ABSTRACT
Background: Acute lymphoblastic leukaemia (ALL) is the most common malignancy in childhood. Despite numerous investigations very little is still known about its aetiology. However, in one genome wide association study conducted to identify the possible genetic risk factors, two allelic variations rs10821936 and rs10994982 in the 3rd intron of the ARID5B gene were identified as possible ALL risk alleles. Association between ARID5B gene variants and ALL risk was also been confirmed for different ethnic groups. Materials and Methods: Eight genetic variants in the gene ARID5B were genotyped - rs10994982, rs7908445, rs7923074, rs10821936, rs10821937, rs7896246, rs10821938 and rs7089424 in 77 ALL patients in remission and in 122 age and gender matched controls; parental samples were also genotyped in 50 cases. Results: Six out of the eight (rs7908445, rs7923074, rs10821936, rs10821937, rs7896246 and rs7089424) analysed allelic variations were identified in the case-control analysis as statistically significant risk alleles for ALL development. In the family study and using hybrid analysis, all allelic variations were significantly associated with ALL. During the study, risk haplotype was identified rs10994982/rs7908445/rs7923074/ rs10821936/ rs10821937/rs7896246/rs10821938/rs7089424 ATACCAAG with a frequency in cases of 0.17 and in the control group at 0.29 (chi square = 6.69, p value = 0.009). In the family association study the same haplotype showed statistical significance (chi squared = 10.3, p value = 0.001). Conclusions: Results of the study replicate and extend previously published findings for ARID5B localized allelic variants, but do not explain the mechanism of action related to the pathogenesis of ALL.
ABSTRACT
BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by allelic variants in ATP7B gene. More than 500 distinct variants have been reported, the most common WD causing allelic variant in the patients from Central, Eastern, and Northern Europe is H1069Q. METHODS: All Latvian patients with clinically confirmed WD were screened for the most common mutation p.H1069Q by PCR Bi-PASA method. Direct DNA sequencing of gene ATP7B (all 21 exons) was performed for the patients with WD symptoms, being either heterozygous for H1069Q or without it on any allele. RESULTS: We identified 15 different allelic variants along with eight non-disease-causing allelic variants. Based on the gene molecular analysis and patients' clinical data variant p.His1069Gln was found in 66.9% of WD alleles. Wide clinical variability was observed among individuals with the same ATP7B genotype. The results of our study confirm that neurological manifestations of WD are typically present later than the liver disease but no significant association between the presence/absence of the most common genetic variant and mode of initial WD presentation or age at presentation was identified. CONCLUSIONS: (1) The most prevalent mutation in Latvian patients with Wilson disease was c.3207C>A (p.His1069Gln); (2) No significant phenotype-genotype correlation was found in Latvian patients with Wilson disease; (3) The estimated prevalence of Wilson disease in Latvia is 1 of 24,000 cases which is higher than frequently quoted prevalence of 1: 30,000.
ABSTRACT
AIM: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. METHODS: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. RESULTS: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). CONCLUSION: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.
