Genetics of pelvic organ prolapse; identification of specific gene defects in patients and their family members.

Pelvic organ prolapse (POP) is a common health problem in women, with
prevalence numbers varying from 8.3% to 30.8% (Eva 2003, MacLennan 2000,
Samuelsson 1999, Slieker-ten Hove 2009, Tegerstedt 2005) . The condition brings
along a substantial impact on quality of life, as is indicated by Digesu and
colleagues (Digesu 2005). Women complaining of prolapse not only experience
more urinary and bowel symptoms, but also encounter greater impairment
regarding for instance general health and personal relationships. The life-time
risk of a woman to undergo at least one operation for prolapse or urine
incontinence is 11.1%. When considering all interventions, 29.2% are repeat
procedures (Olsen 1997). This is not only very inconvenient for the patient, it
also carries a large burden for society. In 1997 the direct annual costs of
prolapse operations in the United States were $1012 million (Subak 2001), a
number that probably only has increased in recent years. Moreover this sum is
presumably an underestimation, because the analysis did not include costs of
evaluation, diagnostic tests, preoperative therapies, complications requiring
readmission to the hospital or outpatient treatment, and indirect costs such as
lost wages. Concluding it can be said that pelvic organ prolapse gives a high
medical and social burden.

In order to take better preventative measurements and provide better treatment
options, it is of critical importance to know the underlying cause of prolapse.
So far, a lot of risk factors are identified. For instance the number of
vaginal births (Chiaffarino 1999, Rortveit 2007) maximal birth weight (Rortveit
2007), heavy physical work (Slieker-ten Hove 2009, constipation (Rortveit 2007)
and race (Dietz 2003, Rortveit 2007) all seem to increase the risk of
developing a pelvic organ prolapse later in life. However, different studies
show conflicting results regarding these factors. Moreover, not all women with
substantial risk factors develop POP, whereas other women with few to no risk
factors develop POP at an early age. This makes an underlying susceptibility
caused by a genetic component likely.

In recent years several studies have suggested a strong genetic component in
the development of pelvic organ prolapse. The risk of a women to develop POP is
significantly increased when her mother or sister has a history of prolapse,
with OR varying from 1.7 to 3.2 (Slieker-ten Hove 2009, Chiaffarino 1999).
However, a potential hereditary risk factor implies that male family members
may also play a role in passing on the genetic factor. For this reason McLennan
et al. (MacLennan 2008) involved both male and female relatives in their
survey. As hernia is considered to have the same pathophysiology as female
prolapse, they considered family history to be positive if at least one of the
family members reported hernia or prolapse in their past medical history. They
demonstrated that, even after adjustment for confounders such as vaginal
delivery, the risk of developing POP was significantly higher in women with a
positive family history (OR 1.4, CI 95% 1.2-1.8).

Jack et al. (Jack 2006) were the first to look at the inheritance pattern of
prolapse within a family. They selected 10 families of patients with a grade
III or IV prolapsed under the age of 55. Within these families they observed a
dominant inheritance pattern with incomplete penetrance, through both maternal
and paternal relatives. For sisters of these prolapse patients the relative
risk to develop POP was five times that of the general population. The study
suggested that inheritable, genetic variation can make women susceptible to
prolapse. However no attempt was made to identify the underlying genetic
mutation.

It is known that type III collagen is of special importance in tissue repair
following mechanical stretch such as in delivery or POP. Several studies have
indeed reported an increase in type III collagen in samples from vaginal and
supportive tissue in women with POP . Type III collagen polymorphisms may
result in a decrease in tissue repair and may lead to impaired tensile strength
of ligaments and supportive tissues. These polymorphisms have been reported in
various diseases in which an impaired tensile strength may be part of the
molecular pathophysiology, including mitral valve prolapse and vascular
aneurisms . Chen and co-workers have suggested that a COL3A1 polymorphism in
exon 30 (rs1800255) was related to POP in Taiwanese women. Our research group
recently confirmed this finding in a larger population of 202 Dutch POP
patients and 102 parous controls. The homozygous nucleotide substitution in
exon 30 of gene encoding type III collagen (COL3A1 2209G>A) can be detected in
13.4% of patients with POP compared to 2.9% in woman without POP. The odds
ratio for the presence of POP in a woman with this homozygous COL3A1 2209G>A
polymorphism is 5.0 (95% confidence interval 1.4; 17.1). Hemizygous
polymorphism does not correlate with the presence of POP.

We hypothesize that the COL3A1 2209G>A polymorphism is a inheritable genetic
defect, responsible for the increased susceptibility to pelvic organ prolapse
in women. To verify this hypothesis, we will have to investigate the family
members of patients with the above mentioned homozygous polymorphsim.

Genetic analysis of the familial inheritance pattern of the COL3A1 2209G>A
polymorphism.

Cohort study

Vena punction
POP-Q (= gynecologic investigation to determine the degree of pelvic organ
prolapse) in female subjects.
Questionnaire regarding general and (in female subjects) obstetric history as
well as prolapse symptoms.

The whole investigation can take place in one out patient department visit en
will take approximately 45 minutes.

Burden: some patients might experience the gynecologic investigation as a
burden. The investigation however, will be done by an experienced doctor en
will take only one or two minutes. Since there is only one (international
acknowledged) standardised method to evaluate pelvic organ prolapse, there is
no alternative for this investigation.
Risks: none.