REVIEWS

The genetics of familial combined

hyperlipidaemia
Martijn C. G. J. Brouwers, Marleen M. J. van Greevenbroek, Coen D. A. Stehouwer, Jacqueline de Graaf
and Anton F. H. Stalenhoef
Abstract | Almost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete
entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two
strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage
approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a
variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas
others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic
heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how
these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose
tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance
of apolipoprotein‑B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein
particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid
traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems
genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or
metabolomics, will attribute functions to genetic variants in addition to revealing new genes.
Brouwers, M. C. G. J. et al. Nat. Rev. Endocrinol. 8, 352–362 (2012); published online 14 February 2012; doi:10.1038/nrendo.2012.15

Introduction
For over four decades, scientists have struggled to unveil The aetiology of FCHL is currently considered to be the
the genetic and metabolic background of familial com­ consequence of multiple defects, which differ between
bined hyperlipidaemia (FCHL). The most prevalent gen­ families.5 These defects include hepatic overproduction
e­tic dyslipidaemia in Western society (1:100), FCHL is of VLDL particles, on a background of adipose tissue
associated with an increased incidence of premature coro­ dysfunction, multiorgan insulin resistance and hepatic
nary artery disease and was originally charac­terized by fat accumulation, combined with a disturbed metabolism
the presence of different lipid phenotypes, that is, hyper­ of lipoprotein particles in plasma. Finally, an impaired
cholesterolaemia, hypertriglyceridaemia or combined clearance of apoB‑containing particles results in the
hyperlipidaemia, within an affected kindred.1 Nowadays, classic FCHL phenotype (Figure 1).6
the presence of multiple hyperlipidaemias of different The second strategy, unbiased by current knowledge of
Department of Internal
types has been abandoned as a diagnostic criterion and the biology of lipid metabolism, is the linkage approach,
Medicine and replaced by a classification on the basis of triglyceride in which family structures are used to screen the genome
Endocrinology, and apolipoprotein (apo) B levels, which should be for loci linked to the FCHL phenotype or associated
Maastricht University
Medical Centre, increased in at least two family members to classify as traits, such as BMI or levels of small, dense LDL or HDL
P. Debyelaan 25, FCHL.2 The adoption of this new diagnostic criterion is cholesterol. This strategy was initially used for rare
6229 HX, Maastricht,
The Netherlands
antici­pated to yield diagnoses that are more consistent over Mendelian disorders and later also for common, complex
(M. C. G. J. Brouwers, time and, therefore, facilitate in particular genetic studies, diseases, such as type 2 diabetes mellitus (T2DM) and
M. M. J. van
in which an accurate phenotype is essential. Another lipid FCHL, albeit with mixed success.7 One chromosomal
Greevenbroek,
C. D. A. Stehouwer). phenotype that has consistently been associ­ated with locus that has been successfully and consistently linked to
Department of Internal FCHL is the presence of small, dense LDL particles.3,4 FCHL is the locus 1q21–23.7 This region harbours many
Medicine, Radboud
University Nijmegen Two complementary methods have been applied to genes, of which TXNIP, RXRG, CRABP2, ATF6 and USF1
Medical Centre, 463 unravel the complex genetic background of FCHL. For have been investigated in patients with FCHL.8–14 TXNIP,
AIG, P. O. Box 9101,
6500 HB Nijmegen,
the first strategy, the candidate-gene approach, concep­ although clearly involved in lipid metabolism,5 has been
The Netherlands tual candidates are tested in association studies. A thor­ abandoned as a causal gene of FCHL.12,15–17 By contrast,
(J. de Graaf, ough knowledge of the metabolic pathways contributing an association between FCHL and polymorphisms in the
A. F. H. Stalenhoef)
to the FCHL phenotype is necessary for this purpose. USF1 gene, which encodes upstream stimulatory factor 1,
Correspondence to: has frequently been replicated.12–14
A. F. H. Stalenhoef
a.stalenhoef@ Competing interests An additional, relatively new ‘hypothesis-free’
aig.umcn.nl The authors declare no competing interests. approach, the genome-wide association study (GWAS),

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© 2012 Macmillan Publishers Limited. All rights reserved

which searches the genome for common gene variants
that are associated with complex traits, has already
proven to be valuable in FCHL. Although GWAS for
plasma lipid traits has only been conducted in the general
population, 18–20 some results have successfully been
extrapolated to FCHL.21
In this Review, we will outline how a substan­
tial number of these genes can be integrated into the
meta­bolic pathways resulting in the FCHL phenotype
(Figure 1). Several illustrative examples are highlighted
to provide insight into FCHL as a genetic disorder in
general, in relation to other dyslipidaemias, such as
T2DM and familial hypercholesterolaemia, and how
the distribution of genetic variants within families with
FCHL may add to the phenotypic heterogeneity observed
in this common lipid disorder. Moreover, we will identify
current gaps in FCHL research to enable the formulation
of new directions for future studies.
Dysfunctional adipose tissue
The role of malfunctioning adipose tissue in the
develop­m ent of the FCHL phenotype was estab­
lished 10–15 years ago,22 but has been reinforced by a
study by Arner et al.,23 who demonstrated reduced tri­
glyceride turnover in adipose tissue from patients with
FCHL. LIPE, a gene that encodes hormone sensitive
lipase (HSL)—a key player in lipolysis (Figure 1)—has
been extensively studied as a candidate gene in FCHL
(Table 1). Outcomes of these analyses have, however,
been somewhat inconsistent,24–26 which suggests that
LIPE is at best a modest modifier gene in FCHL. Another
gene involved in triglyceride hydrolysis in adipose tissue
(and in liver), PNPLA2, which encodes patatin-like phos­
pholipase domain-containing protein 2 (also known as
adipose triglyceride lipase),27 has been associated with
FCHL,28 although replication is currently awaited.
Of interest, gene variants in USF1, which were previ­
ously shown to be associated with FCHL,12 are associ­
ated with catecholamine-induced lipolysis in healthy
women with obesity.29 This effect has been speculated to
be mediated by phosphorylation of HSL and PNPLA2.29
Finally, Marcil and colleagues have shown that a rare
variant in the C5a anaphylatoxin chemotactic receptor
C5L2, which is encoded by the gene GPR77 and results
in decreased triglyceride storage in adipocytes, was
present in one of 61 investigated probands.30 Affected
indivi­duals in this kindred displayed higher plasma
lipid levels than their unaffected relatives.30 This study
demon­strates that, in some cases, the FCHL phenotype
is largely determined by a single genetic defect.
Hepatic fat and VLDL overproduction
Overproduction of VLDL particles and hepatic fat accu­
mulation are both central aspects of FCHL.31,32 The fatty
liver trait has a heritability estimate of 20–36% in FCHL
pedigrees.31 Previous stable isotope studies in patients
with T2DM have suggested that VLDL overproduc­
tion is triggered by an increased amount of hepatic fat
and insulin resistance.33 Hepatic fat accumulation is
the consequence of increased free fatty acid flux (from
NATURE REVIEWS | ENDOCRINOLOGY
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Key points
■■ The list of familial combined hyperlipidaemia (FCHL) susceptibility genes is
expanding and now comprises approximately 35 genes, each with a different
level of scientific evidence
■■ Genes that affect the metabolism and clearance of plasma lipoprotein particles
have been studied in most detail in patients with FCHL
■■ The adoption of new metabolic traits will aid in the identification of genes that
are more proximal in the metabolic processes that eventually result in elevated
plasma lipoprotein levels
■■ The FCHL gene pool consists of a mix of genes, ranging from very rare
with substantial effect sizes to more common with only a moderate effect
on lipid phenotype
■■ Linkage and genome-wide association studies are both hypothesis-free,
complementary strategies, but not sufficient to unravel the complex genetic
background of FCHL
■■ Systems genetic analysis, which integrates genetic polymorphisms with the
wealth of information emerging from new genomic and proteomic technologies,
should reveal new genes and attribute functions to genetic variants
dysfunctional adipose tissue) towards the liver, increased
hepatic de novo lipogenesis and impaired β oxidation
(Figure 1).34,35
An illustrative example of a common gene variant
that affects de novo lipogenesis and β oxidation is the
Pro446Leu variant in GCKR. This amino acid substitu­
tion results in a downstream cascade of increased hepatic
glucokinase activity, increased glycolytic flux, elevated
levels of malonyl-CoA and consequently impaired
β oxidation—via inhibition of carnitine palmitoyl­
transferase 1—and augmented de novo lipogenesis.36
Of interest, this GCKR gene variant has repeatedly been
associated with plasma triglyceride levels in GWAS and
appears to affect this trait in FCHL as well (Table 2),21
whereas the same variant predisposes individuals in
the general population to lower plasma glucose levels.37
FCHL and T2DM are two entities that are both pheno­
typically characterized by multiorgan insulin resistance
and, therefore, GCKR might be a gene that genetically
distinguishes FCHL from T2DM.6 USF1 could also be
such a genetic differentiator, as it has not convincingly
been associated with T2DM,38–40 in contrast to FCHL
(Table 2). USF1 targets liver metabolism by stimulat­
ing fatty acid synthase, an essential enzyme in hepatic
de novo lipogenesis, and glucokinase expression. 41,42
From this perspective, it is anticipated that hepatic fat
accumulation, as observed in patients with FCHL, can
only result from gain-of-function variants of USF1.
Triglyceride-rich lipoproteins
Once secreted into the circulation, triglyceride mol­
ecules, carried by VLDL particles, are hydrolyzed by
lipo­protein lipase (LPL), which is encoded by the gene
LPL. When VLDL particles are less triglyceride-rich, tri­
glyceride molecules are hydrolyzed by hepatic triacyl­
glycerol lipase (HL), which is encoded by the gene LIPC
(Figure 1). ApoC-II and apoE serve as co-factors for
LPL, whereas apoC-III acts as an inhibitor. 43 Oral fat
load tests have shown that the clearance of both chylo­
micron remnants and VLDL particles is delayed in
patients with FCHL.44 In vivo studies have demonstrated
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saturation of this clearance pathway by hepatic VLDL

overproduction. Some investigators have reported
a higher frequency of dysfunctional LPL variants in
ATF6 patients with FCHL,46–52 whereas others have attributed
Hepatic steatosis
SREBP-2 4 only a modifying role to LPL, that is, these variants con­
tribute to the FCHL phenotype but are not enriched in
Glucose the FCHL gene pool.26,53–55 Similar outcomes have been
PCSK9
De novo obtained for LIPC.26,56,57 These results emphasize that
LDLR
2 lipogenesis FCHL is a heterogeneous disease, each pedigree being
USF1/GCKR
composed of a different subset of (genetic) risk factors
ApoB that partly overlap with those of other families.
β oxidation FFA TG The APOA1/C3/A4/A5 gene cluster, which resides on
chromosome 11q23–24, has been studied thoroughly and
MTTP
is associated with FCHL and its related traits.58–65 Again,
some studies have failed to observe any linkage or associ­
ation with FCHL.66–69 Experimental studies show that all
ApoB genes in this cluster are good conceptual candidates,70–73
but their close positional relation on the chromosome
LDL —and the presence of linkage d­isequilibrium—makes it
HL
ApoB 3 difficult to discern which gene is actually the causal one.
ApoC-III Dyslipidaemia Of interest, apoA‑V expression is stimulated by USF1,
IDL TG and population studies have suggested a gene–gene inter­
ApoB ApoE action between APOA5 and USF1 that affects plasma
ApoC-III ApoC-II
lipids and atherosclerotic lesions.74,75
L TG Gene variants in LPL and the APOA1/C3/A4/A5
ApoE VLD LPL
cluster have also been associated with LDL particle size
Apo-CII
ApoC-III
in patients with FCHL.46,76 Small, dense LDL parti­cles,
FFA
which are regarded as a consistent hallmark of FCHL,3,4
are generated when triglyceride-rich VLDL particles are
GPR77
abundant,43 which probably accounts for the associ­
PNPLA2
USF1 ation with these genes. VLDL particles can exchange
Blood HSL triglyceride molecules for cholesteryl esters from LDL
vessel FFA TG
1 particles—mediated by cholesteryl ester transfer protein
Glycerol
(CETP)—resulting in cholesterol-depleted LDL particles
that eventually obtain their small size after hydrolysis of
Adipose tissue
dysfunction their triglyceride content.43 Some studies have attributed
a role for the CETP gene in FCHL,21 which has also been
observed in GWAS (Table 3). Of note, HDL particles
Figure 1 | Key processes in the pathogenesis of familial combined
can be remodelled in analogy to LDL particles as part
hyperlipidaemia. Adipose tissue dysfunction (1): triglycerides, stored in
adipocytes, are hydrolyzed by HSL and PNPLA2 into FFAs and glycerol. Hepatic fat of the reverse cholesterol transport; apoA‑I molecules
and VLDL overproduction (2): FFAs enter the liver to yield ATP or be stored as are lipidated to become mature HDL particles, which
triglycerides. When glucose is abundant, FFAs can be synthesized de novo. are finally absorbed by the liver. Disturbed triglyceride-
Hepatic de novo lipogenesis and β oxidation are tightly balanced. Hepatic rich lipoprotein turnover in FCHL can also result in low
triglycerides are transferred to apoB molecules by MTTP to form VLDL particles. levels of circulating HDL cholesterol. Reverse cholesterol
Metabolism and clearance of triglyceride-rich lipoproteins (3): the triglyceride-rich transport has been reviewed in detail elsewhere.77
content of VLDL particles is hydrolyzed by LPL, to obtain FFAs as an energy
Additional disturbances in HDL composition and
substrate. ApoE and apoC-II facilitate LPL-mediated hydrolysis, whereas apoC-III
impairs LPL function. IDL particles undergo a similar process, resulting in
possibly metabolism might also play a part in FCHL, as
triglyceride-poor, cholesterol-rich LDL particles. HL hydrolyzes triglycerides from illustrated by increased apoA-II levels, concurrent with
IDL and LDL particles. Clearance of LDL particles (4): LDL particles leave plasma low HDL cholesterol, that were linked to a chromosomal
by binding to LDLR. SREBP‑2 stimulates transcription and translation of LDLR. locus on 1q41 in FCHL pedigrees.78 This particular locus
Once translated, the LDLR either migrates towards the cellular membrane or is has now been confirmed in GWAS as a coronary artery
immediately degraded in a process mediated by PCSK9, which also depends on disease locus.79,80
SREBP‑2. PCSK9 also breaks down LDLR after endocytosis. Abbreviations: apo,
apolipoprotein; FFA, free fatty acid; MTTP, microsomal triglyceride transfer protein;
Clearance of LDL particles
TG, triglycerides.
The role of the LDL receptor (LDLR) and impaired
clear­ance of LDL particles in the development of hyper­
that a substantial proportion of patients with FCHL have lipidaemia were previously confined to familial hyper­
decreased LPL activity, which contributes to hyper­ cholesterolaemia. It has now been reported that genetic
triglyceridaemia.45 This finding could be the conse­ defects affecting the LDLR may contribute to the FCHL
quence of either genetic defects in LPL or secon­dary to phenotype as well (Figure 1). Civeira and colleagues

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Table 1 | Genes with suggested roles in adipose tissue dysfunction

Locus Gene Gene name Protein function* Associated traits‡ Corroborating
(origin of populations) evidence§
19q13 GPR77 G-protein-coupled Synonym for C5L2; receptor for acylation- FCHL diagnostic:|| FCHL,30 TC,30 NR
receptor 77 stimulating protein (also known as C3adesArg) TG, apoB30
and decoy for C5a (NA)
1p31 LEPR Leptin receptor Involved in fat metabolism, regulation of body FCHL diagnostic: FCHL99 Linkage data:
weight and in a novel hematopoietic pathway Other: HDL‑C,99 leptin;100 BMI100 1p31 linked to
required for normal lymphopoiesis (EU) apoB101,102
19q13 LIPE Hormone sensitive Short form found in WAT, among other tissues; FCHL diagnostic: none NR
lipase hydrolyzes stored TG to FFAs Other: LDL‑C (men only)24
Long form found in steroidogenic tissues; (EU)
converts cholesteryl esters to free cholesterol
for steroid hormone production
11p15 PNPLA2 Patatin-like Found on the surface of lipid droplets; highest FCHL diagnostic: FCHL,28 TG28 Linkage data:
phospholipase expression in WAT and BAT; when activated, (EU) 11p14 linked to
domain containing 2 breaks down TG to provide energy103 TC7
3p253 PPARG Peroxisome Nuclear receptor and transcription factor; FCHL diagnostic: none Linkage data:
proliferator-activated regulates adipocyte differentiation and Other: Fatty acid,104 glycerol,104 insulin105 3p14 linked to
receptor γ glucose homeostasis (EU) HDL‑C106
1q22–q23 USF1 Upstream Transcription factor; regulates transcription FCHL diagnostic: FCHL,12–14 Linkage data:
transcription factor 1 of over 40 cardiometabolic disease-related TG,13,14,107,108 apoB108 1q23 linked to
genes Other: LDL‑C13 FCHL and TG7
(EU, NA, SA)
Only positive findings are reported, but for several variants absence of an association was reported as well, for reasons that may include: a small number of patients with FCHL and rare FCHL
variant; variants different in relevance between populations; differences in ascertainment of FCHL patients. *Some genes listed may have additional, yet to be identified, functions and might
also be involved in other (metabolic) processes in FCHL. ‡References refer to genes associated with the FCHL diagnosis and/or FCHL diagnostic traits (TC, TG, apoB) in patients with FCHL.
Individual references may refer to different mutations or gene variants. §Linkage in FCHL-based studies for: FCHL, TG, TC, HDL‑C, apoB. Linkage results before 2005 have been reported
elsewhere.7 Since then, novel loci have been reported and previous loci confirmed, including 16q23, 11q22, 14q24–31 for LDL size; 109 3p14, 3q31, 7q32, 12q12, 14q31–32, 16q23–24 for
low HDL cholesterol;106 7p12–21 for fatty liver;31 1p31 for apoB;102 and longitudinal confirmation of 1p21–31 of apoB,101 4q32.2 for apoB,97 and 16q24.1 for FCHL.14 ||Rare variant (1 family).
Abbreviations: apo, apolipoprotein; BAT, brown adipose tissue; EU, Europe (Finland, France, Hungary, Italy, Spain, The Netherlands and/or UK); FCHL, familial combined hyperlipidaemia; FFA,
free fatty acid; HDL‑C, HDL cholesterol; LDL‑C, LDL cholesterol; NA, North America (Canada and/or USA); NR, not reported; SA, South America (Mexico); TC, total cholesterol; TG, triglycerides;
WAT, white adipose tissue.

Table 2 | Genes linked with hepatic fat and VLDL overproduction in FCHL
Locus Gene Gene name Protein function* Associated traits‡ Corroborating
(origin of populations) evidence§
19q13 APOE ApoE Ligand for the LDL (apoB/E) receptor and for FCHL diagnostic: FCHL,111 GWAS data18–20,114
the apoE receptor; may be involved in VLDL TC,111,112 TG,113 apoB111
production110 Other: LDL‑C,111 TG55
(EU, A)
2p23 GCKR Glucokinase Inhibits glucokinase in liver and pancreatic FCHL diagnostic: TG21 GWAS data18–20
(hexokinase 4) islet cells (SA) Linkage data: 2p25
regulator linked to FCHL7
3p22 OSBPL10 Oxysterol binding Intracellular lipid receptor; may be involved in FCHL diagnostic: TG115 NR
protein-like 10 suppression of hepatic lipogenesis and VLDL (EU)
production
1q22–q23 USF1 Upstream Transcription factor; regulates transcription of FCHL diagnostic: FCHL,12–14 Linkage data: 1q23
transcription over 40 cardiometabolic disease-related TG,13,14,107,108 apoB108 linked to FCHL and TG7
factor 1 genes Other: LDL‑C13
(EU, NA, SA)
Only positive findings are reported, but for several variants absence of an association was also reported, for reasons that may include: a small number of patients with FCHL and rare FCHL
variant; variants different in relevance between populations; differences in ascertainment of FCHL patients. *Some genes listed may have additional, yet to be identified, functions and might
also be involved in other (metabolic) processes in FCHL. ‡References refer to genes associated with the FCHL diagnosis and/or FCHL diagnostic traits (TC, TG, apoB) in patients with FCHL.
Individual references may refer to different mutations or gene variants. §Linkage in FCHL-based studies for: FCHL, TG, TC, HDL‑C, apoB. Linkage results before 2005 have been reported
elsewhere.7 Abbreviations: A, Asia (China, China (Hong-Kong) and/or Japan); apo, apolipoprotein; EU, Europe (Finland, France, Hungary, Italy, Spain, The Netherlands and/or UK); FCHL, familial
combined hyperlipidaemia; GWAS, genome-wide association study; HDL‑C, HDL cholesterol; LDL‑C, LDL cholesterol; NA, North America (Canada and/or USA); NR, not reported; SA, South
America (Mexico); TC, total cholesterol; TG, triglycerides.

demonstrated that mutations in LDLR are frequently
(19.6%) observed in patients with FCHL. 81 Although
genetic defects in LDLR are by definition compatible with
the diagnosis of familial hypercholesterola­emia, this study
suggests that the lipid-based diagnosis of FCHL overlaps
with the diagnosis of familial hypercholesterolaemia. Of
note, the second most frequent genetic cause of familial
hypercholesterolaemia, mutations in apoB, has consist­
ently not been observed in FCHL,81–84 whereas common
variants in apoB have repeatedly been associ­ated with
plasma lipid traits by GWAS in the general population.18–20
Finally, mutations in PCSK9, the latest gene to be
added to the list of causes of familial hypercholesterol­
a­emia,85 are present in only a small proportion of FCHL

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Table 3 | Genes with suggested roles in metabolism and clearance of TG-rich lipoproteins in FCHL
Locus Gene Gene name Protein function* Associated traits‡ Corroborating evidence§
(origin of populations)
11q23–24 APOA1 ApoA‑I, apoC‑III, apoA‑IV ApoA‑I: promotes cholesterol efflux; FCHL diagnostic: FCHL,58–64,65 GWAS data18–21,79,114
APOC3 cofactor for LCAT. ApoC-III: inhibits TC,59,116 TG,58,59,61,64,76,116 apoB60 Linkage data: 11q23 linked
APOA4 LPL and HL; may delay catabolism Other: LDL size,76,117 plasma to FCHL7
gene of TG-rich particles apoC-III levels,61,116 LPL activity,118
cluster ApoA-IV: potential role in dietary fat HDL‑C,64,119 VLDL, apoB64
absorption and secretion and (EU, NA)
catabolism of chylomicrons and
VLDL; required for LPL activation by
apoC-II; potent LCAT activator
11q23 APOA5 ApoA‑V May have a role in lipoprotein FCHL diagnostic: FCHL,58,76,123,124 GWAS data18,19
catabolism;120 PPARα target TC,123,124 TG,21,58,76,123–125 apoB123 Linkage data: 11q23 linked
gene,121 also regulated by thyroid Other: HDL‑C,123,124 LDL size76,123 to FCHL7
hormone122 (EU, SA, A)
19q13 APOE ApoE Ligand for the LDL (apoB/E) FCHL diagnostic: FCHL,111 TC,111,112 GWAS data18–20,114
receptor and for the apoE receptor; TG,113 apoB111
may be involved in VLDL Other traits: LDL‑C,111 TG55
production110 (EU, A)
16q21 CETP Cholesteryl ester transfer Transfers cholesteryl esters FCHL diagnostic: TG21 GWAS data18–20
protein between lipoproteins (SA) Linkage data: CETP/LCAT
locus linked to LDL
size;117,109 16q23 linked
to HDL‑C7
1q41–42 GALNT2 UDP‑N-acetyl-alpha‑D- This family transfers N‑acetyl FCHL diagnostic: TG21 GWAS data20
galactosamine:polypeptide galactosamine in O‑linked (SA)
N‑acetylgalactosaminyl­ oligosaccharide biosynthesis
transferase 2 (GalNAc‑T2) (e. g. apoC-III, VLDL receptor and
LDL receptor are O‑glycosylated126)
16q22 LCAT Lecithin-cholesterol Involved in reverse cholesterol FCHL diagnostic: NR GWAS data19,20
acyltransferase transport Linkage data: CETP/LCAT
locus linked to FCHL and
HDL‑C,63 LDL size;117
16q23 linked to HDL‑C7
15q21–23 LIPC Hepatic lipase TG hydrolase and bridging factor for FCHL diagnostic: FCHL,56,57 GWAS data18–20
receptor-mediated lipoprotein TC,56,127 TG127 Linkage data: LIPC locus
uptake; role in HDL metabolism; Other: insulin resistance127 linked to HDL‑C,128
expressed in liver (EU) LDL size128

8p22 LPL Lipoprotein lipase TG hydrolase and ligand or bridging FCHL diagnostic: FCHL46–52|| GWAS data18–20
factor for receptor-mediated TC,47 TG,47,54 apoB47,54 Linkage data: 8p23 linked
lipoprotein uptake; role in VLDL Other: LDL size,46 TG,55 LDL‑C,53 to TG7
metabolism and clearance; HDL‑C54
expressed in heart, muscle and (EU, NA)
adipose tissue
1q22–23 RXRG Retinoid X receptor γ Nuclear receptor and transcription FCHL diagnostic: FCHL,9 TG9 Linkage data: 1q23 linked
factor; polymorphisms may regulate Other: HDL‑C9 to FCHL and TG7
LPL expression9 (A)
1q22–q23 USF1 Upstream transcription Transcription factor; regulates FCHL diagnostic: FCHL,12–14 Linkage data: 1q23 linked
factor 1 transcription of over 40 TG,13,14,107 TC,108 apoB108 to FCHL and TG7
cardiometabolic disease-related Other: LDL‑C13
genes (EU, NA, SA)
Only positive findings are reported, but for several variants absence of an association was reported as well, for reasons that may include: a small number of FCHL and rare FCHL variant;
variants different in relevance between populations; differences in ascertainment of FCHL patients. *Some genes listed may have additional, yet to be identified, functions and might also be
involved in other (metabolic) processes in FCHL. ‡References included refer to genes associated with the FCHL diagnosis and/or FCHL diagnostic traits (TC, TG, apoB) in patients with FCHL.
Individual references may refer to different mutations or gene variants. §GWAS (general or mixed populations) focused on plasma lipids, lipoproteins and cardiovascular disease. Linkage as
reported in FCHL-based studies for: FCHL, TG, TC, HDL‑C, apoB. ||Note that part of the LPL mutations were detected in FCHL families selected for low LPL activity. 45 Abbreviations: A, Asia
(China, China (Hong-Kong) and/or Japan); apo, apolipoprotein; EU, Europe (Finland, France, Hungary, Italy, Spain, The Netherlands and/or UK); FCHL, familial combined hyperlipidaemia; GWAS,
genome-wide association study; HDL‑C, HDL cholesterol; HL, hepatic triacylglycerol lipase; LDL‑C, LDL cholesterol; LPL, lipoprotein lipase; NA, North America (Canada and/or USA); NR, not
reported; SA, South America (Mexico); TC, total cholesterol; TG, triglycerides.

pedigrees (8%). 86 Our group has shown that plasma
PCSK9 levels are heritable and related to the FCHL
pheno­t ype (Table 4). 87 Future research will unveil
whether plasma PCSK9 levels can be used as a trait to
gain more insight into the genetic factors acting upstream
to regulate LDLR expression in patients with FCHL,
such as sterol regulatory element binding protein 2
(SREBP‑2) (Figure 1). Of note, it has been demonstrated
that SREBP‑2 activity is suppressed by cAMP-dependent
transcription factor ATF‑6α (ATF6), a sensor of endo­
plasmic reticulum stress.88 Variants in ATF6 have been
associated with FCHL-related lipid traits.11

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Table 4 | Genes with suggested roles in clearance of LDL particles in FCHL

Locus Gene Gene name Protein function* Associated traits‡ Corroborating evidence§
(origin of populations)
1q22–q23 ATF6 Activating transcription Sensor of ER stress response FCHL diagnostic: TC11 Linkage data: 1q23 linked to
factor 6 Suppresses SREBP‑2-regulated transcription88 (EU) FCHL and TG7
19p13 LDLR LDL receptor Binds LDL, the major cholesterol-carrying FCHL diagnostic: FCHL81 GWAS data18–20,79,114,129
lipoprotein of plasma, and transports it into cells (EU) 19p13 showed suggestive
by endocytosis; expressed mainly on hepatocytes linkage to FCHL130
1p32 PCSK9 Proprotein convertase Role in cholesterol homeostasis; potential role in FCHL diagnostic: FCHL86 GWAS data19,20,79,114,129
subtilisin/kexin type 9 the differentiation of cortical neurons (EU) Linkage data: 1p31 linked
to apoB101,102
Only positive findings are reported, but for several variants absence of an association was reported as well, for reasons that may include: a small number of patients with FCHL and rare FCHL
variant; variants different in relevance between populations; differences in ascertainment of FCHL patients. *Some genes listed may have additional, yet to be identified, functions and might
also be involved in other (metabolic) processes in FCHL. ‡References refer to genes associated with the FCHL diagnosis and/or FCHL diagnostic traits (TC, TG, apoB) in patients with FCHL.
Individual references may refer to different mutations or gene variants. §GWAS (general or mixed populations) focused on plasma lipids, lipoproteins and cardiovascular disease. Linkage in
FCHL-based studies for: FCHL, TG, TC, HDL‑C, apoB. Linkage results before 2005 have been reported elsewhere. 7 Abbreviations: apo, apolipoprotein; EU, Europe (Finland, France, Hungary, Italy,
Spain, The Netherlands and/or UK); ER, endoplasmic reticulum; FCHL, familial combined hyperlipidaemia; GWAS, genome-wide association study; SREBP‑2, sterol regulatory element-binding
protein 2; TC, total cholesterol; TG, triglycerides.

Other genes understanding of the exact metabolic derangements that

In addition to the genes presented in Tables 1–4, of which
some illustrative examples are discussed above, various
other genes have been implicated in FCHL. These genes
and their currently known functions are summarized
in Table 5. Their effects cannot yet be clearly attributed
to one of the main metabolic derangements known in
FCHL (Figure 1). Confirmation, or exclusion, of the
involvement of these genes in the FCHL phenotype will
further our understanding of the metabolic pathways
that underlie the FCHL phenotype.
Discussion
An increased knowledge of the pathways involved in lipid
metabolism and associated traits (Figure 1) and of the
genes involved in the development of FCHL (Tables 1–4)
are both essential to gain a comprehensive overview of the
complex biological and genetic pathogenesis of FCHL.
Several conclusions can be drawn from the list of genes
implicated in FCHL and its associated traits.
First, the genes most frequently reported to be asso­
ciated with FCHL are functionally related to plasma
lipid metabolism and clearance (Figure 1), such as LPL,
LIPC, APOA1/C3/A4/A5 and APOE (Table 3). This
finding might be explained by the fact that these genes
are considered to be ‘the usual suspects’ and, therefore,
have been studied most extensively. Furthermore, some
of the lipid traits that were used in these genetic studies,
such as LDL cholesterol, are mainly determined by their
clearance rate and only to a lesser extent by overproduc­
tion, making it probable that genes which are associated
with LDL cholesterol are indeed removal genes.89 Genes
that predispose individuals to VLDL overproduction,
on the other hand, are more likely to be discovered by
using traits that are known to be more closely linked to
this pathway. As a proof of this principle that requires
replication, our group has shown that significant linkage
peaks were discovered with the fatty liver trait that had
not been detected with the usual plasma lipid traits.31
Thus, adoption of new traits, aside from the classic
plasma lipid traits, could aid in the identification of new
genes in FCHL, whereas, vice versa, identification of
the functions of novel genes in FCHL may advance our
underlie this disease.
The emerging field of metabolomics (or lipi­domics),
which uses mass spectroscopy, nuclear magnetic reso­
nance or other platforms to search for new bio­markers
in plasma or tissue, could eventually provide more
tissue-specific and pathway-specific biomarkers that
can be applied as a trait in genetic studies, as previously
demon­strated.90,91 In addition, whole-genome expres­
sion arrays—potentially combined with pathway analysis
—might yield valuable traits that reflect (tissue-specific)
pathways involved in FCHL.92 These approaches may also
advance the integration of some of the genes reported in
Table 5 into the general picture of the FCHL phenotype.
Finally, lessons can be learnt from genetic studies con­
ducted in entities that are expected to share a common
metabolic background, such as nonalcoholic fatty liver
disease or T2DM.6 This knowledge has led to the identifi­
cation of HNF4A variants in relation to plasma lipid traits
in FCHL,93 a finding that has now also been corroborated
by GWAS (Table 5).19,20
Another inference that can be made from the list of
genes currently linked to FCHL is that many genes have
been discovered by the candidate-gene approach, driven
by the already known biology of these genes. A new
variant of this strategy is to confirm genes initially dis­
covered by GWAS in the FCHL population.21,94 Weissglas-
Volkov and colleagues reported that common variants in
or close to CETP, GCKR, GALNT, APOA1/C3/A4/A5 and
APOA5, which had previously been detected by GWAS in
the general population,18,19 were also associated with lipid
traits in patients with FCHL.21 Although such ‘replication’
strongly suggests that these genes also contribute to the
FCHL phenotype, they probably have only minor effects
on plasma lipids levels, unless a marked gene–gene or
gene–environment interaction occurs.
The GWAS strategy is suitable for the detection of
relatively frequent gene variants with often a small effect
size.95 By contrast, family studies are capable of finding
rare gene variants—due to clustering within a family
—with a more pronounced effect on the trait of interest.95
To date, however, only a handful of new genes have been
discovered by the linkage approach in FCHL, despite an

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Table 5 | FCHL-associated genes, the exact roles of which remain to be determined

Locus Gene Gene name Protein function* Associated traits‡ Corroborating evidence§
(origin of populations)
4p16 ADD1 Adducin 1 Ubiquitous cytoskeleton protein; FCHL diagnostic: FCHL132 Linkage data: 4p15 linked
may modulate various other cell Other: SBP132 to TG7
functions such as ion transport131 (EU)
12p13 APOBEC1 ApoB mRNA editing Involved in the processing of APOB FCHL diagnostic: apoB133 NR
enzyme, catalytic mRNA in the small intestine (SA)
polypeptide 1
1q21–23 CRABP2 Cellular retinoic Transcription factor; regulates FCHL diagnostic: FCHL10 Linkage data: 1q23 linked
acid-binding genes that control lipid metabolism (EU) to FCHL and TG;7
protein 2 via retinoid signalling pathway associated with
hypercholesterolaemia134
11q12–q13 FADS3 Fatty acid Regulates unsaturation of FCHL diagnostic: FCHL;135 TG135 GWAS data18–20
desaturase 3 fatty acids; potentially regulated (SA) Linkage data: 11q12
by USF1135 linked to FCHL7
16q24 FOXC2 Forkhead box C2 Transcription factor; role in FCHL diagnostic: TG10 Linkage data: 16q24
development of the lymphatic Other: HDL‑C10 linked to TC;14 16q23
and cardiovascular systems136 (EU) linked to HDL‑C7
11q13 GAL Galanin Neuropeptide;137 acts on pancreas, FCHL diagnostic: TG94 NR
prepropeptide heart and gut and affects (EU,SA)
consummatory behaviour113
20q13 HNF4A Hepatocyte nuclear Transcription factor; regulates FCHL diagnostic: TC;93 TG93 GWAS data19,20
factor 4α serum lipid and glucose levels; Other: glucose;93 SCD activity138 Linkage data: 20q12‑13
may act in the development of liver, (EU, SA) suggestive linkage to
kidney and intestines FCHL12,139
19p13 CERS4 Ceramide Either a bona fide ceramide FCHL diagnostic: NR GWAS data18–20,79,114,129
synthase 4 synthase or a modulator of its Other: phospholipid transfer activity140 19p13 showed suggestive
activity; regulated by leptin (NA) linkage to FCHL130
10q21 PCDH15 Protocadherin- Calcium-dependent cell-adhesion FCHL diagnostic: TG141 Associated with TG in
related 15 protein; expressed in liver and (EU) Finnish dyslipidaemic
pancreas;141 essential for retinal families142
and cochlear function
7q21 PON1 Paraoxonase 1 May mediate enzymatic protection FCHL diagnostic: FCHL143 NR
of LDLs against oxidative Other: in vitro HDL oxidation144
modification (EU)
10q25 TCF7L2 Transcription factor Key role in Wnt signalling; FCHL diagnostic: TG145 Associated with glucose
7‑like 2 (T-cell implicated in blood glucose (EU, SA) levels and T2DM146
specific, HMG-box) homeostasis
1p36 TNFRSF1B TNF receptor May play a part in ischaemia- FCHL diagnostic: FCHL149 NR
superfamily, induced neovascularization147 and Other: plasma TNFRSF1B149
member 1B as a co-stimulator for antigen-driven (EU)
T cell responses148
16q23–24 WWOX WW domain Has a role in apoptosis FCHL diagnostic: TG150 Linkage data: 16q23
containing Other: HDL‑C150 linked to HDL‑C7
oxidoreductase (EU)
16q21 rs1424032 Unknown Resides in a highly conserved FCHL diagnostic: apoB133 NR
noncoding region; predicted to (SA)
function as a regulatory element133
Only positive findings are reported, but for several variants absence of an association was also reported, for reasons that may include: a small number of FCHL and rare FCHL variant; variants
different in relevance between populations; differences in ascertainment of FCHL patients. *Some genes listed may have additional, yet to be identified, functions and might also be involved in
other (metabolic) processes in FCHL. ‡References included refer to genes associated with the FCHL diagnosis and/or FCHL diagnostic traits (TC, TG, apoB) in FCHL subjects. Individual
references may refer to different mutations or gene variants. §GWAS (general or mixed populations) focused on plasma lipids, lipoproteins and cardiovascular disease. Linkage as reported in
FCHL-based studies: FCHL, TG, TC, HDL‑C, apoB. Abbreviations: apo, apolipoprotein; EU, Europe (Finland, France, Hungary, Italy, Spain, The Netherlands and/or UK); FCHL, familial combined
hyperlipidaemia; GWAS, genome-wide association study; HDL‑C, HDL cholesterol; NA, North America (Canada and/or USA); NR, not reported; SA, South America (Mexico); SBP, systolic blood
pressure; SCD, acyl-CoA desaturase; TC, total cholesterol; TG, triglycerides.

abundance of reported chromosomal loci.7 Many signifi­ Conclusions

cant loci have not passed the first, necessary hurdle of the
laborious and expensive sequence of replication, fine-
mapping, DNA sequence analysis and finally functional
testing of the candidate gene.96 It has been argued that
an increase in sample size as well as larger pedigrees will
generate more significant linkage peaks and thus a higher
likelihood of replication.91,97
Both GWAS and linkage analyses are methods to detect
new gene variants with yet unknown function, each
with different properties regarding the allele frequency
detection and its (inverse) relation with effect size.95
Given that the FCHL gene pool is expected to consist of
a mix of very rare genes, which completely account for
the FCHL phenotype in a minority of pedigrees, such

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© 2012 Macmillan Publishers Limited. All rights reserved
 REVIEWS

as GPR77,30 combined with more common variants that Review criteria

contribute to the FCHL phenotype in the majority of
pedigrees, such as USF1,12 both genome-wide screening
strategies are suitable and in fact complementary to elu­
cidate the genetic background of FCHL. These strategies
are currently, however, not optimally equipped to detect
low-frequency gene variants with an intermediate effect,
nor have they been developed to study the role of copy
number variants in the development of complex traits.95
Progress can be made by employing next-­generation
sequencing, which enables more detailed assessment
of gene variation.98 In addition, systems genetic analy­
sis, which integrates genetic polymorphisms with data
obtained from new genomic and proteomic technolo­
gies, will reveal new genes and attribute function to
genetic variants.
A search for original articles published between 1973
and 1 November 2011 and focusing on the genetics of
familial combined hyperlipidaemia (FCHL) was performed
in PubMed. The search term used was “(familial combined
hyperlipidemia OR hyperlipidaemia) AND (genet* OR
linkage OR association)”. Abstracts (727 hits) were
reviewed and those papers that specifically concerned
the genetics of FCHL were selected. We also searched the
reference lists of identified articles for further papers. We
additionally selected papers that dealt with the hallmark
metabolic aspects of FCHL. All articles identified were
English-language, full-text papers. Information on gene
names, functions and chromosomal location (as presented
in the tables) was obtained from GeneCards (http://www.
genecards.org), ENSEMBL (http://www.ensembl.org) and
additional PubMed searches, where required.

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Author contributions
M. C. G. J. Brouwers, M. M. J. van Greevenbroek,
J. de Graaf and A. F. H. Stalenhoef researched the
data and contributed equally to writing the article. All
authors provided a substantial contribution to
discussions of the content and reviewed and/or
edited the manuscript before submission.