Differences in the genotype frequencies of genes related to blood pressure regulation-a comparative study between South-West Europe and Peri-equatorial Africa

Background: Since the emergence of the genus Homo, hominids have occupied a wide variety of environments, facing different selective pressures. Objectives: The aim this study is to compare genotype frequencies between South-West Europe and Peri-equatorial Africa in genes potentially modulators of blood pressure. Methods: The analyzed sample consisted of 325 individuals from Portugal and 226 individuals from Africa (48 from Mozambique and 178 from São Tomé and Príncipe). The following genetic variants were analyzed: intron 4 VNTR in eNOS, rs1050829 in G6PD, -3.7kb α-thalassemic deletion in HBA, rs1800457 in CYB5R3, Hp 1/2 genotype/phenotype in Hp and intron 16 I/D in ACE. Results: Frequencies of genotypes with the 4a allele in eNOS (p<0.001), the G allele in G6PD (p<0.001), the α-3.7 kb in HBA (p <0.001), the C allele in the CYB5R3 (p<0.001) were higher in Peri-equatorial Africa. The Hp 1.1 genotype of Hp has a higher frequency in Peri-equatorial Africa (p=0.002). ACE shows no significant differences. Conclusion: Results show differences in five genetic variants. Conditions of extreme heat and humidity, characteristic of Peri-equatorial Africa, have been associated with increased sodium loss. This study suggests that selected compensatory mechanisms printed in the genome, are nowadays risk factors for hypertension in Peri-equatorial Africa. Keywords: Blood pressure; genetics; Africa.

CFM6 is an Essential CRM Protein Required for the Splicing of nad5 Transcript in Arabidopsis Mitochondria

Plant CRM domain-containing proteins are capable of binding RNA to facilitate the splicing of group I or II introns in chloroplasts, but their functions in mitochondria are less clear. In the present study, Arabidopsis thaliana CFM6, a protein with a single CRM domain, was expressed in most plant tissues, particularly in flower tissues, and restricted to mitochondria. Mutation of CFM6 causes severe growth defects, including stunted growth, curled leaves, delayed embryogenesis, and pollen development. CFM6 functions specifically in the splicing of group II intron 4 of nad5, which encodes a subunit of mitochondrial complex I, as evidenced by the loss of nad5 intron 4 splicing and high accumulation of its pretranscripts in cfm6 mutants. The phenotypic and splicing defects of cfm6 were rescued in transgenic plants overexpressing 35S::CFM6-YFP. Splicing failure in cfm6 also led to the loss of complex I activity and to its improper assembly. Moreover, dysfunction of complex I induced the expression of proteins or genes involved in alternative respiratory pathways in cfm6. Collectively, CFM6, a previously uncharacterized CRM domain-containing protein, is specifically involved in the cis-splicing of nad5 intron 4 and plays a pivotal role in mitochondrial complex I biogenesis and normal plant growth.

A multicenter case–control study of the effect of e-nos VNTR polymorphism on upper gastrointestinal hemorrhage in NSAID users

Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case–control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): −1.35 (95% CI −5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: −2.68 (95% CI −6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype.

Endothelial nitric oxide synthase G894T, intron 4 VNTR, and T786C polymorphisms in retinopathy of prematurity

BACKGROUND: Our objective in this study was to assess the association between eNOS gene, that achieves synthesis of nitric oxide especially in the endothelial cells known to have an important role in angiogenesis and vasculogenesis, G894T, intron 4 VNTR (27-bp repeat) and T786C functional polymorphisms and retinopathy of prematurity (ROP), which is an important cause of morbidity in premature or low birth weight babies. METHODS: A total of 139 babies who were followed up in our neonatal intensive care unit because of premature birth in our hospital or admitted to our unit. 69 of them had retinopathy of prematurity and comprised the patients group. The remaining 70 babies who did not have ROP comprised the control group. An additional of 1 ml of blood samples were drawn from babies who were in the study groups during routine laboratory analysis. eNOS gene polymorphisms were determined by using polymerase chain reaction method. RESULTS: eNOS G894T, intron 4 VNTR and T786C gene polymorphisms did not differ between the patient and control groups (p > 0.05). Using logistic regression analysis; while gender did not differ between two groups; gestational age, birth weight, time on mechanical ventilation differ between two groups. After adjustment for variables other than eNOS gene polymorphisms, we found no significant difference in the genotype distribution of eNOS G894T, intron 4 VNTR and T786C polymorphisms (p > 0.05). CONCLUSION: We observed no association between ROP and eNOS gene polymorphisms but needs more investigation.

A duplicated amh is the master sex-determining gene for Sebastes rockfish in the Northwest Pacific

Teleost fish are the most diverse group of vertebrates and provide opportunities to study the evolution of sex determination (SD) systems. Using genomic and functional analyses, we identified a male-specific duplication of anti-Müllerian hormone ( amh ) gene as the male master sex-determining (MSD) gene in Sebastes schlegelii . By resequencing 10 males and 10 females, we characterized a 5 kb-long fragment in HiC_Scaffold_12 as a male-specific region, which contained an amh gene (named amhy ). We then demonstrated that amhy is a duplication of autosomal amh that was later translocated to the ancestral Y chromosome. amha and amhy shared high-nucleotide identity with the most significant difference being two insertions in intron 4 of amhy . Furthermore, amhy overexpression triggered female-to-male sex reversal in S. schlegelii , displaying its fundamental role in driving testis differentiation. We developed a PCR assay which successfully identified sexes in two species of northwest Pacific rockfish related to S. schlegelii . However, the PCR assay failed to distinguish the sexes in a separate clade of northeast Pacific rockfish. Our study provides new examples of amh as the MSD in fish and sheds light on the convergent evolution of amh duplication as the driving force of sex determination in different fish taxa.

Endothelial nitric oxide synthase polymorphism and venous thromboembolism: A meta-analysis of 9 studies involving 3993 subjects

Background Endothelial nitric oxide synthase (eNOS) polymorphism may influence the risk of venous thromboembolism (VTE). However, data from published studies with low statistical power are inconclusive. The present meta-analysis aimed to assess the relationship between eNOS polymorphism and the risk of VTE. Method Case-control studies evaluating the association between the eNOS polymorphism and VTE were searched in PubMed, Embase, Web of Science, Google Scholar, Wanfang, Chinese National Knowledge Infrastructure (CNKI), the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), and Chinese Biomedical Literature Database (CBM). Results A total of 1588 cases and 2405 controls from 9 studies were included in the analysis. The results showed that eNOS G894T polymorphism was related to VTE susceptibility and the difference was statistically significant [T vs G: OR = 1.41, 95% CI (1.13, 1.75), P = 0.002; TT + GG vs TG: OR = 0.71, 95% CI (0.60, 0.84), P = 0.000; TT + TG vs GG: OR = 1.45, 95% CI (1.23, 1.70), P = 0.000]. Additionally, eNOS Intron 4 VNTR polymorphism was related to VTE susceptibility and the difference was statistically significant [4b4b vs 4a4a + 4a4b: OR = 2.77, 95% CI (1.01, 7.61), P = 0.048]. Conclusion ENOS G894T and eNOS Intron 4 VNTR polymorphisms were associated with VTE susceptibility, especially in Asian populations. However, multicenter studies with larger samples should be conducted to further clarify this association and verify our findings.

CAG repeats and one polymorphism in androgen receptor gene are associated with renal calcium stone disease

Purpose: Evidence suggests that androgens can be involved in the pathogenesis of renal stones. This study aimed at investigating coding region polymorphisms and CAG repeats in androgen receptor (AR) and their association with active renal calcium stone disease. Materials and Methods: Male patients with calcium kidney stones ( N = 106) with at least two episodes of stone recurrence or size increase during the past 5 years (ASF) were enrolled from December 2008 to April 2009. Control individuals were recruited after matching for age and gender from healthy individuals without current stone or history of stone disease. Genetic sequencing and single strand conformational polymorphism (SSCP) were used to determine AR polymorphisms in the patients and controls. Results: Two polymorphisms were identified in the AR gene: Silent G to A polymorphism in the first exon of the AR gene and C to G polymorphism in intron 4. CAG repeats ranged from 12 to 37. The C/G polymorphism in intron 4 and CAG repeats were associated with the status of active renal calcium stone disease (all p < 0.05). The CC variant of C/G polymorphism was not observed in patients with stone disease. CAG repeats less than 20 and more than 28 were mostly observed in ASF patients ( p < 0.05). Conclusions: CAG repeats and intron 4 C/G polymorphism in the AR gene have an association with renal calcium stone disease.

Intron 4–5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4–5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (−) cases (21 vs 14, p = 0.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.