The balance between heritable and environmental aetiology of human disease

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
Nature Reviews Genetics (Impact Factor: 39.79). 01/2007; 7(12):958-65. DOI: 10.1038/nrg2009
Source: PubMed

ABSTRACT The Human Genome Project and the ensuing International HapMap Project were largely motivated by human health issues. But the distance from a DNA sequence variation to a novel disease gene is considerable; for complex diseases, closing this gap hinges on the premise that they arise mainly from heritable causes. Using cancer as an example of complex disease, we examine the scientific evidence for the hypothesis that human diseases result from interactions between genetic variants and the environment.

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    ABSTRACT: Background We aimed at assessing familial risk of melanoma by considering a detailed family history of multiple primary (invasive/in situ) melanomas (MPM), stratified by histology and location. Methods Among 65,429 melanoma patients diagnosed in 1958–2010 in the Swedish Family-Cancer Database, there were 4248 patients with familial melanoma. A detailed family history of MPM was investigated by number of melanomas in one first-degree relative (FDR) and in ⩾2 FDRs. Familial melanoma risk was assessed by standardised incidence ratios (SIRs) comparing those with family history of melanoma to those without. Combining invasive/in situ melanoma was due to essentially identical familial risks. Results For one affected FDR, familial risk increased from SIR = 2.2 (95% confidence interval (CI) = 2.2–2.3) for single melanoma to 16.3 (9.5–26.1) for ⩾5 melanomas, while for ⩾2 affected FDRs, the risk increased from 5.5 (4.8–6.2) for single melanoma to 23.9 (13.6–38.8) for ⩾2 melanomas. Significantly higher familial risks for superficial spreading melanoma (SSM) [2.5 (2.3–2.6)] than lentigo maligna melanoma (LMM) [1.8 (1.6–2.1)], and for multiple parts [5.3 (3.1–8.4)] and trunk [2.6 (2.5–2.8)] than head/neck [2.0 (1.8–2.2)] were observed. Only at head/neck, significantly higher risk for SSM [2.4 (1.9–3.0)] than LMM [1.6 (1.4–1.8)] was noted. Conclusion We found, for the first time, that familial risks were similar for two/three melanomas in one FDR or for a single melanoma in ⩾2 FDRs and, higher familial risks for SSM than LMM occurred only at head/neck. This study provides new evidence for genetic counselling in melanoma, suggesting the need for considering not only the number of affected family members but also the diagnosis of MPM (even in situ) in relatives.
    European Journal of Cancer 10/2014; DOI:10.1016/j.ejca.2014.07.007 · 4.82 Impact Factor
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    ABSTRACT: Since 2001 researchers have mainly examined the human genome (G) to discover causes of disease despite evidence that G explains relatively little risk. We posit that unexplained disease risks are caused by the exposome (E, representing all exposures) and G×E interactions. It follows that etiologic research has been hampered by scientists' continuing reliance on low-tech methods to characterize E as contrasted with high-tech omics for characterizing G. Because exposures are inherently chemical in nature and arise from both endogenous and exogenous sources, blood specimens can be used to characterize exposomes. To explore the 'blood exposome' and its connection to disease we sought human-blood concentrations of many chemicals along with their sources, evidence of chronic-disease risks and numbers of metabolic pathways. From the literature we obtained human-blood concentrations for 1,561 small molecules and metals, derived from foods, drugs, pollutants and endogenous processes. Chemical similarities were mapped after weighting by blood concentrations, disease-risk citations and numbers of human metabolic pathways. Blood concentrations spanned 11 orders of magnitude and were indistinguishable for endogenous and food chemicals and drugs while those of pollutants were 1,000-times lower. Chemical similarities mapped by disease risks were equally distributed by source categories while those mapped by metabolic pathways were dominated by endogenous molecules and essential nutrients. The complexity of human exposures motivates characterization of the blood exposome, which includes all biologically active chemicals, for studies of disease etiology. Because most small molecules in blood are not human metabolites, investigations of causal pathways should expand beyond the endogenous metabolome.
    Environmental Health Perspectives 03/2014; 122(8). DOI:10.1289/ehp.1308015 · 7.03 Impact Factor


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