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Hecht [1] was the first who studied the role of heredity in acne. Neonatal, nodulocystic, and conglobate acne have proven genetic influences [2]. Postadolescent acne is related with a first-degree relative with the condition in 50 % of the cases. Chromosomal abnormalities, HLA phenotypes, and polymorphisms of various genes have been associated with acne. Data from family studies confirmed familial clustering [3-5]. High heritability estimates for acne in twins were reported [6, 7]. Higher correlations of sebum excretion and the proportion of branched fatty acids in the fraction of sebaceous wax esters were found in monozygotic vs. dizygotic twins [8, 9]. A large twin study demonstrated that 81 % of the variance of the disease was attributed to additive genetic effects, whereas the remaining 19 % was attributed to unique, unshared environmental factors [10]. Apolipoprotein A1 serum levels were significantly lower in acne twins [10]. A family history of acne is associated with earlier occurrence of the disease, increased number of retentional lesions, and therapeutic difficulties, especially a higher risk for a relapse after oral isotretinoin treatment [11]. Another twin study revealed that heritability of acne on the back was very high [12]. Remarkably, at age 14 years, facial acne in girls was less influenced by genetic factors than in boys and was significantly influenced by common environmental factors [12].
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109
C.C. Zouboulis et al. (eds.), Pathogenesis and Treatment of Acne and Rosacea,
DOI 10.1007/978-3-540-69375-8_14, © Springer-Verlag Berlin Heidelberg 2014
Abbreviations
ACTH Adrenocorticotropic hormone
AR Androgen receptor
DHEAS Dehydroepiandrosterone sulfate
DHT Dihydrotestosterone
FGF Fibroblast growth factor
FGFR Fibroblast growth factor receptor
FoxO Forkhead box class O transcription
factor
GH Growth hormone
GHR Growth hormone receptor
IGF Insulin-like growth factor-1
IGF1R Insulin-like growth factor-1 receptor
IL-1 Interleukin 1
IR Insulin receptor
B. C. Melnik
Department of Dermatology,
Environmental Medicine and Health Theory ,
University of Osnabrück ,
Sedanstrasse 115, 49090 Osnabrück , Germany
e-mail: melnik@t-online.de
1 4
Acne and Genetics
Bodo C. Melnik
Contents
14.1 Introduction ............................................. 110
14.2 Steroid 21-Hydroxylase Gene:
CYP21A2 .................................................. 111
14.3 Steroid 5α-Reductase Type 1 Gene:
SRD5A1 .................................................... 111
14.4 Polymorphisms of Androgen
Receptor Gene: AR ................................. 112
14.4.1 Effect of Isotretinoin on Skin Androgen
Receptor Activity ...................................... 114
14.5 Genes of the Somatotropic Axis:
GH1, GHR, IGF1, IGFBP3,
and IGF1R ............................................... 114
14.5.1 IGF-1, Key Regulator of Androgen
Receptor Signaling .................................... 114
14.5.2 Environmental Versus Genetic Impacts on
IGF-1 Serum Levels .................................. 115
14.5.3 IGF-1 Converges with FGFR2b-Signaling ... 115
14.5.4 IGF-1 Activates Androgen Receptor
Transcriptional Activity ............................ 115
14.5.5 IGF1 Polymorphism Determines IGF-1
Serum Levels ............................................ 115
14.5.6 IGF Binding Protein-3 Polymorphisms .... 115
14.6 Forkhead Box Transcription Factor
Class O1A Gene: FOXO1A .................... 116
14.7 Peroxisome Proliferator- Activated
Receptor Genes: PPARA, PPARB,
PPARG, PPARD ....................................... 117
14.8 Fibroblast Growth Factor
Receptor-2 Gene: FGFR2 ....................... 118
14.8.1 FGFR2 Mutations in Apert Syndrome
and Acneiform Nevus ............................... 118
14.9 Melanocortin Receptor Genes:
MC5R and MC1R .................................... 119
14.10 Matrix Metalloproteinase Genes:
MMP1, MMP2, MMP3, MMP9,
MMP13 ..................................................... 120
14.11 Tumor Necrosis Factor-α
Gene: TNF ............................................... 120
14.12 Interleukin-1α Gene: IL1A .................... 121
14.13 Toll-Like Receptor Genes:
TLR2 and TLR4 ....................................... 121
14.14 Conclusion and Future Perspectives ..... 121
References .............................................................. 122
110
LH Luteinizing hormone
LXR Liver X receptor
MAPK Mitogen-activated protein kinase
MC1R Melanocortin 1 receptor
MC5R Melanocortin 5 receptor
MMP Matrix metalloproteinase
PCOS Polycystic ovary syndrome
PI3K Phosphoinositide-3-kinase
PLC Phospholipase C
POMC Proopiomelanocortin
PPAR Peroxisome proliferator-activated
receptor
RAR Retinoic acid receptor
RXR Retinoid X receptor
SHH Sonic hedgehog
SNP Single nucleotide polymorphism
SREBP Sterol regulatory element binding
protein
5 αR-I 5 Alpha reductase type 1
TLR Toll-like receptor
TNF Tumor necrosis factor
14.1 Introduction
Hecht [ 1 ] was the fi rst who studied the role of
heredity in acne. Neonatal, nodulocystic, and
conglobate acne have proven genetic infl uences
[
2 ]. Postadolescent acne is related with a fi rst-
degree relative with the condition in 50 % of the
cases. Chromosomal abnormalities, HLA pheno-
types, and polymorphisms of various genes have
been associated with acne. Data from family
studies confi rmed familial clustering [ 35 ]. High
heritability estimates for acne in twins were
reported [ 6 , 7 ]. Higher correlations of sebum
excretion and the proportion of branched fatty
acids in the fraction of sebaceous wax esters were
found in monozygotic vs. dizygotic twins [ 8 , 9 ].
A large twin study demonstrated that 81 % of the
variance of the disease was attributed to additive
genetic effects, whereas the remaining 19 % was
attributed to unique, unshared environmental fac-
tors [ 10 ]. Apolipoprotein A1 serum levels were
Core Messages
The severity of acne, its extension,
regional variation, clinical course, and
responsiveness to treatment are infl u-
enced by genetic and environmental
factors.
Androgen receptor (AR) transcriptional
activity plays a pivotal role in acne
pathogenesis and is infl uenced by (1)
genetic variants of enzymes modify-
ing the quantity and affi nity of andro-
gens interacting with the AR complex,
(2) AR polymorphisms, and (3) AR
coregulators.
Genetic variants of enzymes involved in
androgen biosynthesis and metabolism
are potential candidate genes for acne
like CYP21A2 and SRD5A1 .
AR polymorphisms with shorter CAG
repeats (<20) increase AR activity and
have been correlated with acne.
Insulin-like growth factor-1 (IGF-1),
insulin, as well as fi broblast growth
factors (FGFs) modulate FoxO-
mediated transcriptional regulation of
cell proliferation, lipogenesis, infl am-
mation, and immunity explaining the
role of FGFR2 gain-of-function muta-
tions in acne associated with Apert syn-
drome and acneiform nevus.
The absence of acne in Laron syndrome
with congenital IGF-1 defi ciency points
to the important role of IGF-1 in the
pathogenesis of acne.
IGF-1/PI3K/Akt-mediated phosphory-
lation of the AR cosuppressor FoxO1
upregulates AR transcriptional activity.
Polymorphisms of MUC1 , CYP1A1 ,
IL1A and TNF have been associated
with acne, whereas studies of TLR2 and
TLR4 polymorphisms showed no corre-
lation with the disease.
Future studies should focus on genetic
variations of FOXO1A , which appears to
orchestrate a plethora of gene regulatory
events involved in acne pathogenesis.
B.C. Melnik
111
signifi cantly lower in acne twins [ 10 ]. A family
history of acne is associated with earlier occur-
rence of the disease, increased number of reten-
tional lesions, and therapeutic diffi culties,
especially a higher risk for a relapse after oral
isotretinoin treatment [ 11 ]. Another twin study
revealed that heritability of acne on the back was
very high [ 12 ]. Remarkably, at age 14 years,
facial acne in girls was less infl uenced by genetic
factors than in boys and was signifi cantly infl u-
enced by common environmental factors [ 12 ].
The lack of intensive research in the fi eld of
acne genetics is surprising considering its high
incidence, morbidity, and immense health service
costs. Polymorphism of CYP1A1 has been
reported in a subgroup of acne patients [ 13 ].
Cytochrome P-450 1A1 regulates the conversion
of endogeneous retinoids, which are important
sebaceous gland morphogens [ 13 , 14 ]. More
recently, androgen receptor gene ( AR ) polymor-
phisms with reduced numbers of CAG repeats
have been associated with increased risk for acne
[ 15 , 16 ]. The fi broblast growth factor receptor-2
(FGFR2)-gain-of-function mutations of Apert
syndrome and acneiform nevus of Munro helped
to elucidate the role of FGFR2-signaling in acne
pathogenesis [ 17 ]. A large number of tandem
repeats in the polymorphic epithelial MUC1 gene
has been associated with severe acne [ 18 ]. The
highly conserved cytoplasmic tail of MUC1
binds β-catenin and modifi es nuclear β-catenin
signaling, which is known to suppress sebaceous
gland development and function [
19 , 20 ]. MUC1
is overexpressed by most human carcinomas and
has been associated with increased phosphoinosi-
tol- 3 kinase (PI3K)/Akt signaling [ 21 ]. Increased
PI3K/Akt signaling with reduced nuclear levels
of FoxO transcription factors has recently been
proposed to play a major role in acne pathogene-
sis [ 22 ]. Gene polymorphisms of peroxisome
proliferator-activated receptors (PPARs), mela-
nocortin receptors (MCRs), matrix metallo-
proteinases (MMPs), and pro-infl ammatory
cytokines like interleukin-1α (IL-1α) and tumor
necrosis factor-α (TNFα) are further acne candi-
date genes, which may increase the disposition
for the disease, modify its clinical course and
responsiveness to treatment, infl uence the rate of
sebum secretion, infl ammation, and the degree of
scarring [ 23 , 24 ] (Table 14.1 ).
14.2 Steroid 21-Hydroxylase
Gene: CYP21A2
Dehydroepiandrosterone (DHEA) and DHEA
sulfate (DHEAS) are important inducers of
hyperandrogenism and acne. All mutations lead-
ing to enzymatic defects with increased adrenal
DHEA synthesis are candidate genes for the
development of acne. Four different cytochrome
P450 (CYP) enzymes are involved in the synthe-
sis of the steroid hormone cortisol in the adrenal
cortex: CYP11A1, CYP11B1, CYP17, and
CYP21A2. Depending on the enzyme affected,
synthesis of the other adrenal steroid hormones,
mineralocorticoids, and sex steroids are deranged
in different ways [ 25 ]. The vast majority of all
cases of congenital adrenal hyperplasia (CAH)
are due to steroid 21-hydroxylase defi ciency.
CYP21A2 is located on chromosome 6p21.3 and
mutations are associated with increased risk of
hyperandrogenism and acne [ 26 ] (for details,
refer to Chap. 31 ).
14.3 Steroid 5α-Reductase Type
1 Gene: SRD5A1
The type 1 5α-reductase (5αR-I) is encoded on
SRD5A1 located on the distal arm of chromo-
some 5p15 [
27 ]. Membrane-bound 5αR-I like
type 2 catalyzes the conversion of testosterone
into 5α-dihydro-testosterone (DHT), the most
potent naturally occurring androgen in the tissue
[ 28 ]. 5αR-I is primarily expressed in the skin and
has been identifi ed in sebaceous glands, epider-
mis, eccrine, and apocrine sweat glands, outer
root sheaths, dermal papilla and matrix of hair
follicles, as well as endothelial cells of small ves-
sels and the Schwann cells of cutaneous myelin-
ated nerves [ 2933 ], [ 3437 ], [ 3841 ]. The
activity of 5αR-I is concentrated in sebaceous
glands and is signifi cantly higher in sebaceous
glands from the face and scalp compared with
non-acne-prone areas [ 42 ]. Full thickness acne
14 Acne and Genetics
112
bearing skin produced from 2 to 20 times more
DHT than did normal skin [ 43 ].
Increased 5αR activity in the skin has been
observed in patients with hirsutism and acne [ 43
46 ]. Predominant expression of 5αR-I was found
in the skin of the pubic region in hirsute female
patients [
47 ]. Total 5αR activity was approxi-
mately four times higher in follicles of patients
with polycystic ovary syndrome (PCOS) than
in healthy women [ 48 ]. A signifi cant associa-
tion between a single nucleotide polymorphism
(SNP) in SRD5A1 affecting the DHT/T ratio has
been found in males with type 2 diabetes [ 49 ]. In
women with PCOS, haplotypes within SRD5A1
and SRD5A2 were associated with the risk of
PCOS, whereas haplotypes only in SRD5A1 were
associated with the degree of hirsutism pointing
to an important role of SRD5A1 haplotypes in
androgenic signaling within the pilosebaceous
follicle [ 50 ].
Addition of IGF-1 to cultures of skin scrotal
broblasts signifi cantly increased 5αR activity
in a dose-dependent manner [ 51 ], whereas
oral isotretinoin therapy reduced skin 5αR
activity [ 52 ]. Conversion of testosterone to DHT
increases AR activity and signaling. Thus, IGF-1
is an important amplifi er of peripheral androgen
metabolism in the skin [ 51 , 53 ] (Fig. 14.1 ).
14.4 Polymorphisms of Androgen
Receptor Gene: AR
The gene encoding androgen receptor ( AR ) is
located on the X-chromosome (Xq11-q12). AR
belongs to a class of nuclear receptors that recog-
nizes canonical androgen response elements..
AR is present in epidermal and follicular kerati-
nocytes, sebocytes, sweat gland cells, dermal
papilla cells, dermal fi broblasts, endothelial
cells, and genital melanocytes [ 54 , 55 ]. There are
three major mechanisms increasing AR tran-
scriptional activity (1) increased AR ligand bind-
ing by raised gonadal or adrenal androgen
Table 14.1 Observed gene variations associated with increased risk for acne
Candidate gene
(gene locus) Protein Mutation Functional abnormality
CYP21A2
6p21.3
Steroid 21-hydroxylase Various mutations leading to
defi ciency
Congenital adrenal hyperplasia
(CAH) with DHEA excess
HSD3B2
1p13.1
3 β-Hydroxysteroid
dehydrogenase II
Mutations leading to
defi ciency
Late-onset CAH, DHEA excess
CYP11B1
8q21
Steroid 11-β-hydroxylase Loss-of-function mutation Late-onset CAH, DHEA excess
CYP1A1
15q22-24
Cytochrome P450 Overexpression of m1-alleles Accelerated retinoid degradation,
modifi cation of sebocyte
differentiation?
SRD5A1
5p15
Steroid 5α-reductase type I Haplotypes with PCOS and
hirsutism
Increased conversion of testosterone
to DHT
AR
Xq11-q12
Androgen receptor CAG repeat polymorphisms
(<20)
GGN repeat polymorphisms
Increased androgen receptor
transcriptional activity
FGFR2
10q26
Fibroblast growth factor
receptor 2
Ser252Trp and Pro253Arg
mutations in Apert syndrome;
Ser252Trp mutation in
acneiform nevus
Gain-of-function mutations with
decreased FGFR2 degradation and
increased PI3K/Akt activation
IL1A
2q14
Interleukin-1α Interleukin 1A +4845(G > T)
polymorphism
Increased susceptibility for acne and
infl ammatory reactions
TNF
6p21.3
Tumor necrosis factor-α TNFα polymorphism Increased susceptibility for acne and
infl ammation
MUC1
1q21
Mucin 1 glycoprotein Large number of tandem
repeats
Association with severe acne,
modifi cation of β-catenin- and PI3K/
Akt/FoxO signaling?
B.C. Melnik
113
production as well as intracutaneous conversion
of less potent to highly potent androgens like
DHT, (2) elevated AR activity due to AR poly-
morphisms observed with shorter CAG and GGN
repeats, and (3) increased AR activation by mod-
ifi cations of AR coregulators like extrusion of
the AR cosuppressor FoxO1 from the AR tran-
scriptional complex [ 56 ] (Fig. 14.1 ). The major
AR domains include the N- and C-terminal acti-
vation domains, the ligand-binding domain
(LBD), and a polyglutamine tract [ 57 , 58 ]. AR is
mutant in androgen insensitivity syndromes like
Kennedy spinal and bulbar muscular atrophy
and Reifenstein syndrome . Androgen-insensitive
subjects cannot produce sebum and do not
develop acne [ 59 ].
Polymorphisms that confer enhanced AR
activity have been associated with androgen-
dependent skin disorders. Exon 1 of AR encodes
the N-terminal activation domain (NTD) and
contains a variable length CAG repeat polymor-
phism that encodes a polyglutamine tract. CAG
repeat numbers range between 8 and 35 and dem-
onstrate a stable inheritance [ 60 ]. Signifi cant
amount of variation in DHT-responsiveness is
related to CAG repeat [(CAG) n ] polymorphism
of AR [ 6163 ]. The number of (CAG) n is
inversely associated with the transcriptional
activity of testosterone target genes [ 64 , 65 ]. A
length beyond 37 repeats leads to Kennedy dis-
ease (androgen defi ciency syndrome) [ 66 ]. ARs
with shorter polyglutamine tracts have greater
ability to activate reporter genes with androgen
response elements [ 65 , 67 ]. Shorter CAG repeats
have been associated with hirsutism [ 68 ], prema-
ture pubarche [ 69 ], ovarian hyperandrogenism
[ 70 ], PCOS [ 7173 ], androgenetic alopecia [ 74 ],
hirsutism, and acne [ 75 ]. Sawaya and Shalita
found a range of CAG repeats of 22 ± 4 in normal
men and 21 ± 3 in healthy women. Men with acne
had 21 ± 3, and women with acne had 20 ± 3,
respectively [ 75 ]. Men with acne and androge-
netic alopecia had 18 ± 4, and women with hirsut-
ism had 16 ± 3 CAG repeats as well as women
P
NC
DBD
DHT T Androstendione DHEAS
Fox 01
Increased transcription of
AR-dependent target genes
Cutaneous androgen conversion
GH
IGF–1
5αR
IR IGF1R
PI3K
Akt
Insulin + IGF–1
NucleusCytoplasm
Hyperinsulinemia Insulin resistance
Western diet (dairy, glycemic load)
Puberty
GHR
IGF–1
Akt
AR
Test es
FoxO1=
AR co–suppressor
Pituitary
Liver
Ovary Adrenal
Insulin
P3
2
1
Fig. 14.1 Regulation of androgen receptor (AR) tran-
scriptional activity by (1) gonadal and adrenal androgens
as well as intracutaneously converted androgens binding
to the ligand-binding domain (LBD) of AR, (2) AR
genetic variants like CAG repeat length polymorphism,
(3) modifi cation of the N-terminal activation domain
(NTD) by AR coregulators like FoxO1. Increased IGF-1/
insulin signaling of puberty, insulinotropic Western diet,
as well as endocrine disorders with insulin resistance and
hyperinsulinemia stimulate adrenal and gonadal androgen
synthesis, 5α-reductase activity, and AR transcriptional
activity
14 Acne and Genetics
114
with at least two androgenetic disorders [ 75 ].
Two recent genetic studies confi rmed the rela-
tionship between shorter CAG and GGN repeats
in AR with acne in Chinese acne patients [ 15 , 16 ].
Moreover, prostate volume and growth in
testosterone- substituted hypogonadal men is
dependent on the CAG repeat polymorphism
[ 76 ]. Low numbers of AR CAG repeats are asso-
ciated with lower levels of high-density lipopro-
tein (HDL) cholesterol [ 77 ]. CAG repeat numbers
are positively associated with serum levels of
apolipoprotein A-I. Decreased apo-A-I serum
levels have been observed in acne twins [ 10 ]. AR
polymorphism with lower CAG repeats would
put these acne patients to an increased risk for
developing coronary heart disease and prostate
cancer. In fact, an epidemiologic association
between severe acne and prostate cancer has been
reported [ 78 ].
Shorter GGN repeats of AR have been pro-
posed to be the major determinant of common
early onset androgenetic alopecia [ 79 ]. A combi-
nation of shorter CAG and GGN repeats in AR
has been associated with increased acne risk in
North East China [ 15 ].
14.4.1 Effect of Isotretinoin on Skin
Androgen Receptor Activity
AR status was investigated in back skin of six
male acne patients before and after 3 months of
oral isotretinoin treatment. The treatment did not
modify the binding affi nity constant of the AR in
the skin (0.44 vs. 0.32 nmol/l), but induced a 2.6-
fold decrease in its binding capacity constant (62
vs. 24 fmol/mg cytosolic protein) [
80 ]. This
isotretinoin-induced effect on AR and the sup-
pression of 5αR activity in the skin of acne
patients treated with isotretinoin explain the
potent inhibitory effects of isotretinoin on the for-
mation of DHT and the amount of DHT bound to
AR. Isotretinoin-mediated reduction of serum
IGF-1 levels as well as isotretinoin-mediated
upregulation of nuclear FoxO1 levels may con-
tribute to the suppressive effects of isotretinoin on
AR transcriptional activity in the skin [ 81 , 82 ].
14.5 Genes of the Somatotropic
Axis: GH1 , GHR , IGF1 , IGFBP3 ,
and IGF1R
Increased levels of growth hormone (GH) during
puberty stimulate hepatic secretion of IGF-1
after binding to the hepatic GH-receptor (GHR).
IGF-1 is the main biological mediator of GH and
participates in the regulation of the cell cycle,
inhibiting the processes of apoptosis and stimu-
lating cell proliferation after binding und activa-
tion of IGF1R [ 83 , 84 ]. In the sebaceous gland,
IGF-1 protein expression is most intensive in
maturing sebocytes and suprabasal cells of the
sebaceous duct [ 85 ]. IGF1R protein expression
is uniform and intense in all regions of the gland
[ 85 ]. In sebaceous glands IGF-1 acts as a mor-
phogen and a mitogen [ 85 ]. Dermal cells pro-
duce IGF-1 as well, whereas epidermal basal
keratinocytes are IGF-1-negative, but express
IGF1R [ 85 , 86 ]. Both, serum androgens and
IGF-1 levels increase at puberty but the course of
acne follows IGF-1 levels more closely than it
does with regard to androgens [ 87 , 88 ]. Increased
IGF-1 levels in addition to androgens infl uence
acne in adult men and women. While IGF-1
appears to have a stronger effect on acne in
women, androgens may play a greater role in
acne for men [ 89 ]. In men, serum IGF-1 levels
showed a linear correlation with the rate of facial
sebum excretion [ 90 ].
14.5.1 IGF-1, Key Regulator of
Androgen Receptor Signaling
Many variables, such as age, sex, nutritional sta-
tus, and GH secretion affect serum IGF-1 levels.
IGF-1 stimulates adrenal, testicular, and ovarian
androgen synthesis and 5αR activity converting
less potent androgens to highly potent DHT.
These IGF-1 effects increase AR transcriptional
activity by upregulation of the quantity and affi n-
ity of androgen binding to AR [ 51 , 53 , 9196 ].
Moreover, IGF-1 increases AR transcriptional
activity by inhibiting FoxO1-mediated AR sup-
pression [ 17 , 53 , 97 , 98 ].
B.C. Melnik
115
14.5.2 Environmental Versus Genetic
Impacts on IGF-1 Serum
Levels
In westernized societies acne has evolved into
an epidemic skin disease of the adolescent
population, pointing to the overwhelming role
of environmental factors [ 99 ]. There is accu-
mulating evidence for the aggravation of acne
by Western diet [ 100 ]. Increased insulin/IGF-1
signaling mediated by consumption of hyper-
glycemic carbohydrates and insulinotropic milk
and dairy products has been associated with the
pathogenesis of acne and other diseases of civi-
lization [ 101105 ]. Milk and dairy protein con-
sumption raises serum IGF-1 levels and elevates
the somatotropic axis in children, adolescents,
and adults [ 106108 ]. Endocrine disorders like
PCOS and acromegaly as well as various acne-
associated syndromes featuring insulin resistance
are associated with increased insulin/IGF-1 sig-
naling [ 109114 ]. Individuals with genetic poly-
morphisms related to exaggerated insulin/IGF-1
signaling may thus be more susceptible to acnei-
genic effects of Western diet.
14.5.3 IGF-1 Converges with
FGFR2b-Signaling
The IGF-1 signaling pathway shares common
downstream signaling cascades with other tyro-
sine kinase receptors like fi broblast growth factor
receptors (FGFRs) (Fig.
14.2 ). FGFR2b-signal
transduction is primarily mediated by the MAPK/
ERK-, PI3K/Akt-, and phospholipase C-γ/pro-
tein kinase C pathway [ 115 , 116 ]. Insulin and
IGF-1 stimulate sebaceous gland lipogenesis
[ 88 ]. IGF-1 via PI3K/Akt induces expression of
SREBP-1, fatty acid synthase, and overall lipo-
genesis in SEB-1 sebocytes [ 117 ]. FGFR2b-,
IGF-1-, and insulin signal transduction pathways
converge downstream and increase PI3K/Akt
signaling [ 118 ] (Fig. 14.2 ). In this regard,
androgen- dependent FGFR2b signaling ampli-
es growth factor signaling of insulin and IGF-1.
Thus, highest levels of sebum production and
sebocyte differentiation are only reached when
androgens cooperate with other growth factors
like IGF-1, insulin, and FGFs [ 88 , 119121 ].
14.5.4 IGF-1 Activates Androgen
Receptor Transcriptional
Activity
IGF-1/insulin signaling activates androgen sig-
naling through inhibition of the AR-cosuppressor
FoxO1 [ 97 , 98 ]. FoxO1 reduces androgen-
induced AR target gene expression. In response
to IGF-1 or insulin, FoxO1 becomes phosphory-
lated and inactivated. The insulin/IGF-1-
mediated inactivation of FoxO1 explains the
increased peripheral androgen responsiveness of
insulin/IGF-1-stimulated pilosebaceous follicles.
14.5.5 IGF1 Polymorphism
Determines IGF-1 Serum
Levels
Despite its pivotal role in acne pathogenesis,
there is still no information on genetic variants of
IGF1 in acne patients. It has been estimated that
between 38 and 77 % of the individual variation
in IGF-1 serum levels is dependent on genetic
factors [ 122 , 123 ]. Circulating IGF-1 levels are
modifi ed by a cytosine–adenine (CA) repeat in
the proximity of the IGF1 promoter [ 124 , 125 ].
IGF1 polymorphisms resulting in elevated circu-
lating levels of IGF-1 may thus be important
genetic factors predisposing for the development
of acne.
14.5.6 IGF Binding Protein-3
Polymorphisms
More than 90 % of circulating IGFs are bound to
insulin-like growth factor-binding protein-3
(IGFBP-3) and less than 1 % of IGFs circulate in
free form [ 126 , 127 ]. Thus, IGFBP-3 modulates
IGF-1 signal transduction. Oral isotretinoin treat-
ment of acne patients has been shown to reduce
14 Acne and Genetics
116
serum levels of IGF-1 and IGFBP-3 [ 81 ]. In
human dermal papilla cells, all - trans -retinoic
acid induced a fi vefold increase of IGFBP-3,
which inhibited IGF activity important for main-
taining hair anagen growth [
128 ]. Remarkably, a
3.43-fold increased expression of IGFBP-3 dur-
ing isotretinoin treatment was exclusively
observed in sebocytes but not in whole skin
[
129 ]. IGFBP-3 is not only a binding protein but
also translocates into the nucleus and interferes
with retinoic acid receptor (RAR)/retinoid recep-
tor X (RXR) leading to changes of receptor trans-
activation [ 130 , 131 ]. Nuclear IGFBP-3 is a
potent inducer of apoptosis [ 131 ]. Intriguingly,
IGFBP-3 is a known FoxO target gene [
132 ].
Nuclear overexpression of IGFBP-3 might medi-
ate isotretinoin’s effect on sebocyte apoptosis.
Moreover, upregulated IGFBP-3 suppressed the
proliferation of transient amplifying keratino-
cytes and may thus contribute to isotretinoin’s
anti-comedogenic effect [ 133 , 134 ].
IGFBP3 is a potential candidate gene for acne
like other gene polymorphisms of the somato-
tropic axis resulting in increased signal transduc-
tion, especially GH1 , GHR , IGF1 , IGF1R , insulin
receptor substrate 1 ( IRS1 ), phosphoinositol
3-kinase regulatory subunits ( PIK3R1 , PIK3R2 ),
PI3K catalytic subunit ( PIK3CA ), as well as Akt
isoforms 1–3 ( AKT13 ), which fi nally control the
transcriptional activities and regulatory functions
of FoxO transcription factors.
14.6 Forkhead Box Transcription
Factor Class O1A Gene:
FOXO1A
FoxO1 is a nutrient- and growth factor-sensing
forkhead box class O transcription factor, which
has recently been suggested to play a key regula-
tory role in the pathogenesis of acne [ 22 ]. FOXO1A
is located on chromosome 13q14.1. FoxO1 protein
Milk and
insulinotropic
dairy products
High
glycemic load
Insulin resistance
with
hyperinsulinemia
PCOS
Acromegaly
TESTIS
OVARY
ADREN AL
FIBROBLAST
perifollicular
PI3K
Akt
IGF-1
IGF1R
FGF-7/10
FGFR2b
T
A
DHEA
Proliferation Lipogenesis Inflammation
GH
GH
DERMIS
KERATINOCYTE
SEBOCYTE
Insulin
IR
P
FoxO1
Puberty
Nucleus Cytoplasm
FoxO1
Fig. 14.2 Converging IGF-1 receptor-, insulin receptor-,
and FGFR2b signal transduction pathways in the patho-
genesis of acne. Increased IGF-1 secretion of puberty
stimulates adrenal and gonadal androgen synthesis.
Androgens induce FGF7 and FGF10 secretion of
perifollicular broblasts, which stimulate FGFR2b on
sebocytes and follicular keratinocytes. IGF1R, IR and
FGFR2b pathways activate the PI3K/Akt cascade result-
ing in nuclear extrusion of FoxO1
B.C. Melnik
117
has been detected in human sebaceous glands by
immunohistochemistry (Liakou A et al., personal
communication). FoxO1 controls major effectors
involved in acne pathogenesis like AR activity,
cell proliferation, apoptosis, lipogenesis, reactive
oxygen species homeostasis, infl ammation, innate
and acquired immunity [ 22 ]. Increased insulin/
IGF-1 signaling activates the PI3K/Akt cascade
resulting in nuclear extrusion of FoxO proteins
into the cytoplasm [ 135 ]. FoxO1 is an important
AR cosuppressor and mediates nutrient and
growth factor signals to the AR regulatory com-
plex [ 56 , 97 , 98 , 136 ]. FOXO1A mutants with
increased transcriptional activity have been asso-
ciated with longevity and reduced incidence of
age-related diseases [ 137 , 138 ]. Intriguingly,
untreated patients with Laron syndrome and con-
genital IGF-1 defi ciency due to loss of function
mutations of GHR do not develop acne and have a
low incidence of age-related diseases like diabetes
and cancer compared to their fi rst-degree relatives
with normal insulin/IGF-1 signaling [ 139141 ].
Cell culture studies with serum of Laron subjects
with low insulin/IGF-1- signaling exhibited higher
levels of nuclear FoxO1 compared to controls
with normal insulin/IGF-1 signaling [ 140 ]. Thus,
FOXO1A is a favorite candidate gene for acne as
FoxO1 orchestrates key regulatory molecular
players involved in the pathogenesis of acne like
AR, PPARγ, LXRα, cyclins D1 and D2, p21, p27,
catalase, superoxide dismutase, β-defensin-2, and
TLR4 among others [ 22 , 82 ]. Polymorphisms of
FOXO1A exhibiting impaired regulatory activity
might increase the risk for acne and other diseases
of civilization [
104 ].
14.7 Peroxisome Proliferator-
Activated Receptor Genes:
PPARA , PPARB , PPARG ,
PPARD
Androgens as single compounds are unable
to modify sebocyte differentiation, which is
stimulated by co-incubation with peroxisome
proliferator- activated receptor (PPAR) ligands
[ 142 , 143 ]. PPARs are members of the nuclear
hormone receptor subfamily of transcription
factors and form heterodimers with RXRs,
which regulate the transcription of various genes.
Three subtypes of PPARs, PPARα, PPARδ, and
PPARγ, are expressed in follicular keratinocytes
and sebocytes and are involved in the regulation
of lipogenesis and differentiation of keratino-
cytes and sebocytes [ 142153 ]. PPARs are mas-
ter regulators of lipid metabolism and cooperate
with liver X receptor (LXR) [ 154 ]. An impor-
tant role of LXRα in differentiation and infl am-
matory signaling in SZ95 sebocytes has been
reported [ 155 ]. Specifi c agonists of each PPAR
isoform stimulated sebocyte differentiation in
vitro [ 142 , 144 , 145 , 151 , 156 , 157 ]. Fatty acids
of n − 3 and n − 6 origin play an important role as
ligands and modulators of PPARs [ 158 ]. PPARδ
ligand linoleic acid is the most effective agonist
in stimulation of lipid formation in sebocytes
and epidermal cells [ 142 , 151 , 159 ]. RXR ago-
nists are known to enhance PPAR effects [ 147 ].
Testosterone metabolism to DHT and synthesis
of sebaceous lipids is regulated by PPAR-ligand
linoleic acid in human sebocytes [ 143 , 151 ].
In cultured sebaceous cells and human seba-
ceous glands PPARβ/δ are expressed in greatest
amounts, followed by PPARγ1 and PPARα [ 146 ,
147 ], whereas PPARα and PPARγ1 were found
to be the main PPARs in cultured sebocytes
[ 145 ]. Studies of mice chimeric for wild type and
PPARγ null genotypes provide the most direct
evidence that PPARγ is essential for sebaceous
gland development and function [ 159 , 160 ],
whereas PPARβ/δ play a more general role in the
regulation of lipid metabolism common to both
sebocytes and keratinocytes [
159 ]. Agonists of
PPARα, PPARδ, PPARα/δ, and PPARγ increased
sebaceous lipogenesis in SEB-1 sebocytes [ 161 ].
Patients treated with thiazolidinediones or fi brates
had signifi cant increases in sebum production
[ 161 ]. Increased release of substance - P upregu-
lated PPARγ protein expression and RNA ampli-
cation in cultured sebocytes [ 162 ]. Peroxidated
squalene induced upregulation of PPARα protein
and mRNA expression [ 163 ]. Endocannabinoids
enhanced lipid synthesis and apoptosis of human
sebocytes via cannabinoid receptor-2-mediated
signaling, which upregulated PPAR transcription
factors and some of their target genes [ 164 ].
14 Acne and Genetics
118
There is yet no information on the role of
genetic variants of PPAR and LXR genes with
regard to the pathophysiology of acne.
Remarkably, the Pro12Ala polymorphism of
PPARG is associated with increased insulin sen-
sitivity and lower hirsutism scores in PCOS [ 165 ,
166 ]. PPARG Pro12Ala appears not to be a potent
modifi er gene of PCOS [ 167 ]. However, a large
genome-wide association study of Finnish
patients identifi ed PPARG as one of ten critical
susceptibility genes for type 2 diabetes [ 168 ].
Recent studies on PPARα, PPARβ/δ, and PPARγ
variants confi rmed the importance of PPAR vari-
ants in lipid metabolism [ 169 ]. Screening of acne
patients for PPAR and LXR polymorphisms might
thus be a promising approach to elucidate the
genetic background of acne.
Remarkably, FoxO1 is a PPARγ-interacting
protein that antagonizes PPARγ activity [ 170
172 ]. FoxO1 is a cosuppressor of PPARγ and
inhibits PPARγ function as well as the expression
of PPARγ protein [ 135 ]. Moreover, it has been
shown in skeletal muscle that FoxO1 regulates
triglyceride content via interaction with the
RXRα/LXRα/SREBP-1c pathway [ 173 ].
14.8 Fibroblast Growth Factor
Receptor-2 Gene: FGFR2
Fibroblast growth factor (FGF) receptor-2
(FGFR2) encoded on chromosome 10q26
belongs to a family of four related but individu-
ally distinct androgen-dependent tyrosine kinase
receptors. FGFRs have a similar protein struc-
ture, with three immunoglobulin-like domains
(D1–D3) in the extracellular region, a single
membrane-spanning segment, and a cytoplas-
mic tyrosine kinase domain [
174 ]. FGFRs bind
in clusters to heparan sulfate proteoglycans,
enabling the ligands to cross-link the receptors.
Two splice variants of FGFR2 are designated
FGFR2b and FGFR2c [ 174 ]. The exclusively in
epithelial cells expressed FGFR2b binds FGF7
and FGF10, but not FGF2, FGF4, FGF6, and
others [ 175 ]. FGFR2b is expressed mainly in
the suprabasal spinous layer of epidermis and
plays a crucial role in controlling epithelial
proliferation and differentiation [ 176 ]. The mes-
enchymally expressed isoform FGFR2c binds
FGF2, FGF4, FGF6, FGF9, FGF17, and FGF18,
but not FGF7 and FGF10 [ 175 ]. The lineage-
specifi c expression of the FGFR2b and FGFR2c
isoforms enables interaction between epithelial
and mesenchymal layers during development
and tissue homeostasis in response to different
FGFs [ 174 ]. FGFR2b is expressed through-
out the epidermis, hair follicles, and sebaceous
glands. Deletion of FGFR2b leads to sebaceous
gland atrophy [ 177 ]. The seminal vesicle shape
(svs) mutation of FGFR2 in the mouse resulted
in branching morphogenesis defects in the
prostate and seminal vesicles [ 178 ]. FGFR2b
has been shown to be important for postnatal
skin development and hair follicle morphogen-
esis [ 179 ]. Mice expressing a membrane-bound,
dominant-negative FGFR2b, lacking tyrosine
kinase activity displayed epidermal atrophy,
hair follicle abnormalities, dermal hyperthicken-
ing with severely delayed reepithelialization of
excisional wounds [ 180 ]. Mice lacking FGFR2b
survived into adulthood but displayed striking
abnormalities in hair and sebaceous gland devel-
opment [ 177 ]. FGFR2b plays an important role
in sebaceous gland development and long-term
survival of sebocytes [ 177 ].
14.8.1 FGFR2 Mutations in Apert
Syndrome and Acneiform
Nevus
Apert syndrome (MIM 101200), an acro-
cephalosyndactyly syndrome, is often asso-
ciated with severe acne and results from
specifi c heterozygous missense mutations at
two adjacent residues of FGFR2, Ser252Trp or
Pro253Arg, in the linker region between D2-
and D3-immunoglobulin- like regions of the
FGFR2-ligand-binding domain [ 181 , 182 ]. The
mutations increase FGF-ligand- binding affi nity
and are gain-of-function mutations [ 181183 ].
Once activated, FGFRs signal downstream via
adapter proteins and cytosolic kinases and mod-
ify responsive target genes [ 174 ]. Intriguingly, a
threefold increased expression of interleukin-1α
B.C. Melnik
119
was observed in osteoblasts expressing
Ser252Trp-mutated FGFR2 [ 184 ]. Besides acti-
vating the MAPK cascade, activated FGFRs also
stimulate PLC-γ/PKC and PI3K/Akt-signaling
cascades [ 116 ]. Increased signaling of the
Ser252Trp- and Pro253Arg- FGFR2 mutations
in Apert syndrome results from maintained
stay of the activated receptor complex at the
cell membrane due to disturbed FGFR2 down-
regulation to the lysosomal compartment [ 185 ].
Increased FGFR2 signaling of mutated FGFR2
in Apert syndrome, increased androgen-stimu-
lated FGFR2-signaling, and IGF1R-signaling
of puberty may share common downstream
pathways involved in the pathogenesis of acne
[ 17 , 118 , 186 ] (Fig. 14.2 ). There is substantial
evidence that anti-acne agents attenuate FGFR2
signal transduction in acne [ 187 ].
Munro and Wilkie described an epidermal
mosaicism producing an acneiform nevus in a
14-year-old boy exhibiting a somatic Ser252Trp-
mutation of FGFR2 [ 188 ]. Sharply demarcated
linear acneiform lesions extending from the left
shoulder to the antecubital fossa with comedones
in virtually every follicle have been reported
[ 188 ]. Recently, the somatic heterozygous
Ser252Trp-FGFR2 mutation has been confi rmed
within the affected skin lesions of another male
patient exhibiting a unilateral acneiform nevus
[ 189 ]. Thus, the FGFR2 mutation in acneiform
nevus presenting a genetic mosaic is the same
gain-of-function mutation observed in the major-
ity of FGFR2 germline mutations in patients with
Apert syndrome frequently associated with
severe acne [
186 , 188 , 189 ].
14.9 Melanocortin Receptor
Genes: MC5R and MC1R
MC5R is mapped on chromosome 18p11.2 and is
highly expressed in multiple exocrine tissues,
including Harderian, preputial, lacrimal, and
sebaceous glands, and is required for production
and stress-regulated synthesis of porphyrins by
the Harderian gland and ACTH/MSH-regulated
protein secretion by the lacrimal gland. MC5R
regulates the function of multiple exocrine glands
by melanocortin peptides [ 190 , 191 ]. Stimulation
of the sonic hedgehog (SHH) pathway in
Smoothened-expressing transgenic mice resulted
in increased expression of the sebocyte markers
Scd3 and MC5R [ 192 ]. MC5R is an important
marker of human sebocyte differentiation [ 193 ].
In human sebocytes MC5R was only detectable
at the onset of differentiation and in fully differ-
entiated cells displaying prominent lipid granules
[ 194 ]. The functional link between MC5R and
sebogenesis has been shown in MC5R-defi cient
mice exhibiting downregulated sebaceous lipo-
genesis [ 195 ]. Centrally produced α-MSH plays
an important role in the regulation of sebaceous
lipids [ 196 , 197 ]. Ablation of the neurointermedi-
ate lobe of the pituitary, the source of circulating
α-MSH, decreased sebaceous lipid production. In
hypophysectomized and castrated rats the reduc-
tion of sebaceous lipids was fully restored by
concomitant administration of α-MSH and tes-
tosterone [ 197 ]. In a primary human sebocyte
culture system, α-MSH stimulated sebocyte dif-
ferentiation, sebaceous lipid production, and
expression of MC5R [ 194 , 198 ]. α-MSH signal-
ing via MC5R acts on a common pathway with
androgen-dependent expression of MC5R by
amplifi cation of the signaling cascade andro-
gen FGF7/FGF10 FGFR2b SHH Gli
MC5R. MC5R is a crucial target gene of SHH
signaling, which plays a role in postnatal func-
tion of sebaceous glands [ 199 , 200 ].. Remarkably,
retinoids, which inhibit sebocyte differentiation,
have been shown to reduce Gli transcriptional
activity in cultured keratinocytes [
201 ].
MC1R is mapped to chromosome 16q23.4.
MC1R is involved in the regulation of skin pig-
mentation, determination of hair color, skin sen-
sitivity to ultraviolet light, and is expressed on
95 % of melanomas [ 202205 ]. MC1R is also
expressed on human sebocytes in vitro and in situ
[ 206 ]. By modulation of interleukin-8 secretion,
α-MSH may act as a modulator of infl ammatory
responses in the pilosebaceous unit [ 206 ]. MC1R
expression has been studied in 33 patients with
acne and seven age-matched controls [ 207 ].
Sebocytes and keratinocytes of the ductus sebo-
glandularis of acne-involved and non-involved
skin showed very intense MC1R expression in
14 Acne and Genetics
120
contrast to less intense immunoreactivity in nor-
mal skin [ 207 ]. Multiple variants of the MC1R
gene have been reported but not yet in relation to
acne genetics [ 208211 ].
The neuroregulatory effects of the proopi-
omelanocortin system play an important role in
sebaceous gland homeostasis [ 198 ]. Remarkably,
FoxO1 suppresses the transcription of proopi-
omelanocortin (POMC) by antagonizing the
activity of signal transducer and activator of
transcription - 3 (STAT3) [ 212214 ]. α-MSH and
ACTH are the main POMC peptide cleavage
products important for sebocyte biology. FoxO1
not only suppresses the expression of POMC but
also of CPE encoding carboxypeptidase E that
processes POMC to α-MSH [ 214 ]. Thus, FoxO1-
regulated POMC gene expression and production
of POMC cleavage products ACTH and α-MSH
may have an important infl uence on downstream
MC5R and MC1R signaling to the sebaceous
gland. Indirect evidence from translational stud-
ies allowed the conclusion that oral isotretinoin
treatment increases nuclear levels of FoxO1 [ 82 ].
Isotretinoin-mediated upregulation of hippocam-
pal FoxO1 could thus inhibit POMC/α-MSH sig-
naling to the sebaceous gland. In fact, it has
recently been demonstrated that oral isotretinoin
treatment in acne patients reduced ACTH serum
levels [ 215 ]. Isotretinoin’s proposed effect on the
hypothalamic-pituitary axis via FoxO1-regulated
POMC expression sheds a new light on MC5R-
and MC1R-mediated signal transduction to the
sebaceous gland. In this regard, not only MC5R
and MC1R but also FOXO1A as an upstream reg-
ulator of MC5R- and MC1R ligand expression
and processing may be important interacting can-
didate genes involved in the pathogenesis of
acne.
14.10 Matrix Metalloproteinase
Genes: MMP1 , MMP2 , MMP3 ,
MMP9 , MMP13
Nuclear factor κB (NF-κB) and activator protein-
1 (AP-1) are activated in acne lesions with conse-
quent elevated expression of infl ammatory
cytokines like TNFα and matrix degrading
metalloproteinases (MMPs). These gene prod-
ucts have been shown to be molecular mediators
of infl ammation and collagen degradation in acne
lesions in vivo [ 216 ]. MMPs are also downstream
targets of the FGFR2b signaling pathway [ 217 ].
MMP-1 and MMP-3 are upregulated in skin
lesions of acne patients [ 218 ]. P . acnes stimu-
lated pro-MMP- 2 expression through TNFα in
human dermal fi broblasts [ 219 ]. Isotretinoin
decreased the expression of MMPs in HaCaT
keratinocytes (proMMP-2, proMMP-9, MMP-
13) and SZ95 sebocytes (proMMP-2, proMMP-9)
and reduced MMP-13 in sebum of acne patients
treated with isotretinoin [ 220 ]. MMPs are impor-
tant for dermal matrix remodeling and support
the expansion and growth of sebaceous glands
into the surrounding connective tissue.
Isotretinoin inhibits scarring in acne and affects
dermal tissue remodeling.
Recent evidence points to the important role
of FoxO proteins in the regulation of MMP
promoter activity [ 221224 ]. In UV-irradiated
dermal fi broblasts, reduced expression of FoxO1a
mRNA was associated with increased MMP-1
and MMP-2 mRNA levels [ 225 ]. Contrary, addi-
tion of a FoxO1a peptide to the culture medium
decreased MMP-1 and MMP-2 expression [ 225 ].
Isotretinoin-induced upregulation of nuclear
FoxO levels may thus suppress MMP promoter
activity as well as FGFR2-mediated MMP activ-
ity [ 82 , 187 ]. It is thus conceivable that genetic
variants of either individual MMP- or FoxO
genes may determine the functional activity of
MMPs intensifying infl ammatory perifollicular
reactions with dermal tissue destruction, abscess
formation, and scarring as observed in conglo-
bate acne.
14.11 Tumor Necrosis Factor-α
Gene: TNF
Pro-infl ammatory cytokines play an important
role in acne pathogenesis [ 216 ]. TNFα is a cen-
tral molecule coded by a gene that shows high
level of genetic polymorphisms especially in its
promoter region. TNF is mapped to chromosome
6p21.3. SNPs of TNF are associated with an
B.C. Melnik
121
increased risk to develop chronic infl ammatory
diseases. Two SNPs in the regulatory region of
TNF have recently been detected. The TNFα-857
minor T allele was found to act as a protective
factor in a Hungarian study population of acne,
whereas a higher occurrence of the minor-308 A
allele was noted in female acne patients [ 24 ].
Intriguingly, dendritic cells from Foxo3-defi cient
mice exhibited enhanced production of TNFα
and interleukin-6 (IL-6) implying a master role
for FoxO3 in regulating pro-infl ammatory cyto-
kine production [ 226 ]. Genetic variants of the
TNFα gene as well as further upstream regulators
of TNFα gene expression like FoxO3a may thus
affect the risk of acne vulgaris and the infl amma-
tory hyper-reactivity of the pilosebaceous unit.
14.12 Interleukin-1α Gene: IL1A
ILIA mapped to chromosome 2q14 encodes
interleukin-1α. IL-1α and IL-1β proteins are syn-
thesized by a variety of cell types, including
sebaceous glands, activated macrophages, kerati-
nocytes, stimulated B-lymphocytes, and fi bro-
blasts, and are potent mediators of infl ammation
and immunity. Recently, a positive association
was found between the minor T allele of the IL1A
+4845(G > T) SNP and acne, whereas no associa-
tion was found with respect to any alleles of the
variable number of tandem repeats (VNTR)
polymorphism of the IL1RN gene. The severity
of infl ammatory acne symptoms correlated with
the percentage of individuals carrying the homo-
zygote T/T genotype [
23 ].
14.13 Toll-Like Receptor Genes:
TLR2 and TLR4
Microbial ligands, including lipopolysaccharide
(LPS) and bacterial lipoproteins, activate mam-
malian toll-like receptors (TLRs) and facilitate
the transcription of genes that regulate the adap-
tive immune responses and induction of antimi-
crobial activity [ 227 ]. TLR2 is encoded on
chromosome 4q32 and TLR4 on 9q32-33, respec-
tively. TLR2- and TLR4 expression was increased
in the epidermis of acne lesions in vivo [ 228 ].
TLR2 is expressed on the cell surface of macro-
phages surrounding pilosebaceous follicles. P .
acnes stimulated cytokine production of mono-
cytes through a TLR2-dependent pathway [ 229 ].
Moreover, distinct strains of P . acnes induced
selective human β-defensin-2 and IL-8 expres-
sion in human keratinocytes through TLRs [ 230 ].
These observations point to an important contri-
bution of TLRs in the induction of innate immu-
nity and TLR-mediated infl ammatory cytokine
responses in acne [ 231 ]. Two mutations of TLR2
causing amino acid changes Arg677Trp and
Arg753Gln, as well as two polymorphisms of
TLR4 causing the amino acid changes Asp299Gly
and Thr399Ile studied in 63 Caucasian acne
patients and 38 healthy controls were not associ-
ated with acne [ 232 ]. Thus, TLR gene expression
in acne may be upregulated as a result of other
upstream regulatory events. In this regard it
should be noticed that IL-1α-mediated activation
of IL1R results in the activation of IL-1 receptor-
associated kinases (IRAKs), which are critically
involved in the IL1R/TLR-mediated signal trans-
duction processes that regulate cellular innate
and adaptive immune responses [ 233 ]. The great
structural homology of IL1R and TLR and their
molecular cross talk via IRAKs might be a rea-
sonable explanation for IL-1α-induced upregula-
tion of TLR-mediated immune responses in acne.
Remarkably, all - trans -retinoic acid downregu-
lated TLR2 expression and function [ 234 ].
14.14 Conclusion and Future
Perspectives
The fact, that AR-insensitive individuals do not
produce sebum and do not develop acne [ 59 ],
points to a genetically determined hierarchy of
AR signaling in the pathogenesis of acne. The
AR is a most sophisticated transcription factor
complex and convergence point integrating a
diversity of upstream signals and functions [ 56 ].
Upregulated GH/IGF-1 signaling of puberty
raises AR transcriptional activity by Akt-
mediated removal of the AR cosuppressor
FoxO1 from the N-terminal AR activation
14 Acne and Genetics
122
domain [ 97 , 98 ]. Genetic AR variants, AR
upstream coregulators, and downstream effec-
tors are most likely candidate gene-promoting
acne. These are gene polymorphisms of enzymes
involved in either (1) increased androgen synthe-
sis of adrenal or gonadal origin, (2) genes
involved in raised formation or conversion of
cutaneous androgens increasing the affi nity of
androgens for AR binding and activation, like
SRD5A1 , (3) mutations of the AR itself leading
to increased transcriptional activity like AR poly-
morphisms with reduced numbers of CAG
repeats, (4) genetic variants of AR coregulators
like FoxO1, and (5) mutations of downstream
AR target genes [ 235 ] (Table 14.1 ).
Any genetic variation of components of the
GH/GHR/IGF-1/IGF1R/IRS-1/PI3K/Akt/FoxO1
cascade may signifi cantly contribute to acne
pathogenesis. The pivotal role of IGF-1 becomes
apparent from observations of untreated patients
with Laron syndrome with congenital IGF-1 defi -
ciency who do not develop acne despite the pres-
ence of normal ARs [ 139 ]. However, when
female subjects with Laron syndrome are substi-
tuted with higher IGF-1-doses, acne and hirsut-
ism developed [ 236 ]. Genetic variants with
increased activity of FoxO1 and FoxO3 have
recently been linked to longevity and lower inci-
dence of age-related diseases [ 137 , 138 ]. Potential
FOXO1A and FOXO3A SNPs with reduced func-
tional capacity may be favorite acne candidate
genes, as these regulatory proteins and transcrip-
tion factors orchestrate the activity of AR, cyclin
D1 and D2, p21, p27, PPARγ, LXRα, SREBP-1,
catalase, superoxide dismutase, β-defensin 2,
TNFα, TLR4, and MMPs, thus interacting with a
high number of important molecular players
involved in acne pathogenesis [
22 , 82 ].
Recent evidence corroborated the important
role of Wnt signaling for sebocyte differentiation
and sebaceous gland morphogenesis [ 20 , 237 ,
238 ]. Intriguingly, in mammalian cells β-catenin
interacts with FoxO1 and FoxO3 [ 239 ]. Binding
of β-catenin to FoxO enhances the transcriptional
activity of FoxO [ 239 ]. Interestingly, high Wnt
signaling with elevated levels of β-catenin is
known to inhibit sebaceous gland morphogenesis
and sebocyte differentiation. High nuclear levels
of β-catenin bind to FoxO3 and FoxO1 and aug-
ment their transcriptional proapoptotic effects
[ 240 ]. FoxOs and Tcf factors compete for the
limited nuclear pool of β-catenin [ 241 , 242 ]. In
this regard, MUC1 polymorphisms associated
with severe acne may modify the nuclear pool of
available β-catenin, a mechanism which may
infl uence the development of acne. Future studies
in acne genetics should thus focus on the regula-
tory components of the AR transcriptional com-
plex and gene regulatory interactions between
FoxO1/AR, FoxO1/PPARγ, FoxO/β-catenin, and
MUC1/β-catenin to understand genetic mecha-
nisms of hereditary factors predisposing for acne
and their relation to other endocrine and environ-
mental factors with increased insulin/IGF-1-
signaling like Western diet [ 104 ] .
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Multidisciplinary investigations into the pathogenesis of acne have significantly progressed over the past three years. Studies of the etiology of acne from the perspectives, for example, of sebaceous gland biology, sebum, genetics, keratinization, differentiation, hair cycles, immunology, bacteriology, and wound healing have elucidated its pathogenesis. This has led to the development of new therapies and paved the way for advanced studies that will enable the further evolution of acne treatment.
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Background: Peroxisomes are small cellular organelles that were almost ignored for years because they were believed to play only a minor role in cellular functions. However, it is now known that peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. In addition, peroxisomes have broad effects on the metabolism of lipids, hormones, and xenobiotics. Through their effects on lipid metabolism, peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity, and peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress. Objective: To review genetically determined peroxisomal disorders, especially those that particularly affect the skin, and some recent information on the specific genetic defects that lead to some of these disorders. In addition, we present some of the emerging knowledge of peroxisomal proliferator activator receptors (PPARs) and how ligands for these receptors modulate different peroxisomal functions. We also present information on how the discovery of PPARs, and the broad and diverse group of ligands that activate these members of the superfamily of nuclear binding transcription factors, has led to development of new drugs that modulate the function of peroxisomes. Conclusion: PPAR expression and ligand modulation within the skin have shown potential uses for these ligands in a number of inflammatory cutaneous disorders, including acne vulgaris, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, and poor wound healing associated with altered signal transduction, as well as for side effects induced by the metabolic dysregulation of other drugs.
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Background: Peroxisomes are small cellular organelles that were almost ignored for years because they were believed to play only a minor role in cellular functions. However, it is now known that peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. In addition, peroxisomes have broad effects on the metabolism of lipids, hormones, and xenobiotics. Through their effects on lipid metabolism, peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity, and peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress. Objective: To review genetically determined peroxisomal disorders, especially those that particularly affect the skin, and some recent information on the specific genetic defects that lead to some of these disorders. In addition, we present some of the emerging knowledge of peroxisomal proliferator activator receptors (PPARs) and how ligands for these receptors modulate different peroxisomal functions. We also present information on how the discovery of PPARs, and the broad and diverse group of ligands that activate these members of the superfamily of nuclear binding transcription factors, has led to development of new drugs that modulate the function of peroxisomes. Conclusion: PPAR expression and ligand modulation within the skin have shown potential uses for these ligands in a number of inflammatory cutaneous disorders, including acne vulgaris, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, and poor wound healing associated with altered signal transduction, as well as for side effects induced by the metabolic dysregulation of other drugs.
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An oral daily dose (mean +/- SD, 0.75 +/- 0.05 mg/kg) of isotretinoin was administered for 3 months to six male patients with acne (scores of 4 and 5 according to Rosenfield). The therapy resulted in complete resolution of acne in four patients and improved acne significantly (score 1) in two patients. In accordance with recent findings, no change in serum testosterone and significant decreases in 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol glucosiduronate, and androsterone glucosiduronate levels were observed after treatment. Androgen receptor status was investigated in back skin biopsies obtained in acne areas before and after 3 months of isotretinoin treatment. The treatment did not modify the binding affinity constant of skin androgen receptor (0.44 vs. 0.32 nmol/L), but it did induce a 2.6-fold decrease in its binding capacity constant (62 vs. 24 fmol/mg cytosolic protein), as assessed by Scatchard plot and confirmed immunologically by Western blot analysis. These data clearl...