IFNL3 polymorphisms and HCV infection in patients with beta thalassemia.

UNLABELLED: BACKGROUND AND RATIONALE FOR THE STUDY: Genome-wide association studies have identified host genetic variation to be critical for spontaneous clearance and treatment response in patients infected with hepatitis C virus. Recently, the role of the IFNL3 polymorphisms in influencing the spontaneous clearance of HCV, the response to interferon and the progression of liver fibrosis, was also demonstrated in patients with thalassemia major infected by genotype 1b. In the present study we retrospectively analyzed 368 anti-HCV positive patients with beta-thalassemia at two Italian major centers in Cagliari and Torino. RESULTS: C/C variant of polymorphism rs12979860 was related to response to interferon treatment and, above all, to spontaneous clearance of the virus. However, the positive predictive power was stronger for viral persistence than spontaneous clearance and in such respect the TT allele was more predictive than CC. The methylation associated polymorphism rs4803221 had independent effects with respect to rs12979860 and the haplotype tagged by SNP rs12979860 and rs4803221 significantly could improve the viral clearance prediction in infected patients. Neither necroinflammation or bilirubin values in the chronic phase of the hepatitis C were related to IFNL3 polymorphisms. No relation among IFNL3 polymorphisms and fibrosis stage directly shown by the liver biopsy was found. CONCLUSIONS: Also in thalassemia the SNPs on chromosome 19q13 closely associates with spontaneous and treatment-induced HCV clearance. The viral clearance prediction is significantly improved by the haplotype tagged by SNP rs12979860 and rs4803221. Neither necroinflammation, bilirubin values or fibrosis stage seem to be related to IFNL3 polymorphisms.

Thalassemia minor, the Gilbert mutation, and the risk of gallstones.

BACKGROUND AND OBJECTIVES: Gallstones are a frequent complication of hemolytic anemias. The association with the mutation of the A(TA)nTAA motif of the promoter of the bilirubin UDP-glucuronosyltransferase gene has also been reported to increase the risk of gallstones. We studied the prevalence of cholelithiasis in thalassemia minor and the role of the Gilbert mutation. DESIGN AND METHODS: A group of 143 women obligate carriers of beta-thalassemia, and a control group of 170 hematologically normal women were compared. In both groups serum bilirubin, total cholesterol, and alanine-aminotransferase were measured and analysis of the mutation of the UGT-1A gene was performed. On the same occasion the women underwent ultrasonography. RESULTS: Total and unconjugated bilirubin were significantly higher in beta-thalassemia heterozygotes. Carriers of thalassemia had a higher prevalence of gallstones (20.3% vs 10.6% OR=2.15). Among the control group, the prevalence of gallstones did not differ significantly in relation to UGT1-A1 genotype, while in women carriers of beta-thalassemia it increased in an allele dose-dependent fashion. As compared to the controls, the odds ratios for the development of gallstones in thalassemic women were 1.68 (95% C.I.: 0.70-4.03) for those who had the normal UGT1-A1 genotype [(TA)6/(TA)6], 2.31 (95% C.I.: 1.06-5.02) for heterozygote carriers of the mutated genotype [(TA)7/(TA)6] and 3.88 (95% C.I.: 1.31-11.55) for those homozygous for the mutated genotype [(TA)7/(TA)7]. INTERPRETATION AND CONCLUSIONS: Thalassemia minor represents a risk factor for cholelithiasis and the Gilbert mutation further increases this risk. This is an additional example of how two genotypes can interact and modify a phenotype.

Molecular characterization of alpha-thalassemia in Pakistan.

Common alpha-thalassemia (thal) rearrangements were studied in a normal random population and in six ethnic groups of Pakistan. Analyses of 204 individuals from the normal population revealed the presence of only the -alpha(3.7) allele with an overall frequency of 8.3%. Ethnic differences were statistically significant for Pashtoon vs. Balochi (p < 0.0005) and Pashtoon vs. Sindhi (p < 0.002). Two hundred and eighty-five thalassemia patients were also studied to identify rare alpha-thal alleles. In this group, 24.6% of the patients had one or two alpha genes deleted. Two rare alleles in the Pakistani population, -alpha(4.2) (0.2%) and alphaalphaalpha(anti3.7) (0.9%), were identified in these patients. The -alpha(4.2) allele was found only in Sindhis, while alphaalphaalpha(anti3.7) was present in Punjabis, Sindhis and Balochis. Five patients with triplicated alpha genes were homozygous for either the beta+ or the beta(0) genotype.