Andrea Flex

A Variant Associated with Nicotine Dependence, Lung Cancer and Peripheral Arterial Disease

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene–environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 × 10−12) and intracranial aneurysm (OR = 1.29, P = 2.5 × 10−6), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Proinflammatory Genetic Profiles in Subjects With History of Ischemic Stroke

Background and Purpose— Proinflammatory genetic profiles, resulting from the combination of single nucleotide polymorphisms in genes encoding inflammatory molecules, may contribute to the development and progression of cardiovascular diseases. We evaluated the association between history of ischemic stroke and genetic profiles determined by the synergistic effects of polymorphisms in genes encoding prototypical inflammatory proteins. Methods— The study included 237 individuals with history of ischemic stroke and 223 age-matched and gender-matched controls. The polymorphisms of the C-reactive protein (CRP), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin (E-sel), and matrix metalloproteinase-3 (MMP-3) genes were studied. Results— IL-6 GG, IL-6 GC, MCP-1 GG, ICAM-1 EE, E-sel AA, and MMP-3 5A5A genotypes were significantly and independently associated with stroke history. The odds of stroke increased with the number of high-risk genotypes: carrying 1 proinflammatory gene variant conferred a risk of 3.3 (1.6 to 6.9), whereas individuals concomitantly carrying 2 and 3 proinflammatory gene variants had adjusted odds ratios of 21.0 (7.6 to 57.5) and 50.3 (10.2 to 248.1), respectively. Conclusions— Proinflammatory genetic profiles are significantly more common in subjects with stroke history. Synergistic effects between proinflammatory genotypes might be potential markers for cerebrovascular diseases.

Synergistic Effect of −174 G/C Polymorphism of the Interleukin-6 Gene Promoter and 469 E/K Polymorphism of the Intercellular Adhesion Molecule-1 Gene in Italian Patients With History of Ischemic Stroke

Background and Purpose— Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) are involved in the pathogenetic mechanisms responsible for several ischemic cardiovascular disorders, including cerebral ischemia. IL-6 and ICAM-1 plasma levels and/or function may be genetically influenced. We sought to evaluate distribution and reciprocal interaction of IL-6 G/C gene promoter polymorphism and ICAM-1 E/K gene polymorphism in Italian patients with history of ischemic stroke. Methods— One hundred nineteen patients with history of ischemic stroke and 133 age- and sex-matched controls were studied. IL-6 and ICAM-1 genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis. Results— The GG genotype of −174 IL-6 G/C gene polymorphism was significantly associated with history of ischemic stroke at both univariate (P <0.0001) and multivariate analysis (odds ratio [OR], 8.6;P <0.0001). Additionally, the EE genotype of ICAM-1 E/K gene polymorphism was significantly more common in the group of patients with history of ischemic stroke (P =0.003) and was an independent variable associated with stroke history (OR, 4.0;P =0.002). Interestingly, a further increased risk of stroke was found in subjects who concomitantly carry the IL-6 GG and ICAM-1 EE genotypes (IL-6 GG/ICAM-1 EE double-homozygous subjects) (OR, 10.1;P =0.004). Conclusions— There is a synergistic effect of IL-6 G/C and ICAM-1 E/K gene polymorphisms in patients with stroke history. Reciprocal interactions between genotypes may contribute in determining the risk profile for cardiovascular diseases and may merit further investigation as potential therapeutic targets.

Age-dependent VEGF expression and intraneural neovascularization during regeneration of peripheral nerves

The physiologic ability of peripheral nerves to regenerate after injury is impaired with aging. However, the mechanisms responsible for this phenomenon are still incompletely characterized. In this study, we investigated whether aging influences the intraneural angiogenic response that occurs after injury and during regeneration of peripheral nerves. We performed a crush injury of the sciatic nerve in old and senescence accelerated mice and found that the peripheral nerves of these animals are unable to locally upregulate vascular endothelial growth factor (VEGF), a prototypical angiogenic cytokine, after injury and have substantial deficits in mounting an appropriate intraneural angiogenic response during nerve regeneration. Our findings provide new evidence of possible interdependent relationships between aging, VEGF, angiogenesis, and nerve regeneration and suggest that vascular abnormalities might play a role in aging-associated neurological dysfunction, with potentially important fundamental and clinical implications.

Monocyte chemoattractant protein-1 (MCP-1) gene polymorphism and risk of Alzheimer's disease in Italians.

Monocyte chemoattractant protein-1 (MCP-1) is a key molecule for monocyte chemotaxis and tissue extravasation and for the modulation of leukocyte function during inflammation. Upregulation of MCP-1 may occur in the brain of subjects affected by Alzheimers disease (AD) and MCP-1 levels in plasma and cerebrospinal fluid have been proposed as biological markers for the inflammatory process that accompanies AD pathogenesis. Importantly, serum levels and biological activity of MCP-1 protein are strongly influenced by a single nucleotide polymorphism occurring at position -2518 of the MCP-1 gene promoter. A recent study has investigated the possible association between this gene polymorphism and AD in a Spanish population, with negative results. Here, we performed a case-control study to test whether the risk for AD might be influenced by the -2518 A/G polymorphism of the MCP-1 gene in an ethnically homogeneous Italian population. The GG genotype and the G allele of the MCP-1 gene polymorphism were significantly more common in the AD group than in control individuals (P<0.0001) A logistic regression analysis indicated that the GG genotype was an independent risk factor for AD in our population. This effect was not influenced by the presence of the APOE 4 high-risk allele, nor by the presence of other gene variations associated with a pro-inflammatory phenotype. These findings indicate that the -2518 A/G polymorphism of the MCP-1 gene is associated with AD in Italians and confirm that inflammatory gene variations may be important contributors in the development and progression of neurodegenerative disorders.

−174 G/C interleukin-6 gene polymorphism and increased risk of multi-infarct dementia: a case-control study

The aim of this study was to evaluate the association between the -174 G/C polymorphism of interleukin-6 (IL-6) gene promoter and multi-infarct dementia (MID). We studied a group of 122 patients affected by MID and 134 age- and sex-matched controls and evaluated classical risk factors for MID, as well as the distribution of IL-6 alleles and genotypes by polymerase chain reaction and restriction enzyme analysis. The distribution of IL-6 genotypes was 63 GG, 47 GC, 12 CC in patients with MID and 29 GG, 58 GC, 47 CC in control subjects. The GG genotype was significantly more common in the MID group (P<0.0001), while the CC genotype was more common in control patients (P<0.0001). Logistic regression analysis indicated that the presence of GG genotype significantly increases the risk of MID (odds ratio 9.1 [3.1-26.1], P<0.0001). This study indicates a strong association between the -174 G/C polymorphism of the IL-6 gene and MID. Our data support the hypothesis that IL-6 and inflammatory mechanisms are important in the pathophysiology of the vascular changes responsible for cognitive deterioration.

The -174 G/C polymorphism of the interleukin-6 gene promoter and essential hypertension in an elderly Italian population.

Several studies have proposed a relationship between blood pressure and inflammation. Interleukin-6 (IL-6) is a multifunctional cytokine involved in inflammation and tissue injury and potentially influencing blood pressure. Recently, a common polymorphism of the IL-6 gene, associated with differences in the transcription rate of the protein, has been described. The aim of this study was to investigate a possible association between genetic variations of the −174GC polymorphism of the IL-6 gene promoter and hypertension in humans. IL-6 gene promoter polymorphism was evaluated by polymerase chain reaction followed by restriction enzyme analysis in 210 elderly Italian patients affected by essential hypertension (EH) and 177 age- and sex-matched controls. The distribution of IL-6 genotypes was 85 GG, 88 GC, 37 CC in the hypertensive patients and 65 GG, 73 GC, 39 CC in the control subjects. In this elderly cohort, no statistically significant association was found between the two groups (P = 0.45 for GG homozygous, P = 0.89 for GC heterozygous and P = 0.27 for CC homozygous). In conclusion the −174 GC polymorphism of the IL-6 gene promoter is not a marker for EH in this sample of elderly Italians.

Intercellular adhesion molecule-1 K469E gene polymorphism and Alzheimer's disease.

Inflammatory processes are considered important in the pathogenesis of Alzheimers disease (AD). Intercellular adhesion molecule-1 (ICAM-1) is an important mediator of inflammatory response and immune cell activation, is expressed on cerebrovascular endothelium and neuritic plaques in brain of AD patients, and seems to be implicated in the process of neuro-degeneration. A common polymorphism of the ICAM-1 gene (K469E) has been recently reported. In this case-control study, we evaluated the distribution of E/K alleles and genotypes of the ICAM-1 gene in 98 patients affected by sporadic AD and 115 age- and sex-matched controls. The frequency of the EE genotype was significantly higher in AD patients (P<0.01). Logistic regression analysis indicated that the presence of EE genotype significantly increased the risk of AD (odds ratio 3.01 [1.1-8.0], P<0.05). This study shows for the first time an association between ICAM-1 E/K gene polymorphism and AD, suggesting that polymorphisms of the ICAM-1 gene may be clinically important and confirming that inflammatory mechanisms may be crucial in the pathophysiology of neuro-degenerative diseases.

Endothelial dysfunction but not increased carotid intima-media thickness in young European women with endometriosis.

BACKGROUNDnAtherosclerosis is a chronic and degenerative disease developing typically in the elderly; nonetheless, a condition of accelerated atherosclerosis can be observed precociously in the presence of some diseases. Endometriosis, a chronic benign gynecological disorder, shows some characteristics, such as oxidative stress, systemic inflammation and a pro-atherogenic lipid profile, which could increase the risk of developing accelerated atherosclerosis. The aim of our study was to evaluate markers of subclinical atherosclerosis in young European women with endometriosis.nnnMETHODSnThis cross-sectional study included 37 women with endometriosis and 31 control subjects. The presence of subclinical atherosclerosis was investigated by ultrasound evaluation of common carotid intima-media thickness (ccIMT) and flow-mediated dilation (FMD); in addition, serum levels of lipids, inflammatory and coagulation parameters, as well as markers of endothelial inflammation and activation, were determined.nnnRESULTSnWomen with endometriosis showed significantly lower values of FMD compared with controls [mean difference: -4.62, 95% confidence interval (CI): -6.52, -2.73; P < 0.001], whereas no significant differences in ccIMT values were found between the two groups. As regards markers of endothelial inflammation and activation, women with endometriosis had significantly higher values of inter-cellular adhesion molecule 1 (P < 0.001), vascular cell adhesion molecule 1 (P < 0.001), E-selectin (P < 0.001), von Willebrand factor (P = 0.004) and ristocetin cofactor (P = 0.001) compared with controls.nnnCONCLUSIONSnOur study suggests that women with endometriosis have more subclinical atherosclerosis, resulting in a higher risk of developing cardiovascular disorders. Moreover, our findings demonstrate that endothelial dysfunction can occur in the absence of structural atherosclerotic changes; its evaluation might be helpful in young women with endometriosis.