Disease Markers - Volume 29, issue 2

Authors: Hadj-Kacem, Hassen | Kallel, Rihab | Belguith-Maalej, Salima | Mnif, Mouna | Charfeddine, Ilhem | Ghorbel, Abdelmounem | Abid, Mohamed | Ayadi, Hammadi | Masmoudi, Saber

Article Type: Research Article

Abstract: Deleterious mutations of SLC26A4 cause Pendred syndrome (PS), an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA), and nonsyndromic hearing loss (NSHL). However, the SLC26A4 hyperactivity was recently associated with the emergence of autoimmune thyroid diseases (AITD) and asthma among human and mouse model. Here, by direct sequencing, we investigate the sequences of the 20 coding exons (2 to 21) of SLC26A4 and their flanking intron-exon junctions among patients affected with …Graves' disease (GD) hyperthyroidism. Ten mono-allelic variants were identified, seven of which are intronic and previously unreported. Two, c.898A>C (p.I300L) and c.1061T>C (p.F354S), of the three exonic variants are non synonymous. The p.F354S variant is already described to be involved in PS or NSHL inheritances. The exploration by PCR-RFLP of p.I300L and p.F354S variants among 132 GD patients, 105 Hashimoto thyroiditis (HT), 206 Healthy subjects and 102 families with NSHL have shown the presence of both variants. The p.F354S variation was identified both among patients (1~HT and 3 GD) and healthy subjects (n=5). Whereas, the p.I300L variant was identified only in GD patients (n=3). Our studies provide evidence of the importance of systematic analysis of SLC26A4 gene sequences on models other than deafness. This approach allows the identification of new variants and the review of the pathogenic effects of certain mono-allelic variants reported responsible for PS and NSHL development. Show more

Keywords: Pendred syndrome, autoimmune thyroid disease, graves' disease, SLC26A4

DOI: 10.3233/DMA-2010-0727

Citation: Disease Markers, vol. 29, no. 2, pp. 63-69, 2010

Authors: Mlakar, Simona Jurkovic | Osredkar, Josko | Prezelj, Janez | Marc, Janja

Article Type: Research Article

Abstract: Recently, oxidative stress has been suggested as participating in the development of osteoporosis. Glutathione peroxidase 1 (GPX1) is one of antioxidant enzymes responsible for the defence of cells against oxidative damage and thus for protection against age related diseases such as osteoporosis. The aim of present study was to associate genetic variances of GPX1 enzyme with bone mineral density (BMD) and biochemical bone turnover markers and to show the influence of antioxidative defence system …in genetics of osteoporosis. We evaluated 682 Slovenian subjects: 571 elderly women and 111 elderly men. All subjects were genotyped for the presence of GPX1 gene polymorphisms Pro198Leu and polyAla region. BMD and biochemical markers were also measured. General linear model analysis, adjusted to height, and (one-way) analysis of variance were used to assess differences between the genotype.and haplotype subgroups, respectively. The significant or borderline significant associations were found between the polyAla or the Pro198Leu polymorphisms and total hip BMD (0.018; 0.023, respectively), femoral neck BMD (0.117; 0.026, respectively) and lumbar spine BMD (0.032; 0.086, respectively), and with biochemical bone turnover markers such as plasma osteocalcin (0.027; 0.025, respectively) and serum C-terminal telopeptide of type I collagen concentrations (0.114; 0.012, respectively) in whole group. Haplotype analysis revealed that the 6-T haplotype is associated significantly with low BMD values (p< 0.025) at all measured locations of the skeleton, and with high plasma osteocalcin concentrations (p=0.008). This study shows for the first time that the polymorphisms polyAla and Pro198Leu of the GPX1 gene, individually and in combination, are associated with BMD and therefore may be useful as genetic markers for bone disease. Moreover, it implies the important contribution of the oxidative stress to pathogenesis of osteoporosis. Show more

Keywords: Osteoporosis, oxidative stress, glutathione peroxidase 1, bone mineral density, osteocalcin

DOI: 10.3233/DMA-2010-0728

Citation: Disease Markers, vol. 29, no. 2, pp. 71-80, 2010

Authors: Ha, Yun-Sok | Yan, Chunri | Lym, Min Su | Jeong, Pildu | Kim, Won Tae | Kim, Yong-June | Yun, Seok-Joong | Lee, Sang-Cheol | Moon, Sung-Kwon | Choi, Yung Hyun | Kim, Wun-Jae

Article Type: Research Article

Abstract: Although polymorphisms in glutathione S-transferase (GST) have been associated with the risk of bladder cancer (BC), few reports provide information about the development of BC. The aim of the present study was to investigate the effect of homozygous glutathione S-transferase-μ (GSTM1) and glutathione S-transferase-� (GSTT1) deletions as prognostic markers in non-muscle-invasive bladder cancer (NMIBC). A total of 241 patients with primary NMIBC were enrolled in this study. GSTM1 and GSTT1 polymorphisms were …analyzed by multiplex polymerase chain reaction (PCR) using blood genomic DNA. The results were compared with clinicopathological parameters. The prognostic significance of the GSTs was evaluated by Kaplan-Meier and multivariate Cox regression model. A statistically significant association between genotype and histopathological parameter was not observed. The patients with the GSTT1-positive genotype had significantly reduced recurrence- and progression-free survival than those with the GSTT1-null genotype (log-rank test, p< 0.05, respectively). Recurrence- and progression-free survival were not related to the GSTM1 genotypes. In multivariate regression analysis, the GSTT1-positive genotype was the independent predictor for recurrence [hazard ratio (HR), 1.631; p=0.043] and progression (HR, 3.418; p=0.006). These results suggested that the GSTT1 genotype could be a useful prognostic marker for recurrence and progression in NMIBC. Show more

Keywords: Urinary bladder neoplasms, polymorphism, biological tumor markers, prognosis

DOI: 10.3233/DMA-2010-0729

Citation: Disease Markers, vol. 29, no. 2, pp. 81-87, 2010

Authors: Tang, Feng-Ying | Zhu, Ying | Wang, Gui Hua | Xie, Xiong-Wei

Article Type: Research Article

Abstract: Background: The development of cardiovascular disease in ESRD patients is considered to be associated with oxidative stress. NAD(P)H oxidase has attracted attention as mechanisms of generating oxidative stress. We investigated the relation between the genotype of the C242T CYBA polymorphism of the NADPH oxidase and the development of cardiovascular disease in ESRD patients. Methods: A total of 289 ESRD patients were recruited and allocated to one of the two groups: patients without cardiovascular disease …(group N; n=192) and patients developing cardiovascular disease (group D; n=97). The C242T CYBA polymorphism was determined by RFLP-PCR methods. Results: The frequency of the C242T CT+TT genotype was significantly lower in group D than in group N (9.1 vs. 20.2%). In multiple Logistic regression analysis, systolic blood pressure, smoking history and this gene polymorphism were shown to be independent variables for the development of cardiovascular disease in ESRD patients. Conclusions: These results suggest that assessment of the C242T CYBA polymorphism of the NADPH oxidase may be useful in identifying the risk for developing cardiovascular disease in ESRD patients. Show more

Keywords: NAD(P)H Oxidase, gene polymorphism, cardiovascular disease

DOI: 10.3233/DMA-2010-0730

Citation: Disease Markers, vol. 29, no. 2, pp. 89-93, 2010

Authors: Brandalize, Ana Paula Carneiro | Bandinelli, Eliane | Santos, Pollyanna Almeida Dos | Schüler-Faccini, Lavínia

Article Type: Research Article

Abstract: This study aimed to investigate the role of maternal polymorphisms, as well as their risk genotypes combinations of MTR A2756G, MTRR A66G, CBS 844ins68, and RFC A80G, involved in folate/homocysteine metabolism, as possible risk factors for Down syndrome (DS) in Southern Brazil. A case-control study was conducted with 239~mothers of DS children and 197~control mothers. The investigation of polymorphisms was performed by PCR and PCR-RFLP. The distribution of genotypic variants was similar in both groups when …they were analyzed separately. An investigation of combined risk genotypes showed that the risk of having a DS child for one, two or three risk genotypes was 6.23, 6.96 and 5.84 (95%CI 1.48–26.26; 1.69–28.66; 1.37–24.86), respectively. The combined MTRR 66G and MTHFR 677T alleles were significantly more common among mothers of children with DS than among control mothers (OR 1.55; IC 95% 1.03–2.35). The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes among MTR, MTRR, CBS and RFC genes are considered maternal risk factors for DS offspring in our population. Show more

Keywords: Down syndrome, folate, MTR, MTRR, CBS, RFC

DOI: 10.3233/DMA-2010-0731

Citation: Disease Markers, vol. 29, no. 2, pp. 95-101, 2010

Authors: Lim, Andrew | Allison, Caris | Tan, Dino Bee Aik | Oliver, Ben | Price, Patricia | Waterer, Grant

Article Type: Research Article

Abstract: Lung disease due to non-tuberculous mycobacteria (NTM) is a poorly understood condition that is difficult to treat. Treatment remains problematic as few tools are available to help clinicians monitor disease progression or predict treatment outcome. In this study, plasma levels of several inflammatory molecules and the frequency of circulating T cell subsets were measured in patients with NTM lung disease and known treatment status, and compared with their adult offspring and with unrelated healthy controls. Plasma …levels of the chemokine CXCL10 and IL-18 were assessed for associations with treatment efficacy. CXCL10 was higher in patients than adult offspring (p< 0.001) and unrelated controls (p< 0.001). Plasma CXCL10 was also lower in patients who responded well to therapy or who controlled their infection without requiring therapy, when compared to patients who did not respond to therapy (p=0.03). Frequencies of activated (HLA-DR^{+} ) CD4^{+} T cells were higher in patients than adult offspring (p<0.001) and unrelated controls (p<0.05), with the highest frequencies in individuals who had completed at least 6 months of treatment. Frequencies of activated (CD38^{+} ) CD8^{+} T cells in most treatment responders were similar to unrelated controls. Low plasma levels of CXCL10 may reflect successful control of NTM lung disease with or without therapy. Compared with responders, patients who responded poorly to treatment generally had higher plasma levels of CXCL10 and IL-18, and higher frequencies of activated CD8^{+} T cells. Show more

Keywords: CXCL10, lung disease, non-tuberculous mycobacteria, T cells

DOI: 10.3233/DMA-2010-0732

Citation: Disease Markers, vol. 29, no. 2, pp. 103-109, 2010

Authors: Chen, Chuanfei | Gan, Yik-Yuen

Article Type: Research Article

Abstract: The cystathionine β-synthase (CBS) 844ins68 polymorphism, methionine synthase (MS) A2756G SNP, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T SNP are associated with homocysteine (Hcy) level in humans. Elevated Hcy level is considered a risk factor for atherosclerotic diseases among Asian populations. Therefore, the three polymorphisms may vary the risk for developing such diseases in Singaporeans. In this study, the three polymorphisms were determined in a group of unrelated healthy Singaporeans (273 Chinese, 127 Indians, …and 156 Malays). Regarding allele frequencies, Indians had the highest frequencies of the CBS insertion allele (2.0%) and the MS 2756G allele (26.4%), while Chinese had the highest MTHFR 677T allele frequency (27.5%). In addition, the MTHFR 677T allele was found significantly lower in Chinese males than in their female counterparts. As the CBS insertion allele was suggested to be associated with lower Hcy level, whereas the MS 2756G allele and the MTHFR T/T genotype were related to higher Hcy level, the MS A/G or G/G genotype and the MTHFR T/T genotype were considered double genetic risk factors for elevated Hcy level. The frequency of such double genetic risk was 0.7% (4 subjects) in the total population consisting of 3 Chinese (1.1%) and 1 Malays (0.6%). No MTHFR T/T genotype was found in Indians. Such results suggested that Chinese could have higher Hcy levels than Malays while the situation for Indians was complicated. Since human Hcy levels are also affected by environmental factors, further studies are required to better evaluate the association between these three polymorphisms and Hcy levels and/or disease susceptibilities in Singaporeans. Show more

Keywords: Cystathionine β-synthase, Methionine synthase, 5, 10-Methylenetetrahydrofolate reductase, Polymorphism, Homocysteine, Singaporean

DOI: 10.3233/DMA-2010-0741

Citation: Disease Markers, vol. 29, no. 2, pp. 111-119, 2010