The common apolipoprotein A-1 polymorphism −75A>G is associated with ethnic differences in recurrent coronary events after recovery from an acute myocardial infarction

Since data regarding the relationship between a common polymorphism (SNP) of the apoA1 gene with apoA1 levels and risk of coronary artery disease are inconsistent, we hypothesized that its association with recurrent coronary events differs for White and Black individuals with diagnosed coronary heart disease. The apoA1 −75G>A SNP was genotyped in a cohort of 834 Black (n=129) and White (n=705) post-myocardial infarction patients. Recurrent coronary events (coronary-related death, non-fatal myocardial infarction, or unstable angina) were documented during an average follow-up of 28 months. Thirty percent of White and 21% of Black patients carried the SNP. Cox proportional-hazards regression analysis, adjusting for clinical and laboratory covariates, demonstrated that the SNP was not associated with recurrent events in the total cohort (HR=1.37, 95% CI 0.95–1.97; p= 0.09) but was the only variable associated with an increased risk of recurrent cardiac events in Blacks (HR=2.40, 95% CI 1.07–5.40; p= 0.034). Conversely in Whites, the SNP was not associated with recurrent events (HR=1.12, 95% CI 0.75–1.67; p= 0.59) whereas apoB (HR=1.78, 95% CI 1.20 −2.65; p= 0.0042) and calcium channel blocker use (HR=2.53, 95% CI 1.72–3.72; p<0.001) were associated; p= 0.0024 for interaction between ethnicity and the SNP. A common apoA1 SNP is associated with a significantly increased risk of recurrent cardiac events among Black, but not White, postmyocardial infarction patients. Relationships with lipoproteins may help explain this finding

Functional SNPs in HSPA1A Gene Predict Risk of Coronary Heart Disease

Background: HSP70 plays crucial roles in endothelial cell apoptosis, which is involved in the early phase and progress of coronary heart disease (CHD). However, the association between polymorphisms of HSP70 genes and the risk of CHD still remains unclear. Our aim was to determine whether genetic variants in the HSPA1A gene are associated with the risk of CHD. Methodology/Principal Findings: By resequencing and genotyping, the associations of 2 single nucleotide polymorphisms (SNPs) +190G/C (rs1043618) and −110A/C (rs1008438) in the HSPA1A gene with risk of CHD were determined in a 1,003 pairs case-control study. The SNP function was further analyzed using a luciferase reporter assay in two cell lines. The results indicated that +190CC genotype was associated with significantly higher risk of CHD when compared with +190GG genotype (OR = 1.56, 95% CI: 1.10–2.20, P = 0.012), while association between −110A/C polymorphism and CHD was not statistically significant (P greater than 0.05). However, the −110C/+190C haplotype had a significantly higher risk of CHD when compared with the −110A/+190G haplotype (OR = 1.17, 95% CI: 1.01–1.34, P = 0.031). Luciferase reporter assays showed that the +190C allele resulted in 14%∼45% reduction in luciferase expression in endothelial and non-endothelial cells when compared with the +190G allele. Conclusions/Significance: The identified genetic variants in the HSPA1A gene combinatorially contribute towards the susceptibility to CHD likely by affecting the level of synthesis of HSP70. This study may provide useful markers for identification of subjects at risk for CHD

Genetic Variations in HSPA8 Gene Associated with Coronary Heart Disease Risk in a Chinese Population

Background: There is ample evidence that Hsp70 takes part in the progress of coronary heart disease (CHD). This implies that genetic variants of Hsp70 genes such as HSPA8 (HSC70) gene might contribute to the development of CHD. The present study aimed to investigate whether certain genetic variants of HSPA8 gene are associated with CHD in Han Chinese people. Methodology/Principal Findings: A total of 2006 subjects (1003 CHD cases and 1003 age- and sex- matched healthy controls) were recruited. Genetic variants in the HSPA8 gene were identified by sequencing of the gene in 60 unrelated Chinese. Four tag single nucleotide polymorphisms (tagSNPs) (rs2236659, rs2276077, rs10892958, and rs1461496) were selected and genotyped. The function of the significant SNP was evaluated using luciferase reporter assays in two cell lines. By sequencing the promoter and all exons and introns of the HSPA8 gene, 23 genetic variants were identified. One promoter SNP rs2236659 was associated with susceptibility to CHD. Carriers of the “C” allele of rs2236659 had decreased CHD risk with odds ratio (OR) of 0.78 (95% CI: 0.62, 0.98; P = 0.033) after adjustment for conventional risk factors. Haplotype analyses indicated that haplotype GCGC contributed to a lower CHD risk (OR = 0.78, 95% CI: 0.65, 0.93; P = 0.006) compared with the common haplotype AGGT. In a transfection assay, the C allele of rs2236659 showed a 37–40% increase in luciferase expression of the reporter gene luciferase in endothelial and non-endothelial cells compared with the T allele. Conclusions/Significance: These findings suggest that genetic variants in HSPA8 gene (especially promoter SNP rs2236659) contribute to the CHD susceptibility by affecting its expression level

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>The ideal malaria parasite populations for initial mapping of genomic regions contributing to phenotypes such as drug resistance and virulence, through genome-wide association studies, are those with high genetic diversity, allowing for numerous informative markers, and rare meiotic recombination, allowing for strong linkage disequilibrium (LD) between markers and phenotype-determining loci. However, levels of genetic diversity and LD in field populations of the major human malaria parasite <it>P. vivax </it>remain little characterized.</p> <p>Results</p> <p>We examined single-nucleotide polymorphisms (SNPs) and LD patterns across a 100-kb chromosome segment of <it>P. vivax </it>in 238 field isolates from areas of low to moderate malaria endemicity in South America and Asia, where LD tends to be more extensive than in holoendemic populations, and in two monkey-adapted strains (Salvador-I, from El Salvador, and Belem, from Brazil). We found varying levels of SNP diversity and LD across populations, with the highest diversity and strongest LD in the area of lowest malaria transmission. We found several clusters of contiguous markers with rare meiotic recombination and characterized a relatively conserved haplotype structure among populations, suggesting the existence of recombination hotspots in the genome region analyzed. Both silent and nonsynonymous SNPs revealed substantial between-population differentiation, which accounted for ~40% of the overall genetic diversity observed. Although parasites clustered according to their continental origin, we found evidence for substructure within the Brazilian population of <it>P. vivax</it>. We also explored between-population differentiation patterns revealed by loci putatively affected by natural selection and found marked geographic variation in frequencies of nucleotide substitutions at the <it>pvmdr-1 </it>locus, putatively associated with drug resistance.</p> <p>Conclusion</p> <p>These findings support the feasibility of genome-wide association studies in carefully selected populations of <it>P. vivax</it>, using relatively low densities of markers, but underscore the risk of false positives caused by population structure at both local and regional levels.</p> <p>See commentary: <url>http://www.biomedcentral.com/1741-7007/8/90</url></p

Bioinformatics in China: A Personal Perspective

Biochemical Research MethodsMathematical &amp; Computational BiologySCI(E)PubMed3EDITORIAL MATERIAL4e1000020

SNP and Haplotype characterisation of Apobec 3G, a protein invovled in Retroviral defence, in Black South Africans

Heritable variation is important in disease progression, therefore its association with HIV/AIDS was analyzed. APOBEC3G is a unique cellular gene that influences HIV infectivity. It belongs to family of cytidine deaminases and is both an RNA and DNA editing enzyme. APOBEC3G is a good candidate for HIV restriction because it allows the expression of an antiviral phenotype in non-permissive cells consequently this innate immune defense may provide the basis for the design of new therapies for HIV. Variation in the upstream non-coding region of APOBEC3G was studied. Six base variants were found at positions -90, -163, -166, -571, -590 and -821. In addition, promoter analysis identified promoters in the upstream non-coding region. Indirect genotyping assays were developed to genotype the participants at -571 and H186R. The frequency of -571 GG was 70 %. The frequency of the TT genotype of H186R was 20 %. The GG genotype was selected against in the HIV + group of the study participants. This is indicative that this SNP has disease modifying effects. The TT genotype was related to increased progression to AIDS confirming the results of previous studies

DNA SEQUENCE VARIATION IN THE PROMOTER REGION OF THE VEGF GENE: IMPACTS ON VEGF GENE EXPRESSION AND MAXIMAL OXYGEN CONSUMPTION

Maximal oxygen consumption (Vo2max) is inversely associated with cardiovascular and all-cause mortality and is responsive to aerobic exercise training. A portion of the increase in Vo2max with aerobic exercise training can be attributed to an increase in skeletal muscle capillarity (i.e., angiogenesis), which contributes to increased blood flow and oxygen extraction in working skeletal muscle. One contributing factor to exercise-induced angiogenesis is vascular endothelial growth factor (VEGF), as it is an endothelial cell proliferation and migration factor that is upregulated by acute aerobic exercise. Significant variability has been observed in VEGF protein levels, VEGF gene expression, skeletal muscle capillarity, and Vo2max before and after aerobic exercise training. Additionally, variability is found in the DNA sequence of the gene encoding VEGF. Variation in the VEGF gene has the ability to impact VEGF gene expression and VEGF protein level and because of the relationship between VEGF, angiogenesis, and Vo2max, we hypothesized that variation in the VEGF gene is related to VEGF gene expression in human myoblasts, plasma VEGF level, and Vo2max before and after aerobic exercise training. The present report shows that VEGF promoter region haplotype impacts VEGF gene expression in human myoblasts in vitro. It was also found that VEGF promoter region haplotype was associated with Vo2max in older men and women before and after exercise training in a manner that is consistent with the results of the VEGF gene expression experiments. Additionally, we found that plasma VEGF level was not associated with VEGF promoter region haplotype, nor did plasma VEGF level correlate with baseline Vo2max or the change in Vo2max with aerobic exercise training. To date, we are the first to report that VEGF promoter region haplotype impacts VEGF gene expression in human myoblasts and is associated with Vo2max. These results have potential implications for aerobic exercise training and may also contribute to the understanding of the function of the VEGF promoter region in different cell types. Furthermore, these results may prove relevant in the study of pathological conditions which can be affected by angiogenesis, namely obesity, cancer, coronary artery disease, and peripheral artery disease

Impact of haptoglobin gene variation on HIV resistance and the rate of disease progression in the South African black population

Student Number : 0318625T - MSc dissertation - School of Molecular and Cell Biology - Faculty of ScienceGenetic variation in haptoglobin, a plasma protein, has been reported to be associated with susceptibility to and the rate of HIV/AIDS progression. The purpose of this study was to investigate the influence of haptoglobin polymorphism on HIV/AIDS in black South Africans. Polymorphism in the coding region of the haptoglobin gene was detected by direct DNA and allele-specific amplification. Polymorphism in the coding region of the gene was detected by amplification of DNA and by polyacrylamide gel electrophoresis of plasma protein. A statistically significant association was observed between allele -61C and resistance to HIV infection. The Hp0 phenotype, in which no haptoglobin protein is detected, was associated with HIV status and some promoter genotypes. Since in our study population there were a few samples with usable clinical data , further investigations need to be done to confirm the association of the -61C allele and the Hp0 phenotype with the risk of HIV infection

The influence of genetic variation in PSIP1 on HIV-1 infectivity in black South Africans

Genetic variation plays an important role in determining an individual’s susceptibility to infectious disease. PSIP1 encodes LEDGF/p75, which stably associates with the core domain of HIV-1 integrase via a highly-conserved integrase binding domain (IBD) located in its C-terminal. Through this interaction, the protein tethers HIV-1 IN to chromosomes at sites corresponding to regions of high LEDGF/p75-mediated transcription. Genetic variation within PSIP1 was identified and characterized in black South Africans to establish whether variation in this influences an individual’s susceptibility to HIV infection. PCR assays were designed to amplify regions within the upstream non-coding region, IBD and DNA-binding domains of the gene and selected polymorphisms were then genotyped using allele-specific PCR, RFLP-PCR and Pyrosequencing™ assays. Three insertion-deletion (indel) and eight single nucleotide polymorphisms (SNP) where identified through sequencing. Four of the SNPs had been recorded previously, while the seven other polymorphisms had not and appear to be unique to our population. Differences in allelic and genotypic frequencies where found between the various ethnic groups represented in this study, which were reflected in the underlying haplotype structure within this gene, suggesting that genetic substructure exists within the black South African population. Differences in allele and genotype frequencies were also seen between HIV+ individuals and the general population. Thus variation within PSIP1 may influence an individual’s susceptibility to HIV-1 infectivity and/or rate of disease progression