`Behind blue eyes`†: the association between eye colour and deep

Human Reproduction, Vol.29, No.10 pp. 2171– 2175, 2014
Advanced Access publication on July 8, 2014 doi:10.1093/humrep/deu169
ORIGINAL ARTICLE Gynaecology
‘Behind blue eyes’†: the association
between eye colour and deep infiltrating
endometriosis
Paolo Vercellini1,*, Laura Buggio 1, Edgardo Somigliana2, Dhouha Dridi 1,
Maria Antonietta Marchese 1, and Paola Viganò 3
1
Istituto Ostetrico e Ginecologico ‘Luigi Mangiagalli’, Department of Clinical Science and Community Health, Università degli Studi, Milano, Italy
Infertility Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano, Italy 3Obstetrics and Gynecology Unit, San Raffaele
Scientific Institute, Milano, Italy
2
*Correspondence address. Istituto Ostetrico e Ginecologico ‘Luigi Mangiagalli’, Department of Clinical Science and Community Health,
Università degli Studi, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda, 12 – 20122 Milano, Italy.
Tel: +39-02-55032917; Fax: +39-02-55030252; E-mail: [email protected]
Submitted on February 16, 2014; resubmitted on May 26, 2014; accepted on June 9, 2014
study question: Is the prevalence of blue eye colour higher in women with deep endometriosis?
summary answer: Blue eye colour is more common in women with deep endometriosis when compared with both women with ovarian
endometriomas and women without a history of endometriosis.
what is known already: Recent and intriguing evidence suggests that women with deep endometriosis may have particular phenotypic characteristics including a higher prevalence of a light-colour iris. Available epidemiological evidence is however weak.
study design, size, duration: Case –control study performed in a large academic department specializing in the study and treatment of endometriosis. Individual iris colour was evaluated in daylight and categorized in three grades, namely blue-grey (blue), hazel-green
(green) and brown. One observer assessed iris colour. In addition, the women themselves were invited to indicate the colour of their eyes according to the same classification system. Cases with discordant eye colour determinations between the observer and the woman were excluded from
the final analysis.
participants (materials, settings, methods): Two hundred and twenty-three women with deep endometriosis (cases),
247 with ovarian endometriomas and 301 without a history of endometriosis were enrolled.
main results and the role of chance: After exclusion of 52 discordant cases, the proportions of brown, blue and green eye
colours were, respectively, 61, 30 and 9% in the deep endometriosis group, 74, 16 and 10% in the endometrioma group and 75, 15 and 10% in the
non-endometriosis group. Women in the deep endometriosis group had a statistically significant excess of blue eyes and a reduced proportion of
brown eyes compared with the two control groups (P ¼ 0.002 and P , 0.001, respectively). The proportion of blue eyes was almost identical in
the ovarian endometrioma group and the non-endometriosis group, and that of green eyes was substantially similar in all study groups. The OR
(95% CI) of having blue eyes in women with deep endometriosis compared with women with ovarian endometriosis and with those without endometriosis was, respectively, 2.2 (1.4–3.6) and 2.5 (1.6 –3.9).
limitations, reason for caution: We cannot exclude that some women without a previous diagnosis of endometriosis indeed
had the disease. However, this would have led to a reduction of the observed difference in proportion of blue eyes, thus to a potential underestimation of the real strength of the association. Moreover, under-ascertainment is possible with regard to peritoneal disease, but unlikely with deep
endometriotic lesions and ovarian endometriomas.
wider implications of the findings: There are two possible explanations for our findings. Both may have intriguing implications
for future research on endometriosis. Firstly, genes involved in the control of iris colour transmission may lie in a region with a strong pattern of
linkage disequilibrium with genes involved in the invasiveness of endometriosis. Alternatively, blue eye colour could be considered an indicator of a
photo-sensitive phenotype resulting in limited exposure to sunlight and UVB radiation. Limited sunlight exposure is associated with reduced circulating 25-hydroxyvitamin D3, an element that has recently been linked to endometriosis development.
†
Pete Townshend. The Who, Decca, UK, 1971.
& The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: [email protected]
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Vercellini et al.
study funding/competing interests: No research funding was received and none of the authors have any conflict of interests.
trial registration number: Not applicable.
Key words: ovarian endometrioma / deep endometriosis / eye colour / endometriosis / vitamin D
Introduction
Endometriosis, a chronic inflammatory condition associated with pelvic
pain and infertility, affects 5% of the female population of reproductive
age (Vercellini et al., 2014). Some investigators observed a relation
between distinct phenotypic characteristics and endometriosis, predominantly in women with deep infiltrating lesions (Lafay Pillet et al.,
2012).
Women with endometriosis show particular pigmentary traits, including a higher number of naevi and freckles, have a specific photo-sensitive
phenotype, self-limit ultraviolet exposure, and protect themselves more
from the sun (Kvaskoff et al., 2009, 2013; Somigliana et al., 2010; Viganò
et al., 2012). We previously observed an association between light eye
colour (green/blue) and endometriosis (Somigliana et al., 2010).
However, due to the small sample size, we were unable to analyse
data separately for blue and green eye colour, and to discriminate
between the various disease forms.
Blue eyes appear to be linked to different disorders, such as type 1 diabetes (Di Stasio et al., 2011), cutaneous and iris melanoma (Regan et al.,
1999; Olsen et al., 2010), deafness after meningitis (Cullington, 2001),
and non-Hodgkin lymphoma (Hughes et al., 2004). Considering that peculiar phenotypic characteristics seem to be expressed mainly by women
with deep endometriosis instead of all women with endometriosis in
general (Lafay Pillet et al., 2012; Viganò et al., 2012) we decided to investigate the prevalence of blue eye colour in a case –control study. Cases
were women with deep endometriosis, controls were those with
ovarian endometriotic cysts and those without a history of endometriosis. The study hypothesis was that the frequency of blue eyes was
higher in the former group than in latter two groups.
Materials and Methods
This case – control study was performed in an academic department specializing in the study of endometriosis. The objective was determination of the
prevalence of blue eye colour in women with different endometriosis
forms and in those without a history of endometriosis. Patients with endometriosis evaluated for chronic pain, infertility or pelvic masses were consecutively recruited from January to December 2013. Women were
categorized in two groups, namely deep endometriosis (cases) and ovarian
endometrioma (control group). The former included women with rectovaginal plaques, bladder detrusor nodules, bowel lesions, intrinsic ureteral
endometriosis, and deep endometriosis infiltrating the pouch of Douglas
and parametria. Cases with iatrogenic, post-Caesarean bladder detrusor
endometriosis were excluded. Both women with a past or current diagnosis
of endometriosis could be enrolled.
The diagnosis of endometriosis was based on standard histologic criteria
and, in case of rectovaginal forms, on vaginal and rectal examination, presence of visible endometriotic lesions at speculum inspection, and transvaginal
and transrectal ultrasonography. When deep and ovarian lesions co-existed,
the woman was included in the case group, as the former lesions are considered more severe than the latter ones (Chapron et al., 2006). Women with
exclusively superficial peritoneal implants were excluded because this condition does not constitute per se definite endometriotic disease (Holt and
Weiss, 2000). In case of affected sisters, only the first evaluated sibling was
recruited, in order to avoid spurious over-representation of a specific eye
colour. In the same time span, asymptomatic women attending our outpatient clinics for periodical gynaecological care, contraception, or cervical
cancer screening programme, and without a previous clinical or surgical diagnosis of endometriosis, were enrolled in a second control group. NonCaucasian women were excluded. Cases and controls were genetically
homogeneous as they were all of Italian origin and ancestry.
Individual iris colour was evaluated in daylight and categorized in three
grades, namely blue, green, and brown, according to a recent, simple and validated classification, easy to use in clinical research (Muinos Diaz et al., 2009).
One observer, who was not blind to the aim of the study and the women’s
condition, assessed iris colour. In addition, the women themselves were
invited to indicate their eye colour according to the same classification. Subjects with discordant eye colour determination between the observer and
the woman were excluded from the final analysis. Data were collected on
standardized forms including demographic information and clinical characteristics. The local Institutional Review Board approved the study (approval no.
1587/12). All patients provided written consent before enrolment.
The prevalence of blue eyes in the general population of central Italy is
10% (Di Stasio et al., 2011). Based on this expected rate of blue eyes
among controls, considering as biologically important at least a 2-fold increase (corresponding to a OR of 2.2) in the rate of blue eyes among
women with deep endometriosis, and setting type I and II errors at, respectively, 0.05 and 0.20, 200 women had to be recruited in each study group.
We planned for a recruitment of at least 220 subjects per group to allow for
subsequent exclusion of discordant cases, expecting a maximum of 10% disagreement rate. Recruitment continued until completion of the pre-planned
sample size in the least numerous group.
A binomial distribution model was used to calculate the standard deviation
(SD) of proportions. In order to assess the extent of agreement between external and self-evaluation of eye colour, the unweighted k-index was calculated. We considered a value .0.60 as ‘good agreement’, and a value
.0.80 as ‘very good agreement’. The x 2 test with continuity correction
was used to compare proportions. To test intergroup associations among
the three groups, we set significance at P ¼ 0.017 (0.05/3) to control for multiple comparisons. Data analysis was carried out with the Statistics Package
for Social Sciences (SPSS 15.0, Chicago, IL, USA).
Results
Nine women refused to participate in the study for personal reasons (six
women with deep endometriotic lesions and three women with ovarian
endometriomas). A total of 771 women were eventually recruited. External and self-assessment of eye colour correlated but did not coincide.
The k-index + SE was 0.86 + 0.02 (P , 0.001). The evaluations did not
correspond in 52 women (7%). The proportion of these incongruent
cases was fairly similar among the three study groups (20/223 women
with deep endometriosis, 9%; 17/247 women with endometriomas,
7%; 15/301 women without a history of endometriosis, 5%;
P ¼ 0.20). Disagreement regarded mainly eyes judged as blue by the
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Blue eyes and deep endometriosis
Table I Baseline characteristics of participants according to study group.a
Group
...............................................................................................................................................
Deep endometriosis
(n 5 203)
Ovarian endometrioma
(n 5 230)
No endometriosis
(n 5 286)
.............................................................................................................................................................................................
Age (years)
38.4 + 6.9
36.9 + 7.4
33.6 + 7.9
BMI (kg/m2)
22.0 + 3.7
21.6 + 3.5
22.2 + 3.6
North
154 (76)
168 (73)
227 (79)
Centre
19 (8)
9 (4)
14 (5)
South
30 (15)
53 (23)
45 (16)
Region of birth (Italy)
Hair colour
Black
7 (4)
8 (3)
14 (5)
Dark brown
73 (36)
96 (42)
151 (53)
Light brown
97 (48)
100 (44)
93 (32)
Blonde
23 (11)
21 (9)
25 (9)
3 (1)
5 (2)
3 (1)
Red
a
Data are expressed as mean + SD or number (percentage).
observer, but as green by the woman (n ¼ 24), and as brown by the observer, but as green by the woman (n ¼ 19).
After exclusion of these 52 subjects, 719 women were included in the
final analysis (203 with deep endometriosis; 230 with ovarian endometriomas; 286 without a history of endometriosis). The deep endometriosis group comprised 104 patients with rectovaginal endometriotic
plaques, 39 with full-thickness bladder detrusor nodules, 32 with deep
lesions infiltrating the pouch of Douglas and parametria, 16 with fullthickness bowel lesions, and 12 with intrinsic ureteral endometriosis.
Some demographic and clinical characteristics of the recruited women
are shown in Table I. A total of 510 (71%) women had brown eyes, 140
(19%) blue eyes and 69 (10%) green eyes. The proportions of the different eye colours were not equally distributed among the three study
groups, as they were, respectively, 61, 30 and 9% in the deep endometriosis group, 74, 16 and 10% in the endometrioma group, and 75, 15 and
10% in the non-endometriosis group (Fig. 1). In particular, women in the
deep endometriosis group had a statistically significant excess of blue
eyes and a reduced proportion of brown eyes compared with the
other two study groups (P ¼ 0.002 and P , 0.001, respectively). The
proportion of blue eyes was almost identical in the ovarian endometrioma group and in the non-endometriosis group, and that of green
eyes was substantially similar in all study groups. The OR (95% CI) of
having blue eyes in women with deep endometriosis compared with
women with ovarian endometriosis and with women without a history
of endometriosis was, respectively, 2.2 (1.4 –3.6) and 2.5 (1.6 –3.9).
Figure 1 Distribution of eye colour according to study group. The
error bars represent SD as estimated based on a binomial distribution
model. Blue eyes are significantly more represented in women with
deep invasive lesions (deep endometriosis versus no endometriosis,
P , 0.001; deep endometriosis versus ovarian endometriomas,
P ¼ 0.002; ovarian endometriomas versus no endometriosis,
P ¼ 0.91), whereas brown eyes are significantly less represented
(deep endometriosis versus no endometriosis, P , 0.001; deep endometriosis versus ovarian endometriomas, P ¼ 0.003; ovarian endometriomas versus no endometriosis, P ¼ 0.76).
Discussion
The results of this case–control study showed that blue eye colour is significantly more common in women with deep endometriosis (30%) than
in those with ovarian endometriomas (16%) and in those without a
history of endometriosis (15%). No statistically significant difference in
blue eye prevalence was observed between the latter two groups, thus
confirming that this phenotypic characteristic is associated mainly with
deep endometriotic lesions, and not with less invasive forms. Moreover,
the unbalanced distribution of iris colour was limited to the blue category,
and not to light colours in general, as the proportion of green eyes was
similar in all study groups. Green is the rarest eye colour in Italy
(Di Stasio et al., 2011), and it was indeed the least frequent one in our
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series. A definitive discrimination between green and light brown
requires the use of ophthalmologic equipment that was not available in
our clinical setting. Photographs of iris colour were not taken. More in
general, adult blue eye colour is a ‘hard’ and stable trait, and its assessment should be little prone to confounding.
Selection bias is a potential threat to the internal validity of the
present study. Because this was not a population-based study, selection
of cases and controls from different underlying populations is possible.
In this study, both groups of endometriosis patients came from the
same underlying population, i.e. women who presented to our academic department’s referral clinic for endometriosis. Women with
deep endometriosis and those with ovarian endometriomas had
similar referral pattern. These self-referrals may come from outside
the clinic’s geographic area. Women without a history of endometriosis
came from our academic department’s gynaecologic clinic, mostly are
from the clinic’s geographic area, consisted of women presenting for
routine care, and they would all have become cases if they had developed endometriosis.
The frequency of blue eyes is expected to be higher in populations
from Northern Italian regions compared with those from Southern
ones. Therefore, assuming that women presenting to gynaecologic
clinic for routine care are from the Milan area (Northern Italy),
whereas those self-referred to the endometriosis outpatient clinic are
from a much broader area, would imply an expected excess of blue
eyes in the former group compared with the latter one, which was not
the case. Moreover, considerations on possible selection bias based
on geographical origin of participants are weakened by the strong migration flows within our country, especially from South to North. Indeed, it
would be difficult to select a specifically native Northern population
within the Milan catchment area.
The discrepancy between the prevalence of blue eyes observed in
women without a history of endometriosis (15%) and that previously
reported in the general Italian population (10%; Di Stasio et al., 2011)
could be explained by the fact that the subjects studied by Di Stasio
et al. (2011) were from central Italy. Interestingly, the results from the
group of women with ovarian endometriomas and from that of
women without a history of endometriosis were substantially similar.
All study participants were equally assisted by the National Health
System. Therefore, a potentially spurious association between socioeconomic status and eye colour can be ruled out.
Very few women refused to participate in the study. Absence of blinding of the investigators could have unduly influenced the results. For this
reason, we decided to include in the analysis of eye colour also the selfevaluation of the patients. Moreover, as a conservative measure, we
excluded from the analysis all women with discordant external and selfevaluation. This should guarantee adequate reliability of the findings. The
proportion of excluded participants was low (52/771; 7%), and should
not have biased the final results. The sample size was large, particularly
considering the deep endometriosis group. Moreover, given the type
of infiltrating forms included and the diagnostic modalities adopted, misclassification of cases appears unlikely. According to the suggestion of
Holt and Weiss (2000), we have selected only patients with deep
lesions or ovarian endometriomas, excluding those with superficial
implants only. In fact, limited peritoneal forms may not always constitute
a definite disease, and their inclusion may decrease the likelihood of observing true associations in etiologic studies (Holt and Weiss, 2000). In
addition, we did not retrieve endometriosis stage according to the
Vercellini et al.
American Society for Reproductive Medicine classification (1997),
because this scheme does not allow discrimination between ovarian
and deep lesions. In fact, this score system assigns points based, together
with other variables, on the presence of ovarian endometriomas and
Douglas pouch obliteration, but deriving the type of lesions present
from the attributed stage is not possible. Moreover, this scheme does
not specifically contemplate deep lesions such as rectovaginal plaques,
bladder detrusor nodules and bowel lesions.
The subjects included in the non-endometriosis group comprised
women without known endometriosis presenting to our clinic for
routine gynaecologic care, contraception or cervical cancer screening.
We cannot exclude that some women without a previous diagnosis of
endometriosis indeed had the disease. However, this would have led
to a reduction of the observed difference in proportion of blue eyes,
thus to a potential underestimation of the real strength of the association
(Holt and Weiss, 2000). Moreover, under-ascertainment is possible with
regard to peritoneal disease, but unlikely with deep endometriotic
lesions and ovarian endometriomas.
The biological explanation of our findings is not straightforward. There
is a strong genetic contribution to eye colour. In general, pigmentary
traits are of genetic origin, and because they involve similar regions and
candidate genes, they often predict each other (Sturm, 2009). Indeed,
a number of genes impacting the melanin biosynthetic pathway are candidates to explain the diversity of human pigmentation (Branicki et al.,
2011). Accordingly, the presence of specific phenotypic traits such as
red hair, freckles and sensitivity to sun exposure has been shown to be
more common in women with endometriosis (Somigliana et al., 2010;
Viganò et al., 2012). Genes involved in the control of human pigmentation may lie in a region with a pattern of linkage disequilibrium with
genes implicated in the invasiveness of endometriosis. However,
whereas some genes involved in the susceptibility to endometriosis
have been recently identified based on results from genome-wide association studies (White and Rabago-Smith, 2011; Rahmioglu et al., 2014),
very few data are available regarding the genetic variants influencing
disease aggressiveness and potential to invade tissues.
Alternatively, blue eye colour could be considered an indicator of a
photo-sensitive phenotype resulting in limited exposure to sunlight and
UVB radiation. Limited sunlight exposure is associated with reduced
circulating 25-hydroxyvitamin D3 (Lucas et al., 2013). Along this
line, an inverse relation has been demonstrated between plasma
25-hydroxyvitamin D3 and risk of endometriosis (Harris et al., 2013).
Vitamin D reduces cell proliferation, increases apoptosis, enhances cell
differentiation, and modulates angiogenesis, extracellular matrix production, and immune response (Holick, 2007). All these biological functions
are consistently involved in the pathogenesis of endometriosis (Vercellini
et al., 2014). More specifically, vitamin D and sun exposure independently stimulate T-regulatory cells and secretion of IL-10, reduce levels of the
pro-inflammatory cytokine IL-17, and dampen T helper (Th)-1 immune
function (Viganò et al., 2012). It may be hypothesized that the ovary might
be less susceptible or more prone to correct the vitamin D deficiencymediated consequences on the local immune system. Additional
studies conducted in different populations and countries are warranted
to substantiate our observations. The present findings, if confirmed, emphasize the intriguing association between specific phenotypic characteristics and the tendency toward progression and tissue infiltration of
particular endometriotic lesions, and may aid in shaping future research
in this area of phenomics (Viganò et al., 2012).
Blue eyes and deep endometriosis
Authors’ roles
P.V. contributed to the design of the study, interpretation of the data, and
drafted the manuscript. L.B. contributed to the design of the study, to the
recruitment of the participants and drafted the manuscript. E.S. contributed to the design of the study, analysis and interpretation of the data, and
critical revision of the manuscript. D.D. contributed to the design of the
study and to the recruitment of study participants. M.A.M. contributed
to the design of the study and to the recruitment of study participants.
P.V. contributed to the design of the study and critical revision of the
manuscript. All authors reviewed and approved the final version of the
manuscript.
Funding
No research funding was received for this study.
Conflict of interest
None declared.
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