BackgroundSingle nucleotide polymorphism (SNP) 309 resulting in a T or G allele in the promoter of MDM2, the negative regulator of p53, has been suggested to affect cancer predisposition and age of onset, primarily in females. However, findings have been inconsistent in various cancers, and ethnicity appears to be a critical factor influencing the effects of the SNP on cancer risk. An increasing trend has been observed in the prevalence of lung cancers in non-smokers, especially females, though the underlying genetic basis is unclear.MethodsWe therefore examined the role of the SNPs in the p53 pathway (p53 codon 72 and MDM2 SNP309) on lung cancer risk and prognosis of a life-time non-smoking female Chinese population, in a hospital-based case-control study of 123 cases and 159 age-matched controls, by PCR analysis.ResultsOur findings reveal that the risk of lung cancer among individuals with the MDM2 SNP309 TT genotype was 2.1 (95% CI 1.01-4.36) relative to the GG genotype, contrary to initial expectations that the GG genotype with elevated MDM2 levels will increase cancer risk. Those who had this genotype in combination with the p53 Pro allele had a risk of 2.5 (95% CI 1.2-5.0). There was however no effect of either polymorphism on age at diagnosis of lung cancer or on overall survival.ConclusionsThe results thus demonstrate that the MDM2 SNP309 TT rather than the GG genotype is associated with increased risk of lung cancer in this population, suggesting that other mechanisms independent of increased MDM2 levels can influence cancer susceptibility.
The intestinal fatty-acid binding protein-2 (FABP2) gene codes a protein responsible for the absorption of longchain fatty acids. To test whether FABP2 is a candidate gene for renal disease in patients with type 2 diabetes, a functional A54T polymorphism was genotyped in 1,042 Brazilians with type 2 diabetes. Patients were classified as having normoalbuminuria (urinary albumin excretion [UAE] <20 g/min; n ؍ 529), microalbuminuria (UAE 20 -199 g/min; n ؍ 217), or proteinuria (UAE >199 g/ min; n ؍ 160). Patients with end-stage renal disease (ESRD) (n ؍ 136) were also included. D iabetic nephropathy develops in up to 40% of diabetic patients at most, even when high glucose levels are maintained for long periods of time (1). Epidemiological (2) and familial (3-5) studies have demonstrated that genetic susceptibility contributes to the development of diabetic nephropathy in both type 1 and type 2 diabetes. The precise genetic model underlying diabetic nephropathy susceptibility is uncertain, but several genes with a minor effect have been associated with diabetic nephropathy (6). Insulin resistance has been implicated in the development of diabetic nephropathy (7), and aggregation of components of the metabolic syndrome is associated with a high prevalence of diabetic nephropathy (8). The intestinal fatty acidbinding protein-2 (FABP2) gene codes a protein expressed in enterocytes and is responsible for the absorption of long-chain fatty acids (9). A single nucleotide polymorphism (SNP) in the FABP2 gene at codon 54 causes an amino acid change (Ala 3 Thr). This change affects the ability of the protein to bind and transport dietary fatty acids (9). Serum saturated fatty acids might induce endothelial dysfunction (10) and are related to increased cardiovascular mortality (11). We have previously reported increased levels of serum saturated fatty acids in patients with type 2 diabetes and microalbuminuria (12), as well as a reduction in albumin excretion rate after replacement of red meat (high content of saturated fatty acids) with chicken (low content of saturated fatty acids) in these patients (13). Based on these observations, we hypothesized that genetically predisposed subjects exposed to a diet with a high content of saturated fatty acids might be at high risk for developing renal disease. Therefore, we decided to examine whether FABP2 is a susceptibility gene for renal disease in patients with type 2 diabetes. Our study focused particularly on the A54T polymorphism, since this polymorphism results in a functionally altered FABP2 protein. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. RESEARCH DESIGN AND METHODSESRD, end-stage renal disease; FABP2, fatty acid-binding protein-2; IHD, ischemic heart disease; SNP, single nucleotide polymorphism; UAE, urinary albumin excretion.
Recent evidence suggests that inflammatory pathways are important mediators of carcinogenesis. Asthma, allergic rhinitis and atopic dermatitis are clinical manifestations of a systemic atopic disorder, which is associated with airway hyper-responsiveness and inflammation. We examined the effect of a history of asthma/atopy among 132 lung cancer cases (of which 72% were adenocarcinomas) and 163 controls, all of whom were non-smoking Chinese women, in combination with a single nucleotide polymorphism (-634C/G) in the interleukin-6 (IL-6) gene which regulates secretion of a pro-inflammatory cytokine found to be predominant in lung tumour tissue. We observed a slight increase in risk of lung cancer [odds ratio, OR = 1.5, 95% confidence interval (95% CI) = 0.8-2.6] and of adenocarcinoma (OR = 1.6, 95% CI = 0.9-3.1) with asthma/atopy alone. There was no effect of the IL-6 CG/GG genotype on lung cancer risk on its own. Among individuals with both asthma/atopy and the IL-6 -634 G allele, however, risk was increased at least 3-fold (OR = 3.1, 95% CI = 1.2-8.3 for all cancers and OR = 4.2, 95% CI = 1.5-11.6 for adenocarcinomas) relative to individuals with no asthma/atopy and the CC genotype. On stratified analysis, a significant increase in risk with asthma/atopy was restricted to those with the at-risk genotype (Pint < 0.05). Our findings are consistent with the role of chronic inflammation as an aetiologic factor among non-smoking Asian women, and suggest that asthma/atopy is a risk marker for susceptibility to the development of lung cancer.
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