RESUMEN
Genes are an important factor for the initiation of any disease. Many genes are associated with rheumatoid arthritis (RA) other than environmental factors. The main objective of the study was to evaluate the association of genes PADI4 (peptidylarginine deiminases 14) (rs2240340, rs1748033) and Human leukocyte antigen class II histocompatibility, D-related beta chain (HLA-DRB1) (rs2395175) polymorphisms in RA patients from Punjab, Pakistan. Blood samples of RA patients were collected from different hospitals of Sargodha. DNA was extracted, followed by PCR. Polymorphic analysis was performed in 300 rheumatoid arthritis patients and 300 healthy controls on PADI4 (rs2240340, rs1748033) and HLA-DRB1 (rs2395175). In PADI4 gene, both homozygous mutant genotype (TT) and heterozygous (CT) of SNP rs2240340 showed significant association by increasing the risk of RA up to two fold (OR 2.55; 95% CI 1.57-4.15; p = 0.0002). In case of rs1748033 polymorphism, homozygous mutant genotype (TT) showed significant association with RA by increasing the risk of disease up to three fold (OR 3.46; 95% CI 1.97-6.07; p = 0.0001), while heterozygous genotype (CT) of the same SNP showed significant association with RA by playing a protective role (OR 0.57; 95% CI 0.36-0.91; p = 0.0197). In HLA-DRB1 gene, homozygous mutant genotype (GG) of SNP rs2395175 showed no significant association with RA, while heterozygous genotype (AG) of the same SNP showed significant association with RA by playing a protective role (OR 0.44; 95% CI 0.27-0.71; p = 0.0009). Highly significance association of genes PADI4 (rs2240340, rs1748033) and HLA-DRB1 (rs2395175) polymorphisms with RA was observed in Pakistani population.
RESUMEN
Polymorphisms in DNA repair genes may alter the repair mechanism which makes the person susceptible to DNA damage. Polymorphic variants in these DNA repair pathway genes such as Poly (ADP-ribose) polymerase- 1 (PARP1) have been associated with susceptibility of several types of cancer including thyroid. Many studies have been published on PARP1 gene polymorphisms and carcinogenesis with inconsistent results. The present study was designed to explore the link between the PARP1 polymorphisms and thyroid cancer risk. This case-control study was comprised of 456 thyroid cancer patients and 400 healthy controls. Three SNPs of PARP1 gene; rs1136410, rs1805414 and rs1805404 were analyzed using ARMS-PCR. The combined genotype and haplotype analysis were performed using haploview software 4.2. Major allele homozygote (CC) of rs1136410 and combined genotype (TT+TC) of rs180414 showed a significant association with thyroid cancer risk (OR = 1.30; 95% CI 0.99-1.77; P = 0.05) and (OR = 0.43; 95% CI = 0.27-0.67; P = 0.03). Histological subtype analysis showed the significant association of selected PARP1 SNPs with papillary, follicular and anaplastic subtypes in thyroid cancer patients. Haplotype analysis showed that TCT (p = 0.01), CTT (p = 0.02) and CTC (p = 0.03) were significantly higher in controls when compared to cases. However, TTC (p = 0.05) and TCC (p = 0.01) haplotype frequency was significantly higher in cases compared to controls. Global haplotype analysis showed that there was an overall significant difference between cases and controls (p = 0.001). Identification of these genetic risk markers may provide evidence for exploring insight into mechanisms of pathogenesis and subsequently aid in developing novel therapeutic strategies for thyroid cancer.
Asunto(s)
Predisposición Genética a la Enfermedad , Haplotipos , Proteínas de Neoplasias/genética , Poli(ADP-Ribosa) Polimerasa-1/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Tiroides/genética , Adulto , Femenino , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Tiroides/epidemiologíaRESUMEN
PURPOSE: Variants in DNA repair genes may alter the repair mechanisms that make the persons vulnerable to DNA damage. These polymorphic variants in the DNA repair pathway genes, such as XRCC1, have been associated with susceptibility of several types of cancer including thyroid cancer. This study was designed to explore the link between XRCC1 polymorphisms and modulation of thyroid cancer risk. METHODS: Our study consisted of 456 thyroid cancer patients and 400 controls. For XRCC1 polymorphisms analyses, three single nucleotide polymorphisms (SNPs) (rs25489, rs25487 and 1799782) were selected and genotyped by ARMS-PCR. RESULTS: The homozygous mutant (AA) of rs25489 SNP showed highly significant association with thyroid cancer risk (OR=0.17; 95% CI=0.10-0.31; p=0.0001). In the rs25487 polymorphism all genotypes showed no significantly increased risk of thyroid cancer in patients compared to controls (p>0.05). In the rs1799782 of XRCC1 gene, the homozygous mutant (TT) significantly decreased the risk of thyroid cancer (OR=0.71; 95% CI=0.50-1.01; p=0.05). Eight haplotypes were generated for three selected SNPs (rs25489, rs25487 and rs1799782) of XRCC1 gene among thyroid cases and controls. The haplotype GAT (OR=1.69; 95% CI=1.25- 2.30; p=0.0005) and GGC (OR=2.75; 95% CI=2.11-3.58; p=1.29e-014) showed highly significant association with increased risk of thyroid cancer. The haplotypes AAC (OR=0.31; 95% CI=0.17-0.57; p=6.68e-005), AAT (OR= 0.51; 95% CI=0.34-0.78; p=0.001), AGT (OR=0.46; 95%CI=0.29- 0.71; p=0.0003) and GGT (OR=0.80; 95% CI=0.64-0.98; p=0.03) had significant reducing effect in thyroid cancer patients. CONCLUSIONS: XRCC1 Arg280His and Arg194Trp were associated with thyroid cancer in Pakistani population. These genetic markers may provide an insight into the disease pathogenesis and help open novel therapeutic strategies for thyroid cancer.
Asunto(s)
Neoplasias de la Tiroides/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias de la Tiroides/patologíaRESUMEN
We aimed to investigate the effect of hotspot variations of XRCC2 gene on the risk of head and neck cancer (HNC) in 400 patients and 400 controls. Five polymorphisms of XRCC2 gene G4234C (rs3218384), G4088T (rs3218373), G3063A (rs2040639), R188H (rs3218536) and rs7802034 were analyzed using Allele- specific polymerase chain reaction (ARMS-PCR) followed by sequence analysis. For rs3218373, the GG genotype indicated a statistically significant 3-fold increased risk of HNC (P < 0.001) after multivariate adjustment. For rs7802034, the GG genotype suggested statistically significant 2-fold increased risk of HNC (P < 0.001). For SNP of rs3218536, the AA genotype indicated a significant 3-fold increased risk of HNC (P < 0.001). Additionally, haplotype analysis revealed that TACAG, TGGAG, TACGG and TAGGA haplotypes of XRCC2 polymorphisms are associated with HNC risk. Two SNPs in XRCC2 (rs2040639 and rs3218384) were found increased in strong linkage disequilibrium. Furthermore, joint effect model showed 20 fold (OR = 19.89; 95% CI = 2.65-149.36, P = 0.003) increased HNC risk in patients carrying four homozygous risk alleles of selected polymorphisms. These results show that allele distributions and genotypes of XRCC2 SNPs are significantly associated with increased HNC risk and could be a genetic adjuster for the said disease.
Asunto(s)
Proteínas de Unión al ADN/genética , Haplotipos/genética , Neoplasias de Cabeza y Cuello/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND/AIMS: In mammalian cells, XRCC3 plays an important role in the DNA double-strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to thyroid cancer. In this study, we used a haplotype-based approach to investigate whether 5 selected SNPs i.e. rs1799796, rs1799794, rs861539, rs709399 and rs861530 of XRCC3 gene are associated with thyroid cancer risk in 456 cancer patients and 400 cancer-free controls. METHODS: Genotyping was performed using Allele-specific PCR followed by sequencing. Statistical analysis was performed to analyse gene and haplotype association. RESULTS: After analysis, frequency of mutant genotype/alleles of SNPs (rs1799796, p<0.0001; rs1799794, p<0.0001; rs861539, p<0.001; rs709399, p <0.0001; rs861530, p<0.002) was found significantly higher in thyroid cancer patients compared to controls. Significant associations were found for most of the variant genotypes in SNPs of rs1799794, rs1799796, rs861539, rs861530 and rs709399 in papillary thyroid and follicular cancer patients compared to other histologic subtypes of thyroid carcinoma. Additionally, haplotype analysis revealed that haplotypes, AACGA (p= 0.0005), AGTAA (p= 0.008), GATAA (p= 0.001), GGCAA (p= 0.001) were linked with significant increase in thyroid cancer risk. However, haplotype AGCGG (p= 0.0009) was associated with a significant reduced thyroid cancer risk. CONCLUSION: Our results suggest that common genetic variants in the XRCC3 gene of DSBR pathway may modulate thyroid cancer risk.