Dinucleotide Repeat Polymorphism Research Articles

456: No association between dinucleotide repeat polymorphism of the Fms-like tyrosine kinase-1 (Flt-1) gene and Korean patients with preeclampsia

456: No association between dinucleotide repeat polymorphism of the Fms-like tyrosine kinase-1 (Flt-1) gene and Korean patients with preeclampsia

Possible Association of CTLA-4 Gene Polymorphism With Cyclosporine-Induced Gingival Overgrowth in Kidney Transplant Recipients

T-lymphocytes may play a role in the pathogenesis of inflammatory periodontal diseases and cyclosporine (CsA)-induced gingival overgrowth (GO). The gene encoding CTLA-4 (Cytotoxic T-lymphocyte antigen 4, a molecule influencing T-cell activation), is known to have a single nucleotide polymorphism (SNP) in promoter C>T −318; an exon 1 A>G 49, and a microsatellite dinucleotide repeat polymorphism (AT) n in exon 4. The purpose of this study was to analyze the possible influence of polymorphisms of CTLA-4, interleukin (IL)-2, and tumor necrosis factor (TNF)-α on GO incidence in eighty two renal transplant recipients. 34 CsA-treated with significant GO (CsAGO+); 22, CsA-treated with no GO (CsAGO−), and 26 tacrolimus (Tac)-treated without GO (TacGO−). The SNPs of CTLA-4 (−318 C>T and +49 A>G), IL-2 (−330T>G), and TNF-α (−308 G>A) were determined by SSP-PCR methods. The CTLA-4 (AT) n genotype was determined using polymerase chain reaction and fluorescence-based analysis with capillary electrophoresis. Allele frequencies in all patient groups were similar for CTLA-4 −318C>T, IL-2, and TNF-α. However, patients with CsAGO+ showed differences from CsAGO− for allele and genotype frequencies in position +49A>G of the CTLA-4 gene. The +49G allele was two times less frequent among CsAGO+ than CsAGO− ( P = .0052; P corrected = .008). Slight differences between CsAGO+ and CsAGO− were noticed for the genotype distribution of CTLA-4 (AT) n ( P = .056). The results suggested that appearance of an adenosine allele(A) in position +49 of the CTLA-4 gene may be a permissive element for CsA-induced GO.

(AC) Dinucleotide Repeat Polymorphism in Intron 1 of Human EGFR Shows Ethnic Specificities and High Evidence for Association with Breast Cancer

A polymorphic AC repeat in intron 1 of the EGFR gene was genotyped on 352 healthy individuals and 118 women with breast cancer sampled from the Kuwaiti and Tunisian populations. We compared allele frequencies in these populations with published data on various ethnic groups. We found very close similarity between Tunisian and Kuwaiti populations for both allelic and genotypic frequencies and in both control and patient groups. Our analysis revealed clear interethnic differences between populations; in Europeans, allele 16 occurred predominantly, whereas in Tunisia and Kuwait allele 17 was the most frequent and allele 20 predominated in Asians. One hundred twenty-three healthy women, matched with the 118 breast cancer patients, were used as controls to test for associations between AC repeat and cancer risk. Strong evidence for such an association was found for allele 18 when considered alone (χ2=27.04, corrected p=0.0000016, OR=3.94) or with longer alleles (>17 repeats) (χ2=20.21, p=0.0005, OR=2.30). This contrasts with Asian populations where allele 16 was identified as the risk allele, showing allele heterogeneity depending on ethnicity.

Estrogen receptor α CA dinucleotide repeat polymorphism is associated with rate of bone loss in perimenopausal women and bone mineral density and risk of osteoporotic fractures in postmenopausal women

The association between a newly identified CA repeat polymorphism of the estrogen receptor alpha gene (ESR1) with osteoporosis was investigated. Postmenopausal women with <18 CA repeats had low BMD, increased rate of bone loss and increased fracture risk. Studies have shown that intronic dinucleotide repeat polymorphisms in some genes are associated with disease risk by modulating mRNA splicing efficiency. D6S440 is a newly identified intronic CA repeat polymorphism located downstream of the 5'-splicing site of exon 5 of ESR1. The associations of D6S440 with bone mineral density (BMD), rate of bone loss and fracture risk were evaluated in 452 pre-, 110 peri- and 622 postmenopausal southern Chinese women using regression models. Post- but not premenopausal women with less CA repeats had lower spine and hip BMD. The number of CA repeats was linearly related to hip BMD in postmenopausal women (beta=0.008; p=0.004). Postmenopausal women with CA repeats <18 had higher risks of having osteoporosis (BMD T-score< -2.5 at the spine: OR 2.46, 95% CI 1.30-4.65; at the hip: OR 3.79(1.64-8.74)) and low trauma fractures (OR 2.31(1.29-4.14)) than those with >or= 18 repeats. Perimenopausal women with <18 CA repeats had significantly greater bone loss in 18 months at the hip than those with >or= 18 repeats (-1.96% vs. -1.61%, p = 0.029). ESR1 CA repeat polymorphism is associated with BMD variation, rate of bone loss and fracture risk, and this may be a useful genetic marker for fracture risk assessment.

Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis

The intracellular pathogens Propionibacterium acnes and Mycobacterium tuberculosis have been leading suspects as the cause of sarcoidosis, a systemic disorder characterized by the formation of non-caseating granulomas. Toll-like receptor (TLR) 2 is important in the innate immune response against both pathogens, and is therefore of interest in sarcoidosis research. In the present study, three single nucleotide polymorphisms and one dinucleotide repeat polymorphism in the TLR-2 gene were genotyped in 419 sarcoidosis patients, divided into a study cohort and a validation cohort, and 196 healthy controls. In the study cohort we found a significant increase in prevalence of the AA-genotype at promotor location -16934 in patients with chronic disease compared to patients with acute/self-remitting sarcoidosis (34.5% versus 15.9%, respectively, P = 0.006, P(c) = 0.019). These results could not be confirmed in our validation cohort, implicating a possible role for TLR-2 genetics in only a small percentage of sarcoidosis patients. Furthermore, linkage was found between the promotor polymorphism -16934 A/T and the number of GT repeats in intron 1 (P < 0.0001). After in vitro stimulation of peripheral blood mononuclear cells (PMBCs) with different TLR-2 agonists, a correlation between induction of TNF-alpha (P = 0.008), interleukin (IL)-12 (P = 0.008) as well as IL-6 (P = 0.02), and the number of GT repeats was observed. In conclusion, the data show that polymorphisms in TLR-2 might be important in a small group of sarcoidosis patients and that their functional consequences explain partly some of the variance in cytokine pattern observed in different clinical phenotypes of this disease.

Intron 1 CA dinucleotide repeat polymorphism and mutations of epidermal growth factor receptor and gefitinib responsiveness in non-small-cell lung cancer

Limited availability of tumoral tissue in non-small-cell lung cancer and presence of epidermal growth factor receptor mutation-independent responses call for investigation of other molecular predictive marker of gefitinib responsiveness. Therefore, CA repeat polymorphism in intron 1 was analyzed for its association with gefitinib responsiveness together with epidermal growth factor receptor mutation in Korean patients. For 86 advanced non-small-cell lung cancer patients treated with gefitinib, epidermal growth factor receptor mutation was analyzed by direct sequencing (exons 18-21) from tumor tissue and CA repeat polymorphism was assessed by fragment length analysis from tumor and/or normal tissue. CA repeat status was identical in 33 patients with matched tumor and normal tissue. CA repeat was low (sum of both alleles < or =37) in 40 (46.5%) and high (sum > or =38) in 46 (53.5%) patients. Although epidermal growth factor receptor mutation was more frequent in high CA repeat patients [17.5% (7/40) in low vs. 28.3% (13/46) in high, P=0.18], response rate was higher in low CA repeat patients [25.0% (10/40) in low vs. 13.0% (6/46) in high, P=0.16]. In multivariate analysis, low CA repeat was associated with better objective response (odds ratio 7.1, 95% confidence interval 1.2-40.8; P=0.029) and time-to-progression (hazard ratio 0.54, 95% confidence interval 0.34-0.88; P=0.014), independent of the epidermal growth factor receptor mutational status. CA repeat status was not associated with epidermal growth factor receptor expression. Low number of CA repeats in intron 1 of epidermal growth factor receptor is associated with gefitinib responsiveness in non-small-cell lung cancer patients independent of epidermal growth factor receptor mutation.

Polymorphisms, Mutations, and Amplification of the EGFR Gene in Non-Small Cell Lung Cancers

BackgroundThe epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experimental systems: a polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one (lower number of repeats) and two single nucleotide polymorphisms (SNPs) in the promoter region, −216 (G/T or T/T) and −191 (C/A or A/A). The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers.Methods and FindingsWe examined the frequencies of the three polymorphisms of EGFR in 556 resected lung cancers and corresponding non-malignant lung tissues from 336 East Asians, 213 individuals of Northern European descent, and seven of other ethnicities. We also studied the EGFR gene in 93 corresponding non-malignant lung tissue samples from European-descent patients from Italy and in peripheral blood mononuclear cells from 250 normal healthy US individuals enrolled in epidemiological studies including individuals of European descent, African–Americans, and Mexican–Americans. We sequenced the four exons (18–21) of the TK domain known to harbor activating mutations in tumors and examined the status of the CA-SSR1 alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) and allele-specific amplification of mutant tumors as determined by a standardized semiautomated method of microsatellite analysis. Variant forms of SNP −216 (G/T or T/T) and SNP −191 (C/A or A/A) (associated with higher protein production in experimental systems) were less frequent in East Asians than in individuals of other ethnicities (p < 0.001). Both alleles of CA-SSR1 were significantly longer in East Asians than in individuals of other ethnicities (p < 0.001). Expression studies using bronchial epithelial cultures demonstrated a trend towards increased mRNA expression in cultures having the variant SNP −216 G/T or T/T genotypes. Monoallelic amplification of the CA-SSR1 locus was present in 30.6% of the informative cases and occurred more often in individuals of East Asian ethnicity. AI was present in 44.4% (95% confidence interval: 34.1%–54.7%) of mutant tumors compared with 25.9% (20.6%–31.2%) of wild-type tumors (p = 0.002). The shorter allele in tumors with AI in East Asian individuals was selectively amplified (shorter allele dominant) more often in mutant tumors (75.0%, 61.6%–88.4%) than in wild-type tumors (43.5%, 31.8%–55.2%, p = 0.003). In addition, there was a strong positive association between AI ratios of CA-SSR1 alleles and AI of mutant alleles.ConclusionsThe three polymorphisms associated with increased EGFR protein production (shorter CA-SSR1 length and variant forms of SNPs −216 and −191) were found to be rare in East Asians as compared to other ethnicities, suggesting that the cells of East Asians may make relatively less intrinsic EGFR protein. Interestingly, especially in tumors from patients of East Asian ethnicity, EGFR mutations were found to favor the shorter allele of CA-SSR1, and selective amplification of the shorter allele of CA-SSR1 occurred frequently in tumors harboring a mutation. These distinct molecular events targeting the same allele would both be predicted to result in greater EGFR protein production and/or activity. Our findings may help explain to some of the ethnic differences observed in mutational frequencies and responses to TK inhibitors.

(AC) dinucleotide repeat polymorphism in intron 1 of human EGFR shows ethnic specificities and high evidence for association with breast cancer

A polymorphic AC repeat in intron 1 of the EGFR gene was genotyped on 352 healthy individuals and 118 women with breast cancer sampled from the Kuwaiti and Tunisian populations. We compared allele frequencies in these populations with published data on various ethnic groups. We found very close similarity between Tunisian and Kuwaiti populations for both allelic and genotypic frequencies and in both control and patient groups. Our analysis revealed clear interethnic differences between populations; in Europeans, allele 16 occurred predominantly, whereas in Tunisia and Kuwait allele 17 was the most frequent and allele 20 predominated in Asians. One hundred twenty-three healthy women, matched with the 118 breast cancer patients, were used as controls to test for associations between AC repeat and cancer risk. Strong evidence for such an association was found for allele 18 when considered alone (chi2=27.04, corrected p=0.0000016, OR=3.94) or with longer alleles (>17 repeats) (chi2=20.21, p=0.0005, OR=2.30). This contrasts with Asian populations where allele 16 was identified as the risk allele, showing allele heterogeneity depending on ethnicity.

Association study of an (AC)n dinucleotide repeat and schizophrenia in Asian and European populations

Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (AC)n dinucleotide repeat polymorphism at D15S118 and schizophrenia was investigated using three independent samples from the Han Chinese population and the Scotland population. In the population-based study, a significant difference was found between the allele frequency distributions in schizophrenia patients and control subjects in the Scottish samples (P = 0.04), but was not replicated in the Chinese samples. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Overall, our results did not support the hypothesis that the (AC)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility, at least in the Chinese population. Further studies are needed to elucidate its role in schizophrenia susceptibility in European population.

No association between dinucleotide repeat polymorphism in intron 1 of the epidermal growth factor receptor gene EGFR and risk of lung cancer

The tyrosine kinase receptor EGFR pathway is one of the oncogenic signaling cascades involved in lung cancer, mediating the epidermal growth factor receptor gene EGFR. First-intron polymorphisms with greater numbers of CA dinucleotide repeats tend to downregulate EGFR expression, which suggests that this polymorphism may modulate susceptibility to lung cancer. The present hospital-based case–control study evaluated the possible association of CA repeat polymorphism in the EGFR gene with risk of lung cancer in a Korean population. A bimodal pattern appeared, with a frequency of 57.1% for 20 CA repeats and 18.6% for 16 CA repeats. There was, however, no significant difference in distribution of allele genotypes between all lung cancer cases and the controls, nor among histological types for the cases.

Association of T Cell Costimulatory and Downregulatory Gene Polymorphisms and Susceptibility to Multiple Myeloma.

Multiple myeloma (MM) is a B-lineage malignancy characterized by an accumulation of isotype-switched, immunoglobulin-producing monoclonal plasma cells. Additionaly phenotype and functional abnormalities of T cell are observed. The implication of T cells in the development of plasmocytoma has been shown in murine model. The study was undertaken to evaluate the association between polymorphisms of the genes encoding major T cell costimulatory (CD28, ICOS) and downregulatory (CTLA-4) molecules and susceptibility to MM in a Polish population. One hundred patients with MM and 202 healthy subjects were studied. Genomic DNA was isolated from whole frozen blood using the NucleoSpinR Blood kit. Allele identification was achieved by PCR amplification. The amplified product for SNP loci was purified and minisequenced using the commercial kit SNapShot (PE Applied Biosystems). The dinucleotide repeat polymorphism was studied by PCR and fluorescence based technique. The products were analyzed on the ABI PRISM 310 Genetic Analyzer (ABI PRISM 310 capillary electrophoresis system).We found an association of 49G in exon 1 and (AT)82 alleles in 3′untranslated region in the CTLA-4 gene with MM [p=0.018, OR=1.57, 95% CI=1.08–2.29 and p=0.0013, OR=1.85, 95% CI=1.27–2.72, respectively] while no association between T/C substitution in intron 3 of the CD28 gene, the dinucleotide (GT)n repeat polymorphism in intron 4 in ICOS gene and C/T base exchange in the promoter (position −318) in the CTLA-4 gene and MM was observed. Our results indicate that the A/G substitution in exon 1 and microsatelite polymorphism in the 3′untranslated region in the CTLA-4 gene might be a susceptibility locus for MM.The present study is the largest and comprehensive to date to evaluate the association between genetic polymorphisms of genes encoding T cell costimulatory and downregulatory molecules and susceptibility to MM.

Association of the CT gene (CA) polymorphism with BMD in osteoporotic mexican women

Calcitonin (CT) plays a role in the pathogenesis of osteoporosis and genetic variations in or adjacent to the CT gene may be associated with loss of bone mineral density (BMD). The correlation between a dinucleotide (cytosine-adenine) repeat polymorphism at the CT locus and BMD was examined in 70 osteoporotic women, 70 non-osteoporotic women and 500 subjects from the Mexican population. The allele A and genotype AA frequencies were significantly higher in osteoporotic women than in non-osteoporotic women (60% vs 32%; p < 0.0001 and 41% vs 14%; p = 0.0007, respectively). Genotype AA was associated with the presence of osteoporosis [odds ratio 2.58; 95% confidence interval (CI); 1.62-4.12]. Likewise, the loss of lumbar BMD and T scores were related to the presence of allele A: subjects with a single A allele displayed lower values for lumbar BMD and T score (84.02% and -1.51, respectively) than those who do not present any A allele (89.61% and -0.88, respectively). Individuals with two alleles A showed the lowest lumbar BMD and T-score values (73.77% and -2.51, respectively). Analysis of potential confounder demonstrated that aging has a significant effect on osteoporosis development (odds ratio 1.1; 95% CI; 1.1052-1.152).

P-351: Interferon-γ gene dinucleotide (CA) repeat polymorphism in patients with endometriosis

P-351: Interferon-γ gene dinucleotide (CA) repeat polymorphism in patients with endometriosis

C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1α gene define HIF-1α protein expression in non-small cell lung cancer

In this study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the patterns of HIF-1alpha protein expression in non-small cell lung carcinomas (NSCLC) and the expression of HIF-1alpha down-stream proteins. Specific HIF-1alpha polymorphisms were assessed in a series of patients with NSCLC: (a) the C to T transition at nucleotide 1744 (position 2028 according to sequence with accession number , which gives rise to Pro/Ser variation at codon 582), (b) the G to A nucleotide substitution at point 1790 (position 2046 according to sequence with accession number , which gives rise to Ala/Thr variation at codon 588), and (c) the dinucleotide GT repeat polymorphism in intron 13. Immunohistochemistry for HIF-1alpha and down-stream proteins (VEGF, LDH-5, GLUT-1) was also performed in tumor material. A strong association of the P582S polymorphism and of GT repeat polymorphism higher than 14/14 with increased HIF-1alpha expression was noted. HIF-1alpha polymorphism did not relate to the expression of the HIF-1alpha downstream proteins analysed, but significant association of HIF-1alpha expression with LDH-5 was confirmed (p=0.008). HIF-1alpha polymorphisms may have an important impact on HIF-protein stability and, eventually, function.

Angiogenesis pathway gene polymorphisms associated with clinical outcome in recurrent ovarian cancer treated with low dose cyclophosphamide and bevacizumab: A California Consortium Trial

5017 Background: Despite advances in chemotherapy, ovarian cancer remains a major cause of cancer mortality worldwide. It has therefore become essential to identify novel therapeutic targets, such as angiogenesis which is a complex process regulated by the delicate balance between various local proangiogenic and antiangiogenic proteins. Bevacizumab, a monoclonal antibody binding to VEGF, has shown significant activity in colon, breast, lung and ovarian cancer. There are no established molecular markers to predict response or time to tumor progression for Bevacizumab based chemotherapy. The key enzymes of the VEGF pathway are: Vascular Endothelial Growth Factor (VEGF), VEGF Receptor (VEGFR), Hypoxia Inducible Factor1 (HIF α and β-subunit), Neuropilin1 (NRP), Interleukin-8 (IL-8), Adrenomedullin (AM) and Leptin. Methods: Seventy patients with refractory ovarian cancer were enrolled in a Phase II clinical trial and treated with Cyclophoshamide 50 mg po/Bevacizumab 10 mg/kg IV every 14 days. From 52 patients blood samples were available for gDNA extraction and PCR-RFLP assays. Results: 13 patients had a PR (25%) and 39 were non responders. 31 pts had progressed. Median follow-up of 8.3 months with a median progression-free survival of 6.6 months. Patients who were homozygous A/A or heterozygous A/T genotype at the −251 locus in the IL-8 gene had a lower response rate than those who were T/T (P = 0.047 Fisher’s exact test). Patients with Vegf936 C/C had a median TTP of 6.5 months, pts with any T (T/T, C/T) had a median TTP of 17.2 months. Pts carrying both AM 3’end alleles &lt;14 CA repeats had 3.4 months median TTP, patients with at least one allele &gt;14 showed a median TTP of 6.6 months; for both alleles &gt;14 patients showed 8.7 months of median TPP (P = 0.0006 Log-rank test) Conclusions: Our data suggest for the first time, that IL-8 may be a potential molecular predictor of response to Bevacizumab based chemotherapy. We also demonstrate that both VEGF 936 and the AM 3’ dinucleotide repeat polymorphisms are potential molecular markers for time to tumor progression. A larger prospective study is needed to validate and confirm our preliminary findings. This study was supported by NCI grant NO1 CM 17101. [Table: see text]

CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype

PurposeThe study's purpose was to understand the molecular basis for different clinical phenotypes of the 5T variant, a tract of 5 thymidines in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which disrupts processing of CFTR mRNA and reduces synthesis from the corresponding CFTR alleles. MethodWe analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, Delta F508. Almost all Delta F508 mutation alleles occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans. ResultsOf the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which we had clinical information, 17.6% of females (6/34) and 66.7% of males (10/15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42% or 5/12) and more than 80% (5/6) in males is 12TG-5T-470V. We also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype. ConclusionOverall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype.

EGFR Dinucleotide Repeat Polymorphism as a Prognostic Indicator in Non-small Cell Lung Cancer

The epidermal growth factor receptor (EGFR) has been implicated in tumor growth and progression. Intron 1 of the EGFR gene contains a polymorphic simple sequence repeat (SSR) of 14 to 21 CA dinucleotides, the length of which correlates inversely with the level of EGFR transcription. The authors hypothesized that a shorter length of tumor SSR would be associated with poorer survival in patients with non-small cell lung cancer (NSCLC). Patients enrolled in Eastern Cooperative Oncology Group E3590 (a randomized, prospective trial of adjuvant therapy following resection of stages II and IIIa NSCLC) were randomized to radiation or radiation plus chemotherapy. Genomic DNA extracted from resected tumors was amplified for EGFR intron 1 by polymerase chain reaction and sequenced in a 3730XL DNA analyzer. One hundred fifty-seven primary tumors were sequenced, 106 (68%) of which were heterozygous for intron 1. The most common genotypes were allele lengths of 17/19 dinucleotides (17.8%), 17/18 (11.4%), and 19/19 (11.4%). Allele status (homozygous versus heterozygous) did not correlate with race, gender, weight, performance status, histology, stage, or survival. Shorter allele length (< or =18 versus >18 CA dinucleotide repeats) was associated with squamous cell histology (p = 0.03). Allele sum of greater than 35 was associated with improved overall survival (log-rank p = 0.03, hazard ratio = 0.66). This is the first study to characterize the EGFR intron 1 SSR polymorphism in NSCLC. Tumors were most commonly heterozygous for SSR length. Squamous histology was associated with a shorter SSR. Longer sequences are associated with improved survival.

EGFR Dinucleotide Repeat Polymorphism as a Prognostic Indicator in Non-small Cell Lung Cancer

EGFR Dinucleotide Repeat Polymorphism as a Prognostic Indicator in Non-small Cell Lung Cancer

Dinucleotide repeat polymorphism in intron II of human Toll‐like receptor 2 gene and susceptibility to rheumatoid arthritis

Human Toll-like receptors (TLRs) participate in innate immune response and signal the activation of adaptive immunity. The presence of a functional intronic polymorphism consisting of guanine-thymine repeats in TLR2 gene was recently reported. Here, we investigated a dinucleotide repeat polymorphism in intron II of TLR2 in Korean patients with rheumatoid arthritis (RA). The numbers of guanine-thymine [(GT)(n)] repeats in intron II of the TLR 2 gene were counted in 183 patients with RA and in 148 healthy controls, using the gene scanning technique. We classified alleles into two subclasses for further analysis, 12-16 GT repeats (S allele) and 17-28 repeats (L allele). By subgroup analysis, we also examined whether the S allele is associated with the presence of shared epitope (SE), rheumatoid factor (RF), joint erosion and extra-articular complications. S-allele frequency was significantly increased in patients with RA than in healthy controls [30.3% vs. 23.0%, P = 0.03, or 1.46, 95% confidence interval (CI) 1.03-2.07], and genotypes containing S alleles were more frequent in patients with RA than in healthy controls (54.4% vs. 46.5%. P = 0.04, or 1.57, 95% CI 1.01-2.42). A skewed S-allele distribution was not found to be related to the presence of SE. Subgroup analysis showed no genotypic or allele frequency differences between patients with/without RF, joint erosion, or extra-articular complications. Genotype containing shorter GT repeats in intron II of the TLR2 gene may confer susceptibility to RA in Koreans.

A microsatellite polymorphism in the heme oxygenase‐1 gene promoter is associated with risk for melanoma

Heme oxygenase-1 (HO-1) has been demonstrated to play an important role in the regulation of signaling systems, which are involved in the control of cell cycle progression and apoptosis. Recently, a (GT)n dinucleotide repeat polymorphism in the HO-1 promoter was shown to modulate HO-1 gene expression. Short (<25 GT) repeats are associated with an increased HO-1 upregulation after stimulation than are longer repeats. Malignant melanoma (MM) is the most serious cutaneous malignancy with high tendency to aggressive growth and resistance to apoptosis. Therefore, we sought to study the influence of this polymorphism on the progression of MM. We determined the HO-1 promoter genotype in 152 patients with MM and 398 healthy controls and studied their association in regard to susceptibility to MM, Breslow thickness and disease-free survival. In our study, the homozygous short allele with <25 (GT)n repeats (S/S) was found more frequently in the melanoma group compared to the healthy control population (21 and 12%, respectively). The calculated risk for acquiring primary MM in S/S carriers was 2-fold higher compared to those with L-allele types (95% confidence interval: 1.2-2.4, p = 0.03). Additionally, the S/S genotype was significantly associated with primary tumors with deeper Breslow thickness compared to L-allele (>25 repeats) carriers (mean Breslow thickness: 4.0 +/- 2.9 mm versus 3.1 +/- 1.7 mm, p = 0.03). These data suggest that HO-1 might render a higher risk for MM in S/S genotype individuals and could represent an important candidate gene in the pathogenesis and growth of malignant melanoma.