LMX1B Locus Associated with Low-Risk Baseline Glaucomatous Features in the POAAGG Study

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and has been associated with multiple genetic risk factors. The LMX1B gene is a genetic susceptibility factor for POAG, and several single-nucleotide polymorphisms (SNPs) were shown to be associated with POAG in our own prior Primary Open-Angle African American Glaucoma Genetics (POAAGG) study genome-wide association study (GWAS). This study evaluated the association of the LMX1B locus with baseline optic disc and clinical phenotypic characteristics of glaucoma patients from our African American cohort. Compared to the GG genotype in SNP rs187699205, the GC genotype in this SNP was found to be significantly associated with a smaller cup-to-disc ratio (CDR) and increased (better) visual field mean deviation (MD) in glaucoma cases. None of the glaucoma cases with the GC genotype had disc hemorrhages, disc notching, or beanpot disc appearance. In conclusion, glaucoma phenotypes differed significantly by LMX1B variant in African American patients with POAG, and a SNP variant was associated with certain disease features considered lower risk.

Anthracycline-Induced Cardiotoxicity: The Role of Endothelial Dysfunction

Cardiovascular disease remains the leading cause of mortality accounting up to 40% of all deaths, but, currently, cancer is prominent cause of death globally. Anthracyclines are the cornerstone of chemotherapy in women with breast cancer. However, its clinical use is limited by their cardiotoxic effects that can trigger heart failure development. Vascular toxicity of chemotherapy may be linked with endothelial dysfunction because anthracycline damage of endothelial cells can lead to the development and progression of cardiomyopathy by decreasing the release and activity of endothelial factors and, ultimately, endothelial cell death. These processes suppress anti-inflammatory and vascular reparative functions and initiate the development of future cardiovascular events. Recent studies have shown that chemotherapy may induce toxicity in the vascular endothelium and is accompanied by systemic endothelial dysfunction in patients with diagnosed cardiovascular diseases. Because the initial endothelial cell insult is likely asymptomatic, there is often a long delay between the termination of doxorubicin therapy and the onset of vascular disorders. In this case, genetic susceptibility factor will help to identify susceptible patients in the future. The objectives of this study were to evaluate prognostic role of molecular (endothelin-1) and genetic factors (gene polymorphisms of endothelial nitric oxide (NO) synthase (NOS3, rs1799983), endothelin-1 receptor type A (EDNRA, C+70G, rs5335) and NADPH oxidase (C242T, rs4673) in development of endothelial dysfunction and anthracycline-induced cardiotoxicity in women without cardiovascular diseases.

SCUBE3 Is Likely a Susceptibility Gene for Systemic Lupus Erythematosus for Chinese Populations

Background. Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic disposition with more than 100 susceptibility genes identified until now. However, our knowledge on SLE genetic background is still limited. The present study was aimed at evaluating the role of single nucleotide polymorphisms (SNPs) in SCUBE3, a TGF-β signaling activator, with SLE susceptibility in Chinese populations. Methods. A total of 2801 individuals (490 cases and 493 controls from GWAS cohort and 1003 cases and 815 controls from our cohort) were enrolled, and SNPs located 10 kb up- and downstream of SCUBE3 (chr6:35182190-35218609) were included in the genetic association study. Multiple layers of bioinformatics were conducted, and the levels of SCUBE3 expression were confirmed. Results. Of the 31 SNPs in SCUBE3 tested, 24 SNPs were significantly associated with SLE at p ≤ 0.05 . The top locus was rs1888822 with p = 8.74 ∗ 10 − 6 in the discovery cohort and was confirmed by the replication cohort with p = 0.012 . Additionally, the levels of SCUBE3 mRNA expression were significantly lower in patients with SLE comparing with healthy controls ( p = 4.28 ∗ 10 − 4 ). Further expression data from ArrayExpress showed that the expression of SCUBE3 was also lower in CD3+ T cells and B cells from patients with SLE. Conclusions. Our research revealed that variants in SCUBE3, which encode SCUBE3 as a TGF-β signaling activator, can be considered as a new genetic susceptibility factor for systemic lupus erythematosus. And the reduced mRNA expression of SCUBE3 was first reported in patients with SLE.

Environment as a Potential Key Determinant of the Continued Increase of Prostate Cancer Incidence in Martinique

Prostate cancer incidence is steadily increasing in many developed countries. Because insular populations present unique ethnic, geographical, and environmental characteristics, we analyzed the evolution of prostate cancer age-adjusted world standardized incidence rates in Martinique in comparison with that of metropolitan France. We also compared prostate cancer incidence rates, and lifestyle-related and socioeconomic markers such as life expectancy, dietary energy, and fat supply and consumption, with those in other Caribbean islands, France, UK, Sweden, and USA. The incidence rate of prostate cancer in Martinique is one of the highest reported worldwide; it is continuously growing since 1985 in an exponential mode, and despite a similar screening detection process and lifestyle-related behaviour, it is constantly at a higher level than in metropolitan France. However, Caribbean populations that are genetically close to that of Martinique have generally much lower incidence of prostate cancer. We found no correlation between prostate cancer incidence rates, life expectancy, and diet westernization. Since the Caribbean African descent-associated genetic susceptibility factor would have remained constant during the 1980–2005, we suggest that in Martinique some environmental change including the intensive use of carcinogenic organochlorine pesticides might have occurred as key determinant of the persisting highly growing incidence of prostate cancer.

Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population

BackgroundTNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported.ObjectiveTo investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc).MethodsThree single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel–Haenszel meta-analysis.ResultsThe rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10−7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10−8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10−9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10−6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10−5).ConclusionThese results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.

The C677T Polymorphism inMTHFRIs Not Associated with Migraine in Portugal

Migraine is a debilitating disorder affecting a large proportion of the population. The effect of methylenetrathydrofolate reductase (GeneID: 4524) polymorphisms in migraine etiology and development has been a theme of great interest. Several populations were evaluated with contradictory results. In this case-control study, we investigated the effect of the C677T polymorphism inMTHFR, as a genetic risk factor for migraine, in the Portuguese population. We observed that, overall, there was no significant difference in the frequencies ofMTHFRC677T genotypes or of the T-allele among the Portuguese migraineurs when compared to controls. There was also no association of migraine with aura withMTHFRgenotypes or with the T-allele, in contrast with previous studies. Regarding the risk of the T-allele homozygote carriers, there was an equal probability to develop migraine with aura over migraine without aura in our patients. Thus, we conclude that the C677TMTHFRpolymorphism, responsible for a reduction of the MTHFR activity in folate metabolism, is not a major genetic susceptibility factor for migraine in the Portuguese population.

Impact of αENaC Polymorphisms on the Risk of Ischemic Cerebrovascular Events: A Multicenter Case–Control Study

Background: Amiloride-sensitive epithelial sodium channels (ENaCs) are important candidates in the development of hypertension, which is a major risk factor for stroke. Two single-nucleotide polymorphisms (SNPs) in the gene that encodes the ENac α-subunit (αENaC) have been identified. We evaluated those SNPs for a possible association with ischemic cerebrovascular events (ICEs). Methods and Results: We genotyped 1399 patients with ICEs [median age, 70 years; interquartile range, 58–78 years; 745 (53%) men] and 1076 control individuals without vascular disease [47 (39–58) years; 557 (52%) men] for the SNPs Trp493Arg and Ala663Thr. The SNP frequencies at nucleotide 3977 (Trp493Arg) in the αENaC gene were significantly different in patients and controls. Carriers of 493Arg had a 1.78-fold increased risk (95% confidence interval, 1.02–3.12) for ICEs compared with Trp/Trp carriers. Interaction analysis revealed that the relative risk was even higher in women in the lowest age tertile [adjusted odds ratio, 3.26 (1.10–9.72)]. Conclusions: Carriers of the 493Arg allele are at increased risk for ICEs compared with Trp/Trp carriers. The effect is independent of traditional vascular risk factors and is particularly evident in younger women. The Trp493Arg variant in αENaC may represent an important candidate genetic susceptibility factor in the development of ICEs.