Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis

Human Reproduction Update, Vol.15, No.1 pp. 97–118, 2009 Advanced Access publication on September 19, 2008 doi:10.1093/humupd/dmn040 Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis C.B. Tempfer1,5, M. Simoni2, B. Destenaves 3, and B.C.J.M. Fauser 4 1 Department of Obstetrics and Gynecology, Medical University, 1090 Vienna, Austria 2Department of Medicine, Endocrinology and Metabolism, University of Modena and Reggio Emilia, I-41100 Modena, Italy 3Stratified Medicine Group, Merck Serono International S.A, 1202 Geneva, Switzerland 4Department of Reproductive Medicine and Gynecology, University Medical Center, 3508 GA Utrecht, The Netherlands 5 Correspondence address. E-mail: table of contents ........................................................................................................................... † Introduction † Genetic association studies of polymorphisms † Systematic review search criteria † Results † Discussion background: Endometriosis has a strong genetic component, and numerous genetic studies have been reported. methods: We have systematically reviewed these studies and included 114 in our final selection. results: We found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case–control studies. conclusions: The evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis. Key words: endometriosis / female reproduction / genetic polymorphisms / detoxification / sex steroids Introduction The association between genetic polymorphisms and clinical disease has long been recognized. For example, a relationship between blood group and gastrointestinal cancer was described in the 1950s (Billington, 1956). More recently, technological advances in molecular biology have fuelled the interest in molecular polymorphisms and their influence on the susceptibility and clinical presentation of diseases (Tempfer et al., 2004). Many aspects of female reproductive function are strongly influenced by genetic factors, and numerous studies have attempted to & The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: The online version of this article has been published under an open access model. 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For many of these conditions, the search for genetic disease markers is ongoing, and no strong candidate has yet emerged. Endometriosis is characterized by the presence and growth of endometrial cells outside the uterus, which impair fertility (Wenzl et al., 2003; Halis and Arici, 2004), and the disease has a strong genetic component (Treloar et al., 1999; Bischoff and Simpson, 2004; Vigano et al., 2007). In a study of the genetic influence on endometriosis risk in an Australian twin sample, for example, the risk ratio of affected versus population prevalence was 3.58 for monozygotic twins and 2.32 for dizygotic twins (Treloar et al., 1999). Clarifying the genetic etiology of endometriosis would have implications for diagnosis, identification of individuals at risk and the development of targeted therapeutics. This disorder has been the focus of a large number of association studies investigating a wide variety of polymorphisms. Previous reviews assessed the possible role of specific polymorphisms or groups of polymorphisms, indicating that the number of robust associations may be low (Falconer et al., 2007). Some have even challenged the evidence for endometriosis having a genetic background (Di and Guo, 2007). In this review, we assess evidence for the role of genetic polymorphisms in endometriosis. We present a systematic review of the published literature across all polymorphisms investigated in relation to endometriosis. We have evaluated the reliability and strength of the evidence for each of the 114 selected studies and discuss methods for improving association studies. However, to enable proper evalauation of the studies, we first explore the methodology of molecular association. Genetic association studies of polymorphisms The genetic basis of disease may be elucidated in different ways. One approach is to scan across the genome to identify markers/genes of interest; a second approach is to investigate specific ‘candidate’ genes. We discuss these approaches below, and provide examples of such studies in endometriosis. Genome-wide linkage analysis using affected sibling-pairs has been applied to endometriosis by Australian, British and Icelandic groups (Stefansson et al., 1998; Treloar et al., 2000; Kennedy et al., 2001). These studies aim to find chromosomal regions shared by related individuals harbouring disease-predisposing genes. In these linkage studies, which are conceptually different from case –control studies in unrelated individuals, a possible informative locus on chromosome 10q has been reported (Treloar et al., 2000). In addition, in a separate linkage analysis of families with three or (...truncated)