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Background: The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography., Methods and Results: MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09-1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07-1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality., Conclusions: MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background: DNA repair mechanisms play a major role in cancer risk and progression. Germline variants in DNA repair genes may result in altered gene function and/or activity, thereby causing inter-individual differences in a patient's tumor recurrence capacity. In genes of the DNA repair pathway the gene variants RAD51 rs1801320 G>C, XRCC2 rs3218536 G>A and XPD rs13181 A>C have been previously related to genetic predisposition and prognosis of various cancer entities. In this study we investigated the association between these polymorphisms and time to recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients after curative surgery., Methods: Two hundred sixty STS patients were included in this retrospective study. Germline DNA was genotyped by 5'-exonuclease (TaqMan) technology. Kaplan Meier curves and multivariate Cox proportional models were calculated for TTR and OS., Results: A statistically significant association was observed between tumor grade and adjuvant radiotherapy and TTR and between tumor grade and OS. No association was found between RAD51 rs1801320 G>C, XRCC2 rs3218536 G>A and XPD rs13181 A>C and TTR and OS in univariate and multivariate analysis., Conclusion: Our results underline a prognostic effect of tumor grade and adjuvant radiotherapy in STS patients but indicate no association between RAD51 rs1801320 G>C, XRCC2 rs3218536 G>A and XPD rs13181 A>C and clinical outcome in STS patients after curative surgery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: Genetic aberrations of DNA repair enzymes are known to be common events and to be associated with different cancer entities. Aim of the following study was to analyze the genetic association of single nucleotide polymorphisms (SNP) of the DNA repair genes with the risk of squamous cell carcinoma of the head and neck (HNSCC)., Materials and Methods: Genetic variants ERCC2 Lys751Gln (rs13181), ERCC2 Asp312Asn (rs1799793), XRCC1 Arg194Trp (rs1799782); XRCC1 Gln399Arg (rs25487), XRCC1 Arg280His (rs25489) and XRCC3 Thr241Met (rs861539) were analyzed in a primary study group comprising 169 patients with histologically confirmed HNSCC and 463 healthy control subjects. Polymorphisms associated with HNSCC were furthermore analyzed in an independent replication study including 125 HNSCC., Results: Only the ERCC2 751 Gln/Gln genotype was associated with HNSCC in the primary study (p=0.033) and in the replication study (p=0.023), resulting in an overall odds ratio of 0.54 (95% confidence interval 0.35-0.92; p=0.006)., Conclusion: Carriers of the homozygous ERCC2 751 Gln/Gln genotype may be at lower risk for HNSCC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Central retinal vein occlusion (CRVO) is a vision-threatening disease, primarily occurring among patients aged more than 60 years. Several risk factors, including arterial hypertension and diabetes mellitus, have been identified. Compression of the central retinal vein by an atherosclerotic retinal artery at the lamina cribrosa also has been implicated in the pathogenesis of the disease. Functional gene polymorphisms of cytokines or chemokines previously shown to affect atherogenesis or hemostasis are potential risk factors for CRVO. The present study investigates a hypothesized association between inflammation-related gene polymorphisms and the presence of CRVO in a relatively large cohort of patients., Design: Case-control study., Participants: The study group consisted of 315 patients with CRVO and 335 control subjects., Methods: Determination of genotypes was done by 5' exonuclease assay (TaqMan)., Main Outcome Measures: Genotypes of interleukin (IL)1β -511C>T, IL1 receptor antagonist (IL1RN) 1018T>C, IL4 -584C>T, IL6 -174G>C, IL10 -592C>A, IL18 183A>G, tumor necrosis factor (TNF)-α -308G>A, monocyte chemoattractant protein (MCP)-1/CCL2 -2518A>G, IL8 -251A>T, and RANTES (CCL5) -403G>A polymorphisms., Results: Genotype distributions and allele frequencies of the investigated gene polymorphisms did not significantly differ between both groups (P>0.05). Arterial hypertension, diabetes mellitus, and cigarette smoking were significantly more frequent in patients with CRVO than among control subjects (arterial hypertension: 67.0% vs. 52.2%, P<0.001; diabetes mellitus: 16.8% vs. 6.3%, P<0.001, cigarette smoking: 32.1% vs. 23.6%, P = 0.02). In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 1.75 (95% confidence interval [CI], 1.26-2.44) in those with CRVO, whereas an OR of 2.52 (95% CI, 1.46-4.35) was found in those with diabetes mellitus. A history of cigarette smoking was associated with an OR of 1.57 (95% CI, 1.09 - 2.25) for CRVO., Conclusions: Our data suggest that the investigated inflammation-related gene polymorphisms are unlikely major risk factors for CRVO., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

C-reactive protein (CRP) has been implicated in the development of atherosclerosis. The genetic polymorphism of apolipoprotein (apo) E is associated with the concentration of CRP. We analyzed the association between the apo E genotype, CRP and angiographic coronary artery disease (CAD). The concentration of CRP was similar in patients with stable CAD and in controls, but increased in patients presenting with acute coronary syndromes. In models adjusting for the main confounding variables, the alleles ɛ4 and ɛ2 were associated with decreased and increased concentrations of CRP, respectively, compared to the wild-type allele ɛ3. In spite of this, the ɛ2 allele was associated with a lower prevalence of angiographic CAD, while the slight over-representation of the ɛ4 allele was statistically not significant. We conclude that the apo E genotype is associated with circulating CRP. A causal role of CRP in the development of CAD would be supported if genotypes that raise CRP in the long-term were themselves associated with CAD. As we found the opposite, we suggest that the association between CRP and cardiovascular events reflects confounding and reverse causation., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: The rs599839 polymorphism A/G in the vicinity of the sortilin 1 gene has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to further characterize the protective effect of the minor allele by analyzing the association with a variety of quantitative traits., Methods: Association of rs599839 with plasma levels of different parameters of LDL and triglyceride (TRIG) metabolism as well as the risk of CAD was tested in the LURIC study cohort., Results: Compared to AA homozygotes, the levels of LDL-C, low density lipoprotein triglycerides (LDL-TRIG) and apolipoprotein B were decreased in carriers of at least one G-allele. The G-allele was also associated with an increasing radius of the LDL particles. Regarding TRIG metabolism we observed a significant decrease in the level of triglycerides for homozygous carriers of the G-allele as well as decreased levels of free fatty acids (FFA), free glycerol and free cholesterol. With each G-allele the prevalence of CAD (multivariate OR 0.806; 95% CI: 0.692-0.940, P=0.006) decreased significantly whereas we observed only a marginal decrease for MI which did not reach significance. For GG homozygotes, the OR for CAD was 0.588 (95% CI: 0.394-0.877; P=0.009) and the OR for previous myocardial infarction (MI) was 0.693 (95% CI: 0.490-0.980; P=0.038). These associations were independent of cardiovascular risk factors., Conclusion: In the LURIC Study the G-allele of rs599839 is associated with LDL and TRIG metabolism and the risk of coronary artery disease and myocardial infarction., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Changes in the balance of cholesterol absorption and synthesis and moderately elevated plasma plant sterols have been suggested to be atherogenic. Measuring cholestanol, lathosterol, campesterol, and sitosterol, we investigated the relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease (CAD) in 2,440 participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. The coronary status was determined by angiography, and the severity of CAD was assessed by the Friesinger Score (FS). An increase in the ratio of cholestanol to cholesterol was associated with high FS (P = 0.006). In contrast, a high ratio of lathosterol to cholesterol went in parallel with low FS (P < 0.001). Whereas the campesterol to cholesterol ratio significantly correlated with the FS (P = 0.026), the relationship of the sitosterol to cholesterol ratio with the FS did not reach statistical significance in the whole group. Increased campesterol, sitosterol, and cholestanol to lathosterol ratios were associated high FS (P < 0.001). To conclude, there is a modest association of high cholesterol absorption and low cholesterol synthesis with an increased severity of CAD. An atherogenic role of plasma plant sterols themselves, however, seems unlikely in subjects without sitosterolaemia.

Background: There is increasing evidence that lipoprotein-associated phospholipase A2 (LpPLA2) is associated with cardiovascular disease. However, it is still unclear whether LpPLA2 is simply a marker or has a causal role as either a pro- or anti-atherogenic factor., Methods: We analyzed the association of five polymorphisms (-1357G>A, -403T>C, Arg92His, Ile198Thr, Ala379Val) and related haplotypes at the PLA2G7 locus with angiographic coronary artery disease (CAD), plasma LpPLA2 activity, and long-term survival in 3234 patients scheduled for coronary angiography., Results: The promoter variant -403C and His(92) were associated with a decrease and Val(379) with an increase in plasma LpPLA2 activity. Both coding variants revealed a clear gene-dose effect. Interestingly, the rare Thr(198) allele, which was not associated with any change in plasma LpPLA2 activity, was more frequent in subjects without CAD (P = 0.009), with an adjusted odds ratio for CAD of 0.69 (95% CI: 0.49-0.96; P = 0.029). None of the analyzed variants showed any robust association with all-cause or cardiovascular mortality., Conclusion: Irrespective of the significant association between some variants with plasma LpPLA2 activity, it is still unclear whether these polymorphisms or haplotypes are associated with the risk and outcome of cardiovascular disease in Caucasians.

A common 825C>T polymorphism in exon 10 of the gene for the beta-3 subunit of heterotrimeric G-proteins, GNB3, has been associated in some studies with traits of the metabolic syndrome as well as coronary artery disease (CAD), but these associations were refuted by other studies. To investigate the role of GNB3 gene variations in CAD and myocardial infarction (MI), we determined five GNB3 polymorphisms (-1429G>A, IVS5 +41G>A, 657T>A, 814G>A and 825C>T) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, including 2575 patients with angiographically documented CAD and 731 individuals in whom CAD had been ruled out by angiography. None of the GNB3 polymorphisms was associated with CAD, MI, diabetes, hypertension, blood pressure, body weight or body mass index. We conclude that a major contribution of GNB3 gene variants to CAD or MI risk is unlikely.

Objective: Exudative age-related macular degeneration (AMD) is a common cause for a severe central visual loss. The complement system has been implicated in the pathogenesis of drusen. Recently, a complement factor H (CFH) polymorphism, which is characterized by a tyrosine (Y)-to-histidine (H) exchange at position 402 of the CFH gene, has been suggested as a major risk factor for AMD in a North American population. The aim of the present study was to investigate a hypothesized association between the CFH Y402H polymorphism and the presence of exudative AMD in a Central European population of Caucasoid descent as well as to determine the genotype distribution among different types of exudative AMD., Design: Retrospective case-control study., Participants: The study cohort consisted of 179 patients with exudative AMD and 163 controls., Methods: Determination of genotypes was carried out by allele-specific digestion of polymerase chain reaction products., Main Outcome Measures: Genotypes of CFH Y402H polymorphism., Results: The prevalence of the CFH 402HH genotype was significantly higher in patients with exudative AMD than among controls (35.2% vs. 8.6%; P<0.001). Homozygosity for the CFH Y402H polymorphism was associated with an odds ratio of 5.78 (95% confidence interval, 3.09-10.83) for exudative AMD. Subgroup analysis revealed that the CFH 402HH genotype was significantly more prevalent in eyes with predominantly classic with no occult choroidal neovascularization (CNV) than in those with either retinal angiomatous proliferation, occult with no classic CNV, or predominantly classic with occult CNV., Conclusion: Our data suggest that the CFH Y402H polymorphism is a major risk factor for exudative AMD in a Central European population.

Purpose: The existence of genetic variations in a number of cytokines has been considered to influence susceptibility or relate to disease severity in various autoimmune diseases. Among these, single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF-alpha) promoter at nucleotides -308 and -238 are considered to be protective against inflammation in HLA-B27-positive individuals, whereas the SNP at position -857 has been associated with disease development in anterior uveitis. We investigate a hypothesized association between the TNF-alpha -857 C-to-T, -308 G-to-A, and the TNF-alpha -238 G-to-A SNPs and the presence of HLA-B27-associated uveitis., Design: Retrospective case-control study., Participants: One hundred fourteen Caucasian patients with HLA-B27-associated uveitis were studied. Mean age of patients was 44.9+/-14 years (range, 16-81), and mean duration of HLA-B27-associated uveitis was 115.6+/-104 months (range, 6 months-51 years). Eighty-six patients (75.4%) suffered from an additional systemic manifestation of the disease. Sixty-three unrelated healthy HLA-B27-positive blood donors and 88 unrelated healthy HLA-B27-negative individuals served as controls., Methods: Genotypes were determined by polymerase chain reaction., Main Outcome Parameters: Association of genotypes at positions -857, -308, and -238 of the TNF-alpha gene with disease development., Results: Frequencies of the TNF-alpha -308GA and TNF-alpha -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative control group, 23% at -308 (P = 0.003), and 7.9% at -238 (P = 0.0003). When compared with healthy HLA-B27-positive controls, a significantly lower frequency of the TNF-alpha -238GA genotype was found among patients (6.3%, P = 0.015). The frequency of the TNF-alpha -308GA genotype was also found to be lower in patients than among HLA-B27-positive control subjects, without, however, reaching statistical significance (6.1%, P = 0.07). No difference in frequencies was seen among the different groups for the SNPs at position -857., Conclusion: Our data suggest that HLA-B27-positive individuals show a higher susceptibility towards development of an intraocular inflammation in the presence of an A allele at nucleotide -238 and, to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.

Objective: Branch retinal vein occlusion (BRVO) is a common cause of severe visual loss. Numerous risk factors, including arterial hypertension, diabetes mellitus, and arteriosclerosis, have been identified. Gene polymorphisms affecting hemostasis may also play a role in the pathogenesis of BRVO. The present study was therefore done to determine the prevalence of genetic polymorphisms in factors implicated in hypercoagulability among patients with BRVO., Design: Retrospective case-control study., Participants: The study cohort consisted of 294 patients with BRVO and 294 control subjects, matched for age and gender., Methods: Determination of genotypes was done by allele-specific digestion of polymerase chain reaction products, or by 5' exonuclease assay (TaqMan)., Main Outcome Parameters: Genotypes of factor V R506Q (factor V Leiden), prothrombin 20210G>A, fibrinogen beta -455G> A, factor XII (FXII) 46C>T, and ITGA2 807C>T (platelet glycoprotein Ia [GPIa] 807C>T) and ITGB3 L59P (platelet GPIIIa PlA1/PlA2) polymorphisms., Results: Genotype distributions of the investigated gene polymorphisms did not differ significantly between patients and control subjects. In contrast, significantly increased prevalences of arterial hypertension and hypercholesterolemia were found among patients with BRVO. In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 2.32 (95% confidence interval [CI], 1.62-3.32), whereas hypercholesterolemia yielded an OR of 2.54 (95% CI, 1.74-3.70) for BRVO., Conclusion: Our data indicate that the prevalences of the investigated gene polymorphisms do not differ significantly in patients with BRVO and control subjects. This suggests that these polymorphisms are not major risk factors for BRVO.

The granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for proliferation and differentiation of myeloid progenitor cells. Here we report on the identification of a rare single nucleotide polymorphism within its intracellular domain (G-CSF-R&#95;Glu785Lys). Screening a cohort of 116 patients with primary myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML) (84 patients), as well as 232 age- and sex-matched controls revealed a highly significant association of the G-CSF-R&#95;785Lys allele with the development of high-risk MDS as defined by more than 5% bone marrow blasts (9.7% versus 0.9% in controls; P = .001; odds ratio [OR], 12.5; 95% confidence interval [CI], 2.4-58.9) or an International Prognostic Scoring System score of intermediate-2 or high (13.0% versus 0.9%; P < .001; OR, 14.0; 95% CI, 3.4-85.0). Functional analysis by retroviral transfer of G-CSF-R&#95;785Lys into myeloid progenitor cells of G-CSF-R-deficient mice showed a significantly diminished colony-formation capacity after G-CSF stimulation as compared with cells transduced with the wild-type receptor. These results suggest that lifelong altered G-CSF response by the G-CSF-R&#95;785Lys may render individuals susceptible to development of high-risk MDS.

Objective: CX(3)CR1 is a novel chemokine receptor located on monocytes. Recently, two polymorphisms were linked to coronary artery disease (CAD), V249I and T280M. Carriers of at least one I-allele or one M-allele were found less frequently among patients with CAD compared to controls. The aim of the present study was to investigate the influence of these polymorphisms on the development of peripheral arterial disease (PAD)., Methods: 522 human subjects with documented PAD and 522 age and sex matched controls were genotyped by polymerase chain reaction followed by restriction digestion., Results: Adjusted odds ratio (OR) of carriers of the I-allele for PAD was 1.34 (95% confidential interval (CI) from 0.86 to 2.09; P=0.19). The OR associated with the M-allele for PAD was 0.65 (95% CI from 0.41 to 1.04; P=0.07), when tested in the same regression analysis with the V249I genotypes. The genotypes were not linked to age at onset or severity of the disease. A subgroup of 137 CAD patients of whom 131 could be genotyped and who did not differ in baseline parameters from the remaining PAD patients, showed VV-genotype in 52.0%, VI in 42.7% and II in 5.3% CAD (OR associated with the I-allele for CAD: 1.29; 95% CI: 0.66-2.51; P=0.46). The distribution of the T280M genotypes was 67.1, 29.8, 3.1% (TT, TM, MM) also showing no association with CAD (OR=0.77; 95% CI 0.36-1.46; P=0.37)., Conclusion: In this study we could not detect a difference in genotype frequencies of the V249I and T280M polymorphisms in CX(3)CR1 between PAD patients and controls. CAD concomitant with PAD was also not affected by the I- or the M-allele.

Background: An insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting-enzyme (ACE) is associated with ACE plasma levels and activity. Conflicting results have been reported about the relevance of this polymorphism for atherosclerotic vascular disease. The aim of the present study was to analyze the role of this polymorphism for peripheral arterial disease (PAD)., Methods: The study was designed as a case-control study including 522 patients with documented PAD and 522 sex- and age-matched controls. ACE genotype was determined by size-analysis of polymerase chain reaction products., Results: ACE genotype frequencies were similar between patients (II: 23.4%; ID: 44.8%; DD: 31.8%) and controls (II: 23.8%; ID: 48.3%; DD: 27.9%, P=0.37). The adjusted odds ratio of carriers of the DD genotype for PAD was 1.29 (95% confidence interval 0.95-1.75). The polymorphism was furthermore not associated with age at onset of PAD (P=0.56), Fontaine stage of the disease (P=0.68) or ankle/brachial index of patients (P=0.86)., Conclusion: The ACE I/D polymorphism is not a significant risk factor for PAD.

Objective: To determine whether hyperhomocyst(e)inemia and methylenetetrahydrofolate reductase (MTHFR) C677T mutation are associated with branch retinal vein occlusion (BRVO)., Design: Retrospective, case-control study., Participants: The study cohort consisted of 84 consecutive patients with branch retinal vein occlusion and 84 controls, matched for age and gender., Main Outcome Measures: Fasting plasma homocyst(e)ine, folate, and vitamin B(12) levels, MTHFR C677T genotypes., Results: Mean plasma homocyst(e)ine levels were significantly higher in patients than in controls (11.4 +/- 4.3 micromol/l vs. 9.9 +/- 2.8 micromol/l; P = 0.002). An increase of plasma homocyst(e)ine level by 1 micromol/l was associated with an odds ratio of 1.19 (95% confidence interval 1.06-1.34; P = 0.004). Mean plasma folate levels were significantly lower in patients than in the control group (4.5 +/- 2.1 ng/ml vs. 5.6 +/- 2.1 ng/ml; P = 0.007). The prevalence of the homozygous genotype of the MTHFR C677T mutation did not differ significantly between patients and controls., Conclusions: Our results suggest that hyperhomocyst(e)inemia, but not homozygosity for the MTHFR C677T mutation, is associated with BRVO. Increased plasma homocyst(e)ine levels in our study are not the result of an increased prevalence of the homozygous genotype of MTHFR C677T mutation.

Formation of reactive oxygen metabolites is vital for the microbicidal activity of phagocytes. As an unwanted side effect, these metabolites may contribute to oxidative stress in the vasculature and thus lead to arteriosclerosis. p22 phox, a component of the NADH/NADPH oxidase in phagocytes and vascular smooth muscle cells, is essential for production of reactive oxygen metabolites. Recently, a C/T polymorphism at position 242 of the p22 phox gene has been associated with coronary artery disease (CAD), suggesting a protective effect of the 242 T allele on the vasculature. In the present study, we analysed the relation of this polymorphism to peripheral arterial occlusive disease (PAOD). C242T polymorphism was determined by restriction fragment polymorphism (RFLP) analysis in 324 patients with documented PAOD and 295 control subjects without any known arterial disease. p22 phox 242 T allele frequencies and genotype distributions were not significantly different between patients and controls; the adjusted relative risk associated with the 242 T allele was 1.14 (95% CI 0.84-1.54, P=0.39), assuming an additive effect of the T allele. C242T polymorphism was not associated with the age of patients at the onset of the disease. Our data indicate that C242T polymorphism of the p22 phox gene is not associated with PAOD.