Pelvic Floor Disorder
Principal Investigator: Lisa Cannon-Albright, PhD
If predisposition genes for PFDs are discovered, then younger women with affected relatives might be identified as being at high risk for PFDs prior to their first childbirth; they would be candidates for primary prevention. After development of a PFD, a woman known to carry a disease-associated variant for a POP predisposition gene might benefit from early interventions that reduce the progression of the condition as secondary prevention, or special surgical treatments as tertiary prevention.
Family History Has Been Recognized As An Important Risk Factor for PFD
Epidemiology surveys have found that women with urinary incontinence were more likely to have family members with urinary incontinence (Diokno et al., 1990, Skoner et al., 1994, Mushat et al., 1996, Hannested et al., 2004) Recent studies using the Swedish Twin Registry estimated that genetic effects may account for as much as 40% of the total variance of UUI (Rohr et al., 2004). and SUI and POP (Altman et al., 2008). Our analysis of POP in the Utah Population Database (UPDB) has shown strong evidence for excess relatedness of POP cases (Norton et al., submitted). Buchsbaum and colleagues (Buchsbaum et al., 2006) compared nulliparous nuns to their own parous sisters and found high concordance between sisters regardless of birth history, suggesting an underlying familial predisposition to POP. While most of these studies have focused on observational or registry data, there are several studies that have focused specifically on genetic variants. Genes involved in skeletal muscle myosin (Hundley et al.,2007), p27 (Copas et al., 2002), and in one genome-wide examination of a single extended family the basement membrane protein laminin LAMC1 (Nikolovsky et al., 2008) have all been implicated. Elastin fiber homeostasis has been implicated through the model of knockout LOXL1 mice who develop POP (Liu et al., 2006)
Given the wide range of presentation of PFDs, no single etiology can be suggested. Childbirth may lead to muscle, nerve, and connective tissue injury, but there may be underlying predisposition genes which determine whether such injury leads to functional decompensation and eventual pelvic floor defects. In this common condition whose etiology remains obscure, identification of predisposition genes may shed light on the pathophysiology of POP and lead to better treatment and prevention.
It will become important to understand the relationship of various PFDs within a single woman, and within high-risk pedigrees. Thus, for all cases we will gather phenotype data for all pelvic floor disorders including POP, SUI, UUI/OAB, and hernia; family history for PFDs and hernias; as well as other comorbid conditions in all relatives. These data will allow us to explore other potential relationships within PFDs as a secondary aim. Research questions that can be posed include: i) Is hernia the male equivalent of PFDs in women? ii)Does early onset POP increase the relative risk seen in family members? iii) Are there other conditions that segregate similar to PFDs that may represent related errors in proteins, such as abdominal aortic aneurysm, collagen and elastin disorders, and joint mobility disorders? The UPDB linked data makes exploration of these questions feasible.