Hemoglobin and HFE gene polymorphisms in Brazilian populations in regions endemic for malaria

Our objective was to determine how the distribution of red blood cell diseases is related to malaria occurrence in north Brazil, a region endemic for malaria. We evaluated the incidence of two mutations in the HFE gene, H63D and C282Y, in two study groups: a control blood donor group, with no indication of malaria infection, and a group constituted of malaria patients of four states of the Amazonian region. The hemoglobin polymorphisms were obtained by HPLC and classical laboratory methodologies, and the two mutations in the HFE gene were assayed by PCR-RFLP. We found a high frequency of alpha thalassemia, but there were no significant differences between blood donors and malaria patients. There were also no significant differences in the frequencies of HbA(2); however, the frequency of HbF was significantly different in individuals with malaria from Para and Rondonia. The mean number of reticulocytes was significantly reduced in the blood donors from the northern region, suggesting an adaptive strategy of these populations to parasitic attack by Plasmodium. Most individuals were heterozygous for the H63D allele of the HFE gene in both study groups. In the blood donors group, the greatest frequency of the H63D allele was found in Caucasians of all the states. In the malaria patients group in Rondonia, there was a high frequency of the H63D allele among the non-Caucasians. In the other states, and in the malaria patients group, the H63D allele was the most frequent among the Caucasians. Based on our results, we suggest that the maintenance of polymorphism of the mutations in the gene HFE can be explained by selective factors other than malaria, or it is due to simple allelic oscillation and by the constant gene flow among the populations in Brazil.

Comparison of oxidative stress and the frequency of polymorphisms in the HFE gene between hemoglobin S trait blood donors and sickle cell disease patients

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Frequency of the HFE C282Y and H63D polymorphisms in Brazilian malaria patients and blood donors from the Amazon region

Malaria is an endemic parasitosis and its causitive agent, Plasmodium, has a metabolism linked to iron supply. HFE is a gene with the polymorphisms C282Y and H63D, which are associated with a progressive iron accumulation in the organism leading to a disease called hereditary hemochromatosis. The aim of the present study was to determine the allelic and genotypic frequencies of the HFE gene polymorphisms in malaria patients and blood donors from the Brazilian Amazon region. We screened 400 blood donors and 400 malaria patients for the HFE C282Y and H63D polymorphisms from four states of the Brazilian Amazon region by polymerase chain reaction and restriction fragment length polymorphism analysis. We did not find any C282Y homozygous individuals, and the only five heterozygous individuals detected were from Pará State. The most frequent genotype in the North region of Brazil was the H63D heterozygote, in both study groups. Our results contribute to the concept that the Brazilian Amazon region should not be regarded as a single entity in South America. These polymorphisms did not influence the symptoms of malaria in the population studied, as neither severe signs nor high parasitemia were observed. Therefore, different hereditary hemochromatosis diagnostic and control measures must be developed and applied within its diverse locations. Investigations are currently being carried out in our laboratory in order to determine the importance of the coexistence of hereditary hemochromatosis in patients affected by parasitic diseases, such as malaria. ©FUNPEC-RP.

Association of estrogen receptor and glucocorticoid receptor gene polymorphisms with sporadic breast cancer

We have utilized a cross-sectional association approach to investigate sporadic breast cancer. Polymorphisms in 2 candidate genes, ESRalpha and GRL, were examined in an unrelated breast cancer-affected and age-matched control population. Several polymorphic regions within the ESRalpha gene have been identified, and some alleles of these polymorphisms have been found to occur at increased levels in breast-cancer patients. Additionally, variations in GRL have the potential to disrupt cell transcription and may be associated with cancer formation. We analyzed 3 polymorphisms, from codons 10 (TCT to TCC), 325 (CCC to CCG) and 594 (ACA to ACG) of ESRalpha, and a highly polymorphic dinucleotide repeat, D5S207, located within 200 kb of the GRL. When allelic frequencies of the codon 594 (exon 8) ESR polymorphism were compared between affected and unaffected populations, a significant difference was observed (p = 0.005). Results from the D5S207 dinucleotide repeat located near GRL also indicated a significant difference between the tested case and control populations (p = 0.001). Allelic frequencies of the codon 10 and codon 325 ESR polymorphisms were not significantly different between populations (p = 0.152 and 0.181, respectively). Our results indicate that specific alleles of the ESR gene (alpha subtype) and a marker for the GRL gene locus are associated with sporadic breast-cancer development in the tested Caucasian population and justify further investigation of the role of these and other nuclear steroid receptors in the etiology of breast cancer.

Endophenotype profiles of MTHFR and ACE gene polymorphisms in migraine susceptibility

Background Migraine is a debilitating neurological disorder affecting approximately 12% of the Caucasian population. There are two main sub-types of migraine, migraine without aura (MO) and migraine with aura (MA). Migraine exhibits varied phenotypic expression with sufferers experiencing a range of neurological and other symptoms. It is likely that multiple susceptibility genes play a role in this varied phenotypic expression, thus investigation of genotype-phenotype relationships may provide valuable insights into the role of susceptibility genes in this disorder. Methods This study investigated the links between migraine susceptibility genes, methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE), and clinical manifestation through statistical analyses. Results The result showed that for the MTHFR genotypes, there was a statistically significant correlation with the TT homozygous genotype and visual disturbances, unilateral head pain and physical activity discomforts. It was also found that bilateral head pain was associated with the male gender. Conclusion From these study results, it is plausible to state that MTHFR genotypes affect the phenotypic expression of migraine disease manifestation.

Association between xenobiotic gene polymorphisms and non-Hodgkin's lymphoma risk

The last four decades have seen a significant increase in the incidence of non-Hodgkin's lymphoma (NHL) as a possible result of increasing environmental carcinogen exposure, particularly pesticides and solvents. Based on the increasing evidence for an association between carcinogen exposure-related cancer risk and xenobiotic gene polymorphisms, we have undertaken a case-control study of xenobiotic gene polymorphisms in individuals with a diagnosis of NHL. Polymorphisms of six xenobiotic genes (CYP1A1, GSTT1, GSTM1, PON1, NAT1, NAT2) were characterized in 169 individuals with NHL and 205 normal controls using polymerase chain reaction-based methods. Polymorphic frequencies were compared using Fisher's exact tests, and odds ratios for NHL risk were calculated. Among the NHL group, the incidence of GSTT1 null and PON1 BB genotypes were significantly increased compared with controls, 34% vs 14%, and 24% vs 11% respectively. Adjusted odds ratios calculated from multivariate analyses demonstrated that GSTT1 null conferred a fourfold increase in NHL risk (OR = 4.27; 95% CI, 2.40-7.61, P < 0.001) and PON1 BB a 2.9-fold increase (OR = 2.92; 95% CI, 1.49-5.72, P = 0.002). Furthermore, GSTT1 null combined with PON1 BB or GSTM1 null conferred an additional risk of NHL. This is the first time that a PON1 gene polymorphism has been shown to be associated with cancer risk. We conclude that the two polymorphisms, GSTT1 null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population NHL risk, particularly among groups exposed to NHL-related carcinogens.

Evidence of associations between cytokine gene polymorphisms and quality of life in patients with cancer and their family caregivers

PURPOSE/OBJECTIVES: To identify latent classes of individuals with distinct quality-of-life (QOL) trajectories, to evaluate for differences in demographic characteristics between the latent classes, and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. DESIGN: Descriptive, longitudinal study. SETTING: Two radiation therapy departments located in a comprehensive cancer center and a community-based oncology program in northern California. SAMPLE: 168 outpatients with prostate, breast, brain, or lung cancer and 85 of their family caregivers (FCs). METHODS: Growth mixture modeling (GMM) was employed to identify latent classes of individuals based on QOL scores measured prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs) and haplotypes in 16 candidate cytokine genes were tested between the latent classes. Logistic regression was used to evaluate the relationships among genotypic and phenotypic characteristics and QOL GMM group membership. MAIN RESEARCH VARIABLES: QOL latent class membership and variations in cytokine genes. FINDINGS: Two latent QOL classes were found: higher and lower. Patients and FCs who were younger, identified with an ethnic minority group, had poorer functional status, or had children living at home were more likely to belong to the lower QOL class. After controlling for significant covariates, between-group differences were found in SNPs in interleukin 1 receptor 2 (IL1R2) and nuclear factor kappa beta 2 (NFKB2). For IL1R2, carrying one or two doses of the rare C allele was associated with decreased odds of belonging to the lower QOL class. For NFKB2, carriers with two doses of the rare G allele were more likely to belong to the lower QOL class. CONCLUSIONS: Unique genetic markers in cytokine genes may partially explain interindividual variability in QOL. IMPLICATIONS FOR NURSING: Determination of high-risk characteristics and unique genetic markers would allow for earlier identification of patients with cancer and FCs at higher risk for poorer QOL. Knowledge of these risk factors could assist in the development of more targeted clinical or supportive care interventions for those identified.

Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene

Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.

Association of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms with the risk of COPD: An updated meta-analysis of 2,644 cases and 4,804 controls

A series of observational studies have been made to investigate the association of the ADAM33 gene polymorphisms with the risk of COPD, but their results were conflicting. Therefore, we performed an updated meta-analysis to quantitatively summarize the associations of ADAM33 gene polymorphisms with the risk of COPD. Thirteen case–control studies referring to nine SNPs were identified: V4 (rs2787094), T+1 (rs2280089), T2 (rs2280090), T1 (rs2280091), S2 (rs528557), S1 (rs3918396), Q−1 (rs612709), F+1 (rs511898) and ST+5 (rs597980). A dominant model (AA+Aa vs. aa), recessive model (AA vs. Aa+aa), additive model (AA vs. aa) and allelic model (A vs. a) were used to evaluate the association of ADAM33 polymorphism with the risk of COPD. The results indicated that significant associations were found for ADAM33 T1, T2, S1, Q−1, F+1 and ST+5 polymorphisms associated with the risk of COPD in different populations. However, no significant associations were found for V4, T+1 and S2 polymorphisms with the risk of COPD in all genetic models, even in the subgroup analysis by ethnicity. This meta-analysis provided evidence that the ADAM33 T1, T2, S1, Q−1, F+1 and ST+5 six locus polymorphisms association with the risk of COPD. Furthermore, T2, Q−1 and ST+5 indicated an association with the risk of COPD in the European populations, whereas T1, T2, S1, F+1 and Q−1 indicated an association with the risk of COPD in the Asian populations.

The effect of transforming growth factor β1 gene polymorphisms in ankylosing spondylitis

Objectives. To determine whether genetic polymorphisms in or near the transforming growth factor β1 (TGFB1) locus were associated d with susceptibility to or severity of ankylosing spondylitis (AS). Methods. Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index). Results. A weak association was noted between the rare TGFB1 + 1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/ +915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent-case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers. Conclusion. This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.