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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclin D1 (CCND1) is critical in the transition of the cell cycle from the G1 to S phases, and unbalanced cell cycle regulation is a hallmark of carcinogenesis. Numerous epidemiological studies have evaluated the association between the CCND1 A870G polymorphism and the risk of prostate cancer (PCa). However, these studies have yielded conflicting results. In the present study, the possible association above was assessed by a meta-analysis. Eligible articles were identified for the period up to July 2014. Pooled odds ratios (ORs) with 95% confidence intervals (95% CI) were appropriately derived from fixed effects or random effects models. A total of ten case-control studies, which included 3,820 cases and 3,825 controls, were identified. Overall, the allelic/genotypic association between the G870A polymorphism and prostate cancer was nonsignificant (OR = 1.045, 95% CI = 0.947 to 1.153 for A versus G, P = 0.380; OR = 1.088, 95% CI = 0.896 to 1.321 for AA versus GG, P = 0.393; OR = 1.044, 95% CI = 0.941 to 1.158 for GA versus GG, P = 0.414; OR = 1.053, 95% CI = 0.955 to 1.161 for the dominant model AA + GA versus GG, P = 0.303; OR = 1.072, 95% CI = 0.881 to 1.306 for the recessive model AA versus AA + GA, P = 0.486). Moreover, subgroup analyses according to ethnicity failed to demonstrate a significant association between this polymorphism and prostate cancer. In addition, we also performed a stratified analysis of cases with PCa metastasis, and the results supported the findings of no significant association between CCND1 A870G polymorphism and metastasis risk of PCa. Our results suggest that the CCND1 A870G polymorphism might not be a potential candidate for predicting prostate cancer risk, including metastasis risk.
    World Journal of Surgical Oncology 12/2015; 13(1). DOI:10.1186/s12957-015-0479-8 · 1.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological studies indicate a genetic contribution to colorectal cancer (CRC), but specific genetic variants remain unknown. Genome-wide association studies have identified rs4444235 at BMP4 as a new colorectal cancer (CRC) and colorectal adenoma (CRA) susceptibility locus in populations of European descent. After that, several validation studies have been conducted among various ethnic populations to investigate if the SNP was associated with CRC/CRA, but the results have been inconsistent. To investigate this inconsistency and derive a more precise estimation of the relationship, a meta-analysis involving 54,631 CRC cases, 3995 CRA cases and 88,098 controls from 15 studies was performed. Potential sources of heterogeneity including ethnicity, sample size, study design and endpoint were also assessed. Overall, the summary OR of CRC was 1.06 (95% CI: 1.04-1.08, P<10(-5)). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians (OR=1.07, 95% CI: 1.01-1.12, P=0.01) and Caucasians (OR=1.07, 95% CI: 1.05-1.10, P<10(-5)); while no significant associations were found among African Americans and other ethnic populations in all genetic models. In addition, significant associations were also detected for CRA with per-allele OR of 1.09 (95% CI: 1.03-1.14, P=0.001). Our findings demonstrated that BMP4-rs4444235 is a risk factor associated with increased CRC and CRA susceptibility, but these associations vary in different ethnic populations. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine 01/2015; 72(2):154-159. DOI:10.1016/j.cyto.2014.12.021 · 2.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review aimed at covering cancer risk trends by site and histology in first-generation and second-generation immigrants in Sweden compared with natives. In addition, we reviewed data on cancer survival in immigrants to explore factors explaining cancer survival in the entire population. The Swedish Family-Cancer Database was used to calculate standardized incidence ratios and hazard ratios (HRs) of death from cancer in 77 360 and 993 824 cases among first-generation, and 4356 and 263 485 cases among second-generation immigrants and Swedes, respectively. Ordinal logistic regression analyses were used to calculate odds ratio. To obtain the maximum number of cases, we classified the immigrants according to geographical setting, population, and/or cancer risk. Compared with native Swedes, the highest risk of cancer was observed for nasopharyngeal carcinoma in Southeast Asian men (standardized incidence ratio=35.6) and women (24.6), for hypopharyngeal carcinoma in Indian men (5.4), for squamous-cell carcinoma of the esophagus in Iranian women (3.8), for cardia of the stomach in East Asian women (4.2), for signet-ring cell carcinoma of the stomach in Southeast Asian women (6.7), for the liver in East Asian men (6.8), for the gall bladder in Indian women (3.8), for the pancreas in North African men (2.2), for large cell carcinoma of the lung in former Yugoslavian men (4.2), for pleural mesothelioma in Turkish women (23.8), for the cervix in Danes (1.6), for seminoma in Chileans (2.1), for transitional-cell carcinoma of the bladder in Asian Arab men (2.3), for meningioma in former Yugoslavians (1.3), and for papillary carcinoma of the thyroid in East and Southeast Asian men (3.6). No immigrant groups had an increased risk of breast, uterus, ovary, and prostate cancers or nervous system tumors. The HRs for all breast cancers were between 1.0 in low-risk Europeans and 1.2 in lowest-risk non-Europeans. Low-risk non-Europeans had an HR of 2.9 for lobular carcinoma. Low-risk non-Europeans were diagnosed in a higher T-class (odds ratio=1.9) than Swedes. The HRs for prostate cancer were 0.6 in Turks, Middle Easterners, Asians, and Chileans. In conclusion, environmental and behavioral factors, early-childhood exposures, and infections may play a major role in the risk of esophageal, stomach, liver, nasopharyngeal and hypopharyngeal cancers, malignant pleural mesothelioma, breast, gynecological, testicular, urinary bladder, and thyroid cancers. Pancreatic cancer and nervous system tumors may have a major genetic component in the etiology. The ethnic differences in the risk of breast cancer by histology had no major influence on survival. Middle Easterners, Asians, and Chileans, with the lowest risk of prostate cancer, also had the most favorable survival, suggesting a biological mechanism for this finding.
    European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 01/2015; DOI:10.1097/CEJ.0000000000000106 · 2.76 Impact Factor


Available from