Antonino Crivello

Tumor necrosis factor-α−308A/G polymorphism is associated with age at onset of Alzheimer's disease

Abstract Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimers disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-α is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60–87) and 240 non-demented age-matched healthy controls for TNF-α −308 G/A single nucleotide polymorphism (SNP). No significant differences were observed in genotyped frequencies between patients and controls, whereas carriers of −308A showed a significantly lower mean age at onset than non-carriers of this allele. This difference was more evident taking into account ApolipoproteinE (ApoE) status since the lowest age at onset was observed in patients carrying the −308ATNF+/APOE4+ genotypes. In conclusion, our data support previous suggestions that, at least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising, bringing to light the importance of genetic variation at the pro-inflammatory components in the progression of AD.

Regulatory Cytokine Gene Polymorphisms and Risk of Colorectal Carcinoma

Abstract:  It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori–associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease–associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti‐inflammatory cytokine interleukin (IL)‐10 and transforming growth factor‐beta1 (TGF‐β1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL‐10‐deficient mice develop severe atrophic gastritis and a chronic enterocolitis, developing colorectal cancer similar to human inflammatory bowel disease–associated neoplasia. TGF‐β1 is a multifunctional signaling molecule with a wide array of roles. Animal experiments suggest that TGF‐β1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting a significant stimulation of tumor growth invasion and metastasis during tumor progression. We assessed association of functional polymorphisms (–1082G/A; –592C/A) and TGF‐β1 (–509C/T; +869C/T) influencing the IL‐10 production to colorectal cancer risk in a case–control study of 62 patients and 124 matched controls. No significant differences were observed among cancer patients and controls for IL‐10 –1082G/A; –592C/A genotype frequencies. Evaluation of odds ratios (OR) for the TGF‐β1 +869C/T genotypes showed a significant increased risk for individuals bearing +869CC genotype compared to +869CT‐ and +869TT‐positive individuals. These results suggest that the +869C allele, responsible for a Leu→Pro substitution in the signal peptide sequence of the TGF‐β1 protein, may have a predisposing role in the development of colorectal cancer.

Cytokine gene polymorphisms and breast cancer susceptibility

Abstract:  Human breast cancer (BC) is characterized by a considerable clinical heterogeneity. Steroid hormone receptor expression and growth factor receptor expression have been considered suitable diagnostic and prognostic markers, whereas mutations of oncosuppressor and gatekeeper genes have been found associated with an increased risk for this malignancy. To evaluate the role that polymorphisms of genes involved in the regulation of inflammatory response might play in BC susceptibility, we investigated associations between cytokine functionally relevant polymorphisms in 84 BC patients compared to 110 age‐ and sex‐matched controls. TNF‐α (‐308G/A), TGF‐β1 (+869C/T), IL‐10 (−1117G/A; −854C/T; −627C/A), and IFN‐γ (874T/A) single nucleotide polymorphisms (SNPs) were identified by sequence‐specific primers (SSP)‐PCR or restriction fragment length polymorphism (RFLP)‐PCR. Genotype or haplotype distributions for each polymorphisms were consistent with the HWE in these populations. We were unable to demonstrate differences in genotype or allele frequencies between patient and control groups. Data obtained in this study indicate that none of the cytokine SNPs studied is likely to have predisposing or protective effects on BC susceptibility. On the other hand, both positive and negative association with BC have been reported for some of the studied genotypes by different research groups. In conclusion, further studies involving larger numbers of subjects are required.

Role of environmental and genetic factor interaction in age-related disease development: the gastric cancer paradigm.

The association of Helicobacter pylori (Hp) infection with gastric cancer is well known and might be considered a paradigmatic example of the role that interaction among environmental factors and individual background might play in inducing age-associated disease. To evaluate the role of interaction of Hp infection with genetic background, gastric cancer and chronic gastritis patients as well as random selected controls were typed for five inflammation-related polymorphisms of IL-1 and IL-10 cytokine genes. No association among IL-10 or IL-1 variants with an increased risk of gastric cancer was found, whereas an Hp-independent association of IL-1beta -511T positive genotypes to an increased risk of chronic gastritis was found (Hp-/511T+ OR 1.89, 95% CI: 1.01-3.54; Hp+/-511T+ OR 1.83, 95% CI: 1.05-3.19). Stratification of gastric cancer group according to Hp infection does not allow finding a statistically significant association of Hp+ to the higher histological grading (G3) of gastric cancer (OR 1.54, 95% CI: 0.46-5.11). Our findings seem to confirm that cytokine genetic variants might contribute to determining the background for inflammaging in which H. pylori infection might facilitate cancer development.

Association between Platelet Glycoprotein Ib‐α and Myocardial Infarction

Abstract:  Myocardial infarction (AMI) is a complex multifactorial disorder. Platelet adhesion and thrombosis are pivotal events in the development of atherosclerotic lesions. Occlusive thrombus is almost exclusively initiated by plaque rupture and adhesion of platelets to subendothelial von Willebrand factor (vWf) by its specific platelet receptor, the α‐chain of glycoprotein (GP) Ib‐IX‐V complex of the human platelet‐specific antigens (HPA). Two polymorphisms have been reported in the sequence of GPIb‐α. The first, a C/T transition at nucleotide 1018 results in an amino acid dimorphism (Thr/Met) at residue 145 of GPIb‐α, which is located within the vWF‐binding domain of the receptor. The second is a T/C polymorphism in the Kozak sequence at position −5 from the initiator ATG. This affects the receptor density on the platelet surface. We assessed 1018 C/T and −5 T/C Kozak polymorphisms to see whether they are associated with AMI in homogeneous populations of Sicilian patients with AMI. To this end, we have analyzed the distribution of 1018 C/T and −5 T/C Kozak polymorphisms in 105 young Sicilian patients (<46 years) and 110 healthy age‐related controls, by PCR–SSP and PCR–RFLP. Our results demonstrate no significant differences in the frequency of 1018 C/T and −5 T/C Kozak polymorphism between patients with AMI and controls. Stratifying by gender, there is no difference between male and female patients and control data. Thus, our results indicate that the HPA‐2 polymorphisms are not associated with an increased risk for AMI at early onset (< 46 years) both in men and in women.

The Genetics of Innate Immunity and Inflammation in Ageing, Age-Related Diseases and Longevity

Inflammation is a key component of age-related diseases such as atherosclerosis and Alzheimer’s disease (AD) and genes coding for inflammatory or anti-inflammatory molecules are, therefore, good candidates for influencing the risk of developing these pathologies. Findings discussed in this chapter suggest that different alleles of genes coding for pro-or anti-inflammatory genes may affect individual life-span expectancy by influencing the type and intensity of immune-inflammatory responses against environmental stressors involved in the development of age-related disease. Our immune system has evolved to control pathogens and so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections in earlier life. However, this may have a deleterious effect on cardiovascular and other inflammatory diseases in later life, such that cardiovascular diseases are a late consequence of an evolutionary beneficial pro-inflammatory response programmed to resist infections in earlier life. Genetic polymorphisms responsible for a low inflammatory response might result in an increased chance of a long life-span in an environment with a reduced antigen (i.e., pathogens) load, such as a modern day healthy environment and may also permit a lower grade survivable inflammatory response to atherogenesis and atherosclerosis-related disease. Here, we review the available data in the literature on inflammatory gene polymorphisms in successful and unsuccessful ageing.