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A novel geneenvironmentinteraction involved inendometriosis

ByAzano Syahriza SitepuSupervisorDr. Elida Sidabutar SpOG

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Objective: To establish a well-defined cohort for geneticepidemiology studies of

endometriosis and conduct apilot study to confirm validity

using existing data associatedwith endometriosis.

Methods: Between January andMay 2010, a nested cohortwithin a population-based

biobank was established inMarshfield, Wisconsin, USA.

The inclusion criteria werewomen who had laparoscopy or

hysterectomy. Fifty-onepleiotropic genetic

polymorphisms and otherestablished risk factors, such assmoking status and body massindex, were compared between

endometriosis

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Introduction

Endometriosis is acomplex disease and amajor women's healthproblem, the causes of

which are not entirelyunderstood

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Definition

Endometriosis is anestrogen-dependent

inflammatory diseasethat is characterized by

the presence ofendometrium-like

tissue in sites outsidethe uterus

mainly, the pelvicperitoneum, ovaries,

and rectovaginalseptum

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The effect

Pelvic pain Ovarian cancer Reduced Fertility

Non-hodgkinlymphoma

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Incidence

Under the assumption of a prevalence rate of 10%among women of reproductive age, the estimatedtotal health- care cost of treating endometriosis inthe United States was US$ 22 billion in 2002

Although the heritability of endometriosis has beenestimated to be 52%, so far genetic polymorphism

studies have failed to identify major geneticcontributors to endometriosis

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Material and methods

To form a definedcohort for genetic

epidemiology studies

Blood sample fromwhich DNA was

extracted and storedwith plasma andserum samples

98 % of participantsbeing Caucasian and78% being German

ancestry

The informed consentdocument contained a

tick-box

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Material and methods

Women who had undergonelaparoscopy orhysterectomy

Endometriosis status was

diagnosed by gynecologicvisual confirmation onprocedure and/or by

pathology confirmation

Smoking status

Age

affected women rangedfrom 18 to 86 years (mean43.9 years) and the control

women ranged from 18 to 63years (40.8 years).

BMI 796 cases and 501 controls

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Table 1

Polymorphisms examined in the whole cohort.

Rs1137101 rs486907 rs1042031 rs231775 rs5186rs6280 rs1799883 rs4961 rs1042714 rs351855

rs5370 rs6296 rs2227983 rs213950 rs7493rs328 rs2383206 rs1800861 rs1801253 rs2227564rs17999750 (MMP1) rs1063856 rs6313 rs2236225 (MTHFD1)rs1800588 rs243865 rs4673 rs708272 rs4291 rs4792311rs16430 rs601338 rs688 rs7121 rs234706 rs4680 rs1544410rs16944 rs1799983 rs1800469 rs1800629 rs1800795 (IL6)rs1800796 (IL6) rs1800872 rs1801133 rs268 rs429358 rs4343 rs731236

rs7412 rs7975232

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Results

Table 2

Differences between endometriosis cases and controls in epidemiologic factors previ-ously associated with endometriosis.a

Epidemiologic factor Controls Cases 2 P value Odds ratio

Age 50 years 93 (18.6) 222 (27.9) 14.5 0.0001 1.70 (1.292.23

Never smoked 266 (67.3) 420 (70.1) 0.9 0.35 1.14 (0.871.50)

Upper tertile of BMI 204 (40.9) 270 (34.2) 6.3 0.037 0.75 (0.600.95)

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Table 3

Significant univariate associations of endometriosis with genetic markers available for thewhole cohort.

Genetic marker Controls Cases 2 P value Odds ratio(95%

confidence interval)

IL6 haplotype H3

Total number 496 794

% homozygous 62.3 71.7 12.6 0.0019 1.53 (1.211.94)

or heterozygous

MTHFD1

Total number 496 790

Minor allele frequency % 49.8 57.1 12.6 0.0018 1.51 (1.151.97)

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Table 4

Association of the MMP1 SNP with endometriosis among the whole cohort and strati- fied by smoking status.

Study group Controls Cases 2 P value Odds ratio(95% confidence interval)

Whole cohort

Total number 496 791

Minor allele frequency, %48,5 48.5 0,84 0,66 0.94 (0.731.21)

Never smokers

Total number 263 416 0,90 0,54 1.11 (0.791.57)

Minor alelle frequency,% 47,0 49,5 0,90 0,64 1,11 (0,79-1,57)

Current smoker

Total number 128 178

Minor allele frequency, % 55.5 45.5 8.17 0.017 0.45 (0.260.79)

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Discussion

The strengths of the study and its cohort include therigorous phenotyping, the availability of questionnairedata to quantify personal and environmental exposure,

the additional data related to co- morbid conditions, andthe availability of treatment history from the medicalrecords

The relatively high ethnic homogeneity is a limitation to

the generalizability of the results

Larger sample sizes will be needed to evaluate geneenvironment and genegene interactions in full

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Thank you