Sex differences in disease risk from reported association study findings

Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5415, USA.
Human Genetics (Impact Factor: 4.82). 08/2011; 131(3):353-64. DOI: 10.1007/s00439-011-1081-y
Source: PubMed


Men and women differ in susceptibility to many diseases and in responses to treatment. Recent advances in genome-wide association studies (GWAS) provide a wealth of data for associating genetic profiles with disease risk; however, in general, these data have not been systematically probed for sex differences in gene-disease associations. Incorporating sex into the analysis of GWAS results can elucidate new relationships between single nucleotide polymorphisms (SNPs) and human disease. In this study, we performed a sex-differentiated analysis on significant SNPs from GWAS data of the seven common diseases studied by the Wellcome Trust Case Control Consortium. We employed and compared three methods: logistic regression, Woolf's test of heterogeneity, and a novel statistical metric that we developed called permutation method to assess sex effects (PMASE). After correction for false discovery, PMASE finds SNPs that are significantly associated with disease in only one sex. These sexually dimorphic SNP-disease associations occur in Coronary Artery Disease and Crohn's Disease. GWAS analyses that fail to consider sex-specific effects may miss discovering sexual dimorphism in SNP-disease associations that give new insights into differences in disease mechanism between men and women.

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    • "As pointed out in recent studies, gender bias represents a considerable issue in biomedical research (Kim et al. 2010; Liu et al. 2012; Regitz-Zagrosek 2012). For example, besides gender-specific disease susceptibility, sexual dimorphisms play a substantial role for pharmacokinetics and—dynamics (Gandhi et al. 2004). "
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    ABSTRACT: The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender-stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses.
    Metabolomics 08/2015; 11(6). DOI:10.1007/s11306-015-0829-0 · 3.86 Impact Factor
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    • "Clinical and experimental data show the presence of a gender dimorphism in the immune response [36-39]: male and female hormones influence the immune system and they behave in opposite ways [40-42] (Figure 7). The research has revealed that the gender is associated with important incidence differences and with a prevalence of differential age-related pathologies [43]. "
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    ABSTRACT: Low-grade inflammatory state causes the development of the principal chronic-degenerative pathologies related with ageing. Consequently, it is required a better comprehension of the physiologic origins and the consequences of the low-grade inflammatory state for the identification of 1) the basic mechanisms that lead to the chronic inflammatory state and, after that, to the progression toward the pathologies and 2) the parallel identification of the prognostic biomarkers typical of these passages. These biomarkers could bring to several improvements in the health quality, allowing an early diagnosis and more effective treatments for: a) the prevention strategies on the healthy population, to assure a healthy longevity and b) the identification of personalized treatment in patients, to assure the benefit of the therapy. For the identification of these biomarkers it is necessary to consider that the ageing processes produce alterations of the physiologic systems and that these modifications compromise the communications between these networks: this state constitutes an obstacle for an appropriate physiologic homeostasis, that plays a fundamental role for the safeguard of the health. It is also to be considered that immune senescence affects both men and women, but it does it in different ways: a sexual dimorphism of immune pathways in the setting of immune response homeostasis is normally present, as we previously underlined. Therefore we hypothesize that, in order to prevent the development of the chronic-degenerative pathologies related with ageing, it is important to identify "Biomarkers of Homeostasis " specific for each gender: these are biologic molecules that should be measurable in a practical and no-invasive way and whose variations can quantify the male and female risk of losing the physiologic system homeostatic capacity. This competence is not only critical in the control of inflammation, but it is also prognostic for the passages from low-grade inflammatory state to the chronic inflammation and to the progression toward the degenerative pathologies. Beginning from the actual results, our intent is 1) to discuss and underline the importance of these new research perspectives in the definition of ageing gender-specific clinical "Biomarkers of Homeostasis" and 2) to propose homeostasis biomarkers, already present in the research results.
    Immunity & Ageing 02/2014; 11(1):3. DOI:10.1186/1742-4933-11-3 · 3.54 Impact Factor
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    • "With the increasing effect size in the sex which shows the association exclusively, the statistical power will be much higher than that in the pooled sample. Even some of the missing heritability in GWAS (Manolio et al., 2009) may be identified through routine use of sex-specific analysis, as the post hoc analysis done in one study suggested (Liu et al., 2012). "
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    ABSTRACT: The gender difference in cancer susceptibility is one of the most consistent findings in cancer epidemiology. Hematologic malignancies are generally more common in males and this can be generalized to most other cancers. Similar gender differences in non-malignant diseases including autoimmunity, are attributed to hormonal or behavioral differences. Even in early childhood, however, where these differences would not apply, there are differences in cancer incidence between males and females. In childhood, few cancers are more common in females, but overall, males have higher susceptibility. In Hodgkin lymphoma, the gender ratio reverses toward adolescence. The pattern that autoimmune disorders are more common in females, but cancer and infections in males suggests that the known differences in immunity may be responsible for this dichotomy. Besides immune surveillance, genome surveillance mechanisms also differ in efficiency between males and females. Other obvious differences include hormonal ones and the number of X chromosomes. Some of the differences may even originate from exposures during prenatal development. This review will summarize well-documented examples of gender effect in cancer susceptibility, discuss methodological issues in exploration of gender differences, and present documented or speculated mechanisms. The gender differential in susceptibility can give important clues for the etiology of cancers and should be examined in all genetic and non-genetic association studies.
    Frontiers in Genetics 11/2012; 3:268. DOI:10.3389/fgene.2012.00268
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