Tumor necrosis factor-alpha g308α gene polymorphism and essential hypertension: a meta-analysis involving 2244 participants

Background

The tumor necrosis factor-alpha (TNFα) G308A gene polymorphism has been implicated in susceptibility to essential hypertension (EH), but study results are still controversial.

Objective and Methods

The present meta-analysis is performed to investigate the relationship between the TNFα G308A gene polymorphism and EH. Electronic databases were searched and seven separate studies on the association of the TNF α G308A gene polymorphism with EH were analyzed. The meta-analysis involved 1092 EH patients and 1152 controls. The pooled odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated by a fixed or random effect model.

Results

A significant relationship between the TNFα G308A gene polymorphism and EH was found in an allelic genetic model (OR: 1.45, 95% CI: 1.17 to 1.80, P = 0.0008), a recessive genetic model (OR: 3.181, 95% CI: 1.204 to 8.408, P = 0.02), and a homozygote model (OR: 3.454, 95% CI: 1.286 to 9.278, P = 0.014). No significant association between them was detected in both a dominant genetic model (OR: 1.55, 95% CI: 0.99 to 2.42, P = 0.06) or a heterozygote genetic model (OR: 1.45, 95% CI: 0.90 to 2.33, P = 0.13).

Conclusion

The TNFα G308A gene polymorphism is associated with EH susceptibility.     

Test for positional candidate genes for body composition on pig chromosome 6

One QTL affecting backfat thickness (BF), intramuscular fat content (IMF) and eye muscle area (MA) was previously localized on porcine chromosome 6 in an F₂ cross between Iberian and Landrace pigs. This work was done to study the effect of two positional candidate genes on these traits: H-FABP and LEPR genes. The QTL mapping analysis was repeated with a regression method using genotypes for seven microsatellites and two PCR-RFLPs in the H-FABP and LEPR genes. H-FABP and LEPR genes were located at 85.4 and 107 cM respectively, by linkage analysis. The effects of the candidate gene polymorphisms were analyzed in two ways. When an animal model was fitted, both genes showed significant effects on fatness traits, the H-FABP polymorphism showed significant effects on IMF and MA, and the LEPR polymorphism on BF and IMF. But when the candidate gene effect was included in a QTL regression analysis these associations were not observed, suggesting that they must not be the causal mutations responsible for the effects found. Differences in the results of both analyses showed the inadequacy of the animal model approach for the evaluation of positional candidate genes in populations with linkage disequilibrium, when the probabilities of the parental origin of the QTL alleles are not included in the model.     

Functional Assessment of Human Coding Mutations Affecting Skin Pigmentation Using Zebrafish

A major challenge in personalized medicine is the lack of a standard way to define the functional significance of the numerous nonsynonymous, single nucleotide coding variants that are present in each human individual. To begin to address this problem, we have used pigmentation as a model polygenic trait, three common human polymorphisms thought to influence pigmentation, and the zebrafish as a model system. The approach is based on the rescue of embryonic zebrafish mutant phenotypes by “humanized” zebrafish orthologous mRNA. Two hypomorphic polymorphisms, L374F in SLC45A2, and A111T in SLC24A5, have been linked to lighter skin color in Europeans. The phenotypic effect of a second coding polymorphism in SLC45A2, E272K, is unclear. None of these polymorphisms had been tested in the context of a model organism. We have confirmed that zebrafish albino fish are mutant in slc45a2; wild-type slc45a2 mRNA rescued the albino mutant phenotype. Introduction of the L374F polymorphism into albino or the A111T polymorphism into slc24a5 (golden) abolished mRNA rescue of the respective mutant phenotypes, consistent with their known contributions to European skin color. In contrast, the E272K polymorphism had no effect on phenotypic rescue. The experimental conclusion that E272K is unlikely to affect pigmentation is consistent with a lack of correlation between this polymorphism and quantitatively measured skin color in 59 East Asian humans. A survey of mutations causing human oculocutaneous albinism yielded 257 missense mutations, 82% of which are theoretically testable in zebrafish. The developed approach may be extended to other model systems and may potentially contribute to our understanding the functional relationships between DNA sequence variation, human biology, and disease.     

Comparing Techniques for the Identification of the MTHFR A1298C Polymorphism

The restriction fragment length polymorphism (RFLP) technique with the MboII enzyme is used by a number of researchers as a methodology for the identification of the genetic polymorphism MTHFR A1298C. However, the reliability of this enzyme for genotyping this polymorphism has been questioned, since the silent polymorphism T1317C, located close to the polymorphic region A1298C on gene MTHFR, also has a recognition site for MboII. Thus, the fragments formed by the digestion of MboII present similar sizes, making it difficult to differentiate the allele MTHFR 1298A in the presence of the allele MTHFR 1317C. Hence, we investigated the A1298C polymorphism in a Brazilian population of renal transplant patients, using the RFLP technique with digestion by Mbo II and using sequencing, in order to examine the concordance between the two techniques. Our results showed an 8.6% difference in genotyping between RFLP and sequencing, but the statistical concordance test presented a kappa coefficient equal to 0.81 (CI 95% 0.74–88), which indicates a virtually perfect concordance, according to the criterion of Landis and Koch. Therefore, we concluded that the RFLP technique is concordant with automated sequencing in the detection of polymorphism A1298C under our laboratory conditions.     

Effective utilization of genetic information for athletes and coaches: focus on ACTN3 R577X polymorphism

Training variants (type, intensity, and duration of exercise) can be selected according to individual aims and fitness assessment. Recently, various methods of resistance and endurance training have been used for muscle hypertrophy and VO₂max improvement. Although several genetic variants are associated with elite athletic performance and muscle phenotypes, genetic background has not been used as variant for physical training. ACTN3 R577X is a well-studied genetic polymorphism. It is the only genotype associated with elite athletic performance in multiple cohorts. This association is strongly supported by mechanistic data from an Actn3-knockout mouse model. In this review, possible guidelines are discussed for effective utilization of ACTN3 R577X polymorphism for physical training.     

Endothelial Nitric Oxide Synthase Gene G894T Polymorphism and Myocardial Infarction: A Meta-Analysis of 34 Studies Involving 21068 Subjects

Background

Researches have revealed that the endothelial nitric oxide synthase (eNOS) gene G894T polymorphism is associated with the risk of Myocardial infarction (MI), but the results remain conflicting.

Objective and Methods

A meta-analysis was conducted to investigate the association between eNOS G894T polymorphism and MI. Published studies from PubMed, Embase, CNKI and CBM databases were retrieved. The pooled odds ratios (ORs) for the association between eNOS G894T polymorphism and MI and their corresponding 95% confidence intervals (CIs) were estimated using the random- or fixed- effect model.

Results

A total of 34 studies including 8229 cases and 12839 controls were identified for the meta-analysis. The eNOS G894T polymorphism was significantly associated with MI under a homozygous genetic model (OR = 1.41, 95% CI = 1.08–1.84; P = 0.012), a recessive genetic model (OR = 1.35, 95% CI = 1.06–1.70; P = 0.014), a dominant genetic model (OR = 1.18, 95% CI = 1.04–1.34; P = 0.009). In the subgroup analysis by ethnicity (non-Asian and Asian), no significant association was observed between eNOS G894T polymorphism and MI risk among non-Asians (P>0.05), but a positive significant association was found among Asians (P<0.05).

Conclusions

The eNOS G894T polymorphism is associated with increased MI risk in Asians. The results indicate that ethnicity plays important roles in the association between eNOS G894T polymorphism and MI.     

The pattern of polymorphism in Arabidopsis thaliana

We resequenced 876 short fragments in a sample of 96 individuals of Arabidopsis thaliana that included stock center accessions as well as a hierarchical sample from natural populations. Although A. thaliana is a selfing weed, the pattern of polymorphism in general agrees with what is expected for a widely distributed, sexually reproducing species. Linkage disequilibrium decays rapidly, within 50 kb. Variation is shared worldwide, although population structure and isolation by distance are evident. The data fail to fit standard neutral models in several ways. There is a genome-wide excess of rare alleles, at least partially due to selection. There is too much variation between genomic regions in the level of polymorphism. The local level of polymorphism is negatively correlated with gene density and positively correlated with segmental duplications. Because the data do not fit theoretical null distributions, attempts to infer natural selection from polymorphism data will require genome-wide surveys of polymorphism in order to identify anomalous regions. Despite this, our data support the utility of A. thaliana as a model for evolutionary functional genomics.     

Caspase8 rs1035142 G>T polymorphism was associated with an increased risk of esophageal cancer in a Chinese population

Esophageal cancer is one of the ten most common cancers in the world and has poor prognosis. Apoptosis is considered a fundamental component in cancer pathogenesis. We conducted a hospital-based case–control study to evaluate the genetic effects of 16 apoptosis associated single nucleotide polymorphisms (SNPs) on esophageal cancer development. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. Genotypes were determined using a custom-by-design 48-Plex SNPscan? Kit. The caspase8 (CASP8) rs1035142 G>T polymorphism was associated with increased risk of ESCC by heterozygote comparison, homozygote comparison, a dominant genetic model and a recessive genetic model. However, no significant association was detected between the other 15 SNPs and ESCC risk. Stratified analyses indicated a significantly increased risk of ESCC associated with CASP8 rs1035142 G>T polymorphism was evident among all subgroups. These findings indicated that the functional polymorphism CASP8 rs1035142 G>T might contribute to ESCC susceptibility.     

Poecilia picta,a Close Relative to the Guppy,Exhibits Red Male Coloration Polymorphism: A System for Phylogenetic Comparisons

Studies on the evolution of female preference and male color polymorphism frequently focus on single species since traits and preferences are thought to co-evolve. The guppy, Poecilia reticulata, has long been a premier model for such studies because female preferences and orange coloration are well known to covary, especially in upstream/downstream pairs of populations. However, focused single species studies lack the explanatory power of the comparative method, which requires detailed knowledge of multiple species with known evolutionary relationships. Here we describe a red color polymorphism in Poecilia picta, a close relative to guppies. We show that this polymorphism is restricted to males and is maintained in natural populations of mainland South America. Using tests of female preference we show female P. picta are not more attracted to red males, despite preferences for red/orange in closely related species, such as P. reticulata and P. parae. Male color patterns in these closely related species are different from P. picta in that they occur in discrete patches and are frequently Y chromosome-linked. P. reticulata have an almost infinite number of male patterns, while P. parae males occur in discrete morphs. We show the red male polymorphism in P. picta extends continuously throughout the body and is not a Y-linked trait despite the theoretical prediction that sexually-selected characters should often be linked to the heterogametic sex chromosome. The presence/absence of red male coloration of P. picta described here makes this an ideal system for phylogenetic comparisons that could reveal the evolutionary forces maintaining mate choice and color polymorphisms in this speciose group.     

Genetic Predisposition for Development of Nephropathy in Type 2 Diabetes Mellitus

The aim of the study was to explore the association of the angiotensin-converting enzyme (ACE) gene I/D polymorphism and the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with development of diabetic nephropathy in type 2 diabetes mellitus. Three groups were recruited during 2007–2011: 232 normal controls, 185 type 2 diabetics without nephropathy, and 407 type 2 diabetics with nephropathy. The ACE I/D and MTHFR C677T polymorphisms were examined using PCR and PCR-RFLP methods. We found no significant association of the ACE I/D polymorphism with diabetic nephropathy in genotype, allele, dominant, and recessive models. We observed a significant association of MTHFR C677T with development of diabetic nephropathy in type 2 diabetics. The MTHFR C677T polymorphism plays a significant role in predisposition of renal insufficiency in diabetic patients.     

Identification of a new susceptibility variant for multiple sclerosis in OAS1 by population genetics analysis

Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/?) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072?C1.513, p?=?0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits.     

The association between the Lys751Gln polymorphism in the XPD gene and the risk of bladder cancer

The Lys751Gln polymorphism in the XPD gene have been suggested as a risk factor for bladder cancer, however the results were inconclusive. The aim of the current study is to assess the association by meta-analysis. A total of 15 case–control studies concerning the association between the XPD Lys751Gln polymorphism and bladder cancer risk were included in the meta-analysis. The results suggested that the Lys751Gln polymorphism was not associated with an increased risk of bladder cancer in the dominant model (OR = 1.03, 95 % CI 0.95–1.11, P = 0.53 for Lys/Gln+Gln/Gln vs. Lys/Lys) in overall analysis. In the subgroup analysis by ethnicity, no significant association was found in Caucasians or Asians. Other comparatives suggested a slight significant association between the polymorphism with the risk of bladder cancer in the recessive comparative (OR = 1.14, 95 % CI 1.02–1.29, P = 0.03). The current meta-analysis indicated that the Lys751Gln polymorphism in the XPD gene might be a risk factor for bladder cancer. In the future, more large-scale case–control studies are needed to validate our results.     

MHC polymorphism in Caribbean African green monkeys

African green monkeys (AGM) are among the most widely used nonhuman primate models used in various fields of medical research. One species of AGM that originated from West Africa, Chlorocebus sabaeus, was introduced three centuries ago in the Caribbean islands. We present here a systematic study of the major histocompatibility complex (MHC) polymorphism of Caribbean AGM which is currently frequently used as an animal model. We studied 54 animals originated from Barbados (N?=?25) or Saint Kitts (N?=?29). The MHC polymorphism was characterized by means of 17 MHC microsatellites spread across MHC and DRB genotyping by DGGE sequencing. We defined nine frequent MHC haplotypes of which two were found in the two insular populations suggesting either past exchanges between the two populations or a common origin of the founders of the two populations. By the analysis of a previously described EST library, we characterized 38 MHC cDNA sequences (17 class I and 21 class II). In conclusion, we characterized for the first time the MHC polymorphism of Barbados and Saint Kitts AGM. We found a restricted polymorphism due to a founding effect, which is responsible for a strong bottleneck. The poorness of MHC polymorphism observed in the Caribbean AGM populations is similar to that observed in the Mauritian cynomolgus macaque population.     

ATP-binding cassette transporter A1 R219K polymorphism and coronary artery disease in Chinese population: a meta-analysis of 5,388 participants

The ATP-binding cassette transporter A1 (ABCA1) R219K gene polymorphism has been suggested to lower the risk of coronary artery disease (CAD). However, research results remain debatable. Meta-analysis involving 2,730 CAD patients and 2,658 controls was performed to investigate the relationship between ABCA1 R219K gene polymorphism and CAD in Chinese population. A total of 14 studies which were obtained from electronic databases were analyzed. The pooled odds ratios (ORs) and their corresponding 95?% confidence intervals (95?% CIs) were estimated by a random effect model. A significant association between ABCA1 R219K gene polymorphism and CAD was found in the Chinese population under the following genetic models: an allelic genetic model (OR 0.70, 95?% CI 0.62–0.78, P?<?0.00001), a recessive genetic model (OR 0.51, 95?% CI 0.41–0.64, P?<?0.00001), an additive genetic model (OR 0.816, 95?% CI 0780–0.855, P?=?0), a dominant genetic model (OR 1.326, 95?% CI 1.232–1.427, P?=?0), a homozygote genetic model (OR 0.640, 95?% CI 0.575–0.712, P?=?0), and a heterozygote genetic model (OR 0.640, 95?% CI 0.575–0.712, P?=?0). The K allele of the ABCA1 R219K gene has a protective role for CAD risk in Chinese population and is possibly associated with decreased CAD susceptibility.     

Comparison of four molecular markers for genetic analysis in Diospyros L. (Ebenaceae)

Four molecular markers, including inter-retrotransposon amplified polymorphism (IRAP), retrotransposon-microsatellite amplified polymorphism (REMAP), sequence-specific amplified polymorphism (SSAP), and amplified fragment length polymorphism (AFLP), were compared in terms of their informativeness and efficiency for analysis of genetic relationships among 28 genotypes in the genus Diospyros. The results were as follows: (1) the highest level of detected polymorphism were observed for IRAP; (2) AFLP was the most efficient marker system due to the simultaneous detection of abundant polymorphism markers per single reaction; (3) the marker index (MI) value was lower for SSAP than for AFLP, but SSAP had a higher level of detected polymorphism than AFLP; (4) the correlation coefficients of similarity were statistically significant for all four marker systems; (5) the four molecular markers yielded similar phylogenetic trees. To our knowledge, this was the first detailed report of a comparison of performance among three retrotransposon-based molecular markers (IRAP, REMAP, SSAP) and the AFLP technique (DNA-based molecular marker) on a set of samples of Diospyros. The results provide guidance for future efficient use of these molecular methods in the genetic analysis of Diospyros.     

The Effects of Interspecific Competition on the Dynamics of a Polymorphism in an Experimental Population of DROSOPHILA MELANOGASTER

Populations of Drosophila melanogaster with a fourth-chromosome polymorphism were subjected to different levels of competition with Drosophila simulans. The dynamics of the polymorphism and the equilibrium frequencies of the sparkling allele were seen to depend on the competitive level, while the higher productivity of the competing populations was shown to be due to the initial parental density. The effects of competition on fitness components were quantified by fitting the data to both a two-stage selection model and a fertility model. Additional experiments were performed to verify that the interspecific competition caused the changes in fitness. The results are discussed in light of the importance of considering selection components in models of ecological genetics.     

hOGG1 Ser326Cys Polymorphism and Risk of Hepatocellular Carcinoma among East Asians: A Meta-Analysis

Background

The hOGG1 gene encodes a DNA glycosylase enzyme responsible for DNA repair. The Ser326Cys polymorphism in this gene may influence its repair ability and thus plays a role in carcinogenesis. Several case-control studies have been conducted on this polymorphism and its relationship with the risk of hepatocellular carcinoma (HCC) among East Asians. However, their results are inconsistent.

Methods

We performed a meta-analysis of published case-control studies assessing the association of the hOGG1 Ser326Cys polymorphism with HCC risk among East Asians. PubMed, EMBASE, SCI, BIOSIS, CNKI and WanFang databases were searched. A random-effect model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Analyses were conducted for additive, dominant and recessive genetic models.

Results

Eight studies were identified involving 2369 cases and 2442 controls assessing the association of the hOGG1 Ser326Cys polymorphism with HCC risk among East Asians. Applying a dominant genetic model, only in the Chinese population, the Cys allele was significantly associated with increased risk of HCC (OR 1.56, 95% CI 1.12–2.17). However, two studies influenced this finding according to sensitivity analysis. Furthermore, considerable heterogeneity and bias existed among Chinese studies.

Conclusion

There is limited evidence to support that the hOGG1 Ser326Cys polymorphism is associated with HCC risk among East Asians. Well-designed and large-sized studies are required to determine this relationship.     

Population Dynamics of the Segregation Distorter Polymorphism of DROSOPHILA MELANOGASTER

Two two-locus models of the population dynamics of the segregation distortion (SD) polymorphism of Drosophila melanogaster are described. One model is appropriate for understanding the population genetics of SD in nature, whereas the other is a special case appropriate for understanding an artificial population that has been extensively analysed. The models incorporate the general features of the Sd and Rsp loci which form the core of the SD system. It is shown that the SD polymorphism can be established only when there is sufficiently tight linkage between Sd and Rsp. An approximate treatment, valid for tight linkage, is given of all the equilibria of the system and their stabilities. It is shown that the observed composition of natural and artificial populations with respect to the Sd and Rsp loci is predicted well by the model, provided that restrictions are imposed on the fertilities of certain genotypes. Highly oscillatory paths towards equilibrium are usually to be expected on the basis of this model. The selection pressures on inversions introduced into this system are also investigated.     

p53 codon 72 polymorphism and Hematological Cancer Risk: An Update Meta-Analysis

Background

Previous studies on the association of p53 codon 72 (Arg72Pro) polymorphism with hematological malignancies risk have produced conflicting results. The purpose of this meta-analysis is to define the effect of p53 Arg72Pro polymorphism on hematological malignancies risk.

Methodology/Principal Findings

Through searching PubMed databases (or hand searching) up to April 2012 using the following MeSH terms and keywords: “p53”, “codon 72” “polymorphism” and “leukemia”, or “lymphoma”, or “myeloma”, thirteen were identified as eligible articles in this meta-analysis for p53 Arg72Pro polymorphism (2,731 cases and 7, 356 controls), including nine studies on leukemia (1,266 cases and 4, 474 controls), three studies on lymphoma (1,359 cases and 2,652 controls), and one study on myeloma. The overall results suggested that p53 Arg72Pro polymorphism was not associated with hematological malignancies risk. In stratified analyses, significantly increased non-Hodgkin lymphomas risk was found in p53 Arg72Pro polymorphism heterozygote model (Arg/Pro vs. Arg/Arg: OR = 1.18, 95%CI: 1.02–1.35) and dominant model (Arg/Pro+Pro/Pro vs. Arg/Arg: OR = 1.18, 95%CI: 1.03–1.34), but no significant association was found between leukemia risk and p53 Arg72Pro polymorphism. Further studies showed no association between leukemia risk and p53 Arg72Pro polymorphism when stratified in subtypes of leukemias, ethnicities and sources of controls.

Conclusions/Significance

This meta-analysis indicates that the p53 Arg72Pro polymorphism may contribute to susceptibility to non-Hodgkin lymphomas.