ARTICLE
Auteur(s) : Etgar Levy-Nissenbaum, Michal Bar-Natan,
Moshe Frydman, Elon
Pras
Danek Gartner Institute of Human Genetics, Sheba Medical Center,
Tel Hashomer, Israel; affiliated to The Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel
accepté le 13 Avril 2005
Male pattern baldness (MPB), also referred to as androgenic
alopecia, is the most common form of hair loss in humans, affecting
up to 80% of all males by the age of 80. MPB is androgen dependent
and is most likely a multifactorial disorder caused by interactions
between several genes and environmental factors. Nyholt et al. [1]
concluded from studies of dizygotic and monozigotic twins that
additive genetic and environmental factors, best explain individual
differences in MPB. Under a multiple threshold model they proposed
that 81% of the total variance in hair loss could be attributed to
genetics and the rest to environmental factors, though the latter
have been poorly defined [2]. To date only the androgen receptor
(AR) gene has been implicated in the pathogenesis of MPB. Ellis et
al. [3] found an association between polymorphism in this gene and
MPB, but this result has not been confirmed in other studies. In
this study, we compared the frequency of a StuI restriction site
located in the first exon of the AR gene in bald and non-bald males
and confirmed the results obtained by Ellis et al. [3].
Materials and methods
The Helsinki Committee at the Sheba Medical Center approved the
study, and participants gave informed consent. We recruited 41 men
who were completely bald before the age of 40 (Grade VII,
Hamilton-Norwood classification [4, 5]), and 39 non-bald men (Grade
I and II, Hamilton-Norwood classification) older than 50 years of
age. The AR gene StuI restriction site was analyzed as previously
described [3]. Statistical analysis was performed using the
Fisher’s exact test (GraphPad InStat V2.05a, Israel).
Results
The StuI restriction site in the AR gene was present in 39 of 41
bald males compared to only 26 of 38 of non-bald males (p <
0.0026) (table 1( Table 1 )). Since this
polymorphism is located on the X chromosome, males present either
with the 359 bp band or with the 310 and 49 bp bands. A
heterozygous state does not exist (( figure 1 )). Although there
is an overwhelming representation of the “cut” allele among the
bald, the majority of non-bald also exhibit this allele, a finding
consistent with multifactorial inheritance.
Table 1 Androgen Receptor StuI restriction site in bald
versus non-bald males
|
StuI restriction site
|
Bald
|
Non-Bald
|
|
Un-Cut
|
2
|
12
|
|
Cut
|
39
|
26
|
|
Total
|
41
|
38
|
Discussion
The search for genes involved in multifactorial disorders or traits
include two main strategies: systematic genome-wide screening in
phenotypic identical sibs, or association studies. The first
approach has been applied to diseases such as diabetes mellitus
[6], Crohn’s disease [7], systemic lupus erythematosus [8] and
rheumatoid arthritis [9] with variable success. In many of these
disorders the genes identified were unpredicted and revealed new
pathways involved in disease pathogenesis. This approach however,
necessitates a large cohort of sibs with an identical phenotype and
huge resources. Association studies are performed mainly on
candidate genes, selection of which is based on evidence from
biochemical, pharmacological or other non-genetic data. However,
for various reasons, association studies often yield false positive
results. Ioannidis et al. [10] estimate that only 16% of such
studies are eventually confirmed and therefore follow up studies
are needed.
The search for genes implicated in the pathogenesis of MPB has
concentrated mainly on those involved in the androgenic pathway.
The importance of this pathway in the pathogenesis of MPB is
strongly supported by the absence of baldness in castrated men
[11], by high levels of dihydrotestosterone and increased
expression of the androgen receptor in scalps of balding men [12].
Recently, Ellis et al. [3] reported the presence of a StuI
restriction site in the AR gene, in 98% of 54 young bald men and
92% of 392 older bald men, compared to only 76% of 107 non-bald men
(p = 0.0005 and 0.000004, respectively). This restriction site
(AGG/CCT) is located in the first exon of the gene, and is caused
by a single third base change, Adenine (A) to Guanine (G), that
does not cause an amino acid change. Another polymorphism in the
same gene, the combination of a short run of CAG and GGC triplet
repeats was also found more prevalent in bald males, although the
result was less significant (p = 0.03). Our result, obtained on a
cohort from a completely different ethnic background, are very
similar to those obtained by Ellis et al. [3] thus confirming the
association between the AR gene and MPB.
We do not know if the StuI polymorphism has a functional effect.
A third base change can occasionally influence the level of RNA
expression or it may alter mRNA splicing and result in a longer or
shorter protein [13]. Alternatively this mutation may be in linkage
disequilibrium with a yet unknown functional mutation in the
promoter, in one of the introns or in a regulatory element in the
3′ region. Functional studies involving the androgen receptor and a
search for additional polymorphism in the gene and in its
surroundings may help to resolve these issues.
A number of studies in the past have found striking similarities
in hair loss patterns between fathers and sons [14-16]. Obviously,
these similarities can not be explained by x-linked inheritance of
the AR gene, but in a multifactorial inheritance model it is
reasonable that other as yet unidentified genes located on other
chromosomes may be responsible for these similarities.
The complex inheritance of MPB highly suggests that additional
genes are involved in its pathogenesis. Studies on 3 genes
implicated in the androgenic pathway, 5α-reductase and
steroid-5α-reductase 1 and 2 failed to detect any significant
association. Other possible candidates include additional genes
implicated in androgen metabolism such as the aromatase gene,
growth factors required for the different stages of the anagen
(STAT3, WNT, NOTCH, and HOXC13), telogen, (FGF5, TGFβ1 and VDR),
and structural molecules of the hair follicle and surrounding
tissues [17].
Acknowledgments
This work was performed in partial fulfilment of the requirements
for Ph.D. degree of E. Levy-Nissenbaum, Department of Human
Genetics and Molecular Medicine, Sackler School of Medicine, Tel
Aviv University, Tel Aviv, Israel.
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