
Probable FH	�� A + D�� or�� A + E

Age (Years)	TC (LDL-C) Levels inmmol/L
Age (Years)	First-Degree Relative with FH	Second-Degree Relative with FH	Third-Degree Relative with FH	General Population
<20	5.7 (4.0)	5.9 (4.3)	6.2 (4.4)	7.0 (5.2)
20-29	6.2 (4.4)	6.5 (4.6)	6.7 (4.8)	7.5 (5.7)
30-39	7.0 (4.9)	7.2 (5.2)	7.5 (5.4)	8.8 (6.2)
=40	7.5 (5.3)	7.8 (5.6)	8.0 (5.8)	9.3 (6.7)

Familial Hypercholesterolemia: A Call for Increased Awareness in the Asian Indian Population

Abstract

Introduction

Background and prevalence

Molecular pefects

Diagnosis

Cascade screening

Management

Upcoming Pharmacotherapies

Concluding Remarks

References