Genetic Characterization of Endometriosis Patients: Review of the Literature and a Prospective Cohort Study on a Mediterranean Population.

The pathogenesis of endometriosis is unknown, but some evidence supports a genetic predisposition. The purpose of this study was to evaluate the recent literature on the genetic characterization of women affected by endometriosis and to evaluate the influence of polymorphisms of the wingless-type mammalian mouse tumour virus integration site family member 4 (WNT4), vezatin (VEZT), and follicle stimulating hormone beta polypeptide (FSHB) genes, already known to be involved in molecular mechanisms associated with the proliferation and development of endometriotic lesions in the Sardinian population. Materials and Methods: In order to provide a comprehensive and systematic tool for those approaching the genetics of endometriosis, the most cited review, observational, cohort and case-control studies that have evaluated the genetics of endometriosis in the last 20 years were collected. Moreover, 72 women were recruited for a molecular biology analysis of whole-blood samples-41 patients affected by symptomatic endometriosis and 31 controls. The molecular typing of three single nucleotide polymorphisms (SNPs) was evaluated in patients and controls: rs7521902, rs10859871 and rs11031006, mapped respectively in the WNT4, VEZT and FSHB genes. In this work, the frequency of alleles, genotypes and haplotypes of these SNPs in Sardinian women is described. Results: From the initial search, a total of 73 articles were chosen. An analysis of the literature showed that in endometriosis pathogenesis, the contribution of genetics has been well supported by many studies. The frequency of genotypes observed in the groups of the study population of 72 women was globally coherent with the law of the Hardy-Weinberg equilibrium. For the SNP rs11031006 (FSHB), the endometriosis group did not show an increase in genotypic or allelic frequency due to this polymorphism compared to the control group (p = 0.9999, odds ratio (OR) = 0.000, 95% confidence interval (CI), 0.000-15.000 and p = 0.731, OR = 1639, 95% CI, 0.39-683, respectively, for the heterozygous genotype and the polymorphic minor allele). For the SNP rs10859871 (VEZT), we found a significant difference in the frequency of the homozygous genotype in the control group compared to the affected women (p = 0.0111, OR = 0.0602, 95% CI, 0.005-0.501). For the SNP rs7521902 (WNT4), no increase in genotypic or allelic frequency between the two groups was shown (p = 0.3088, OR = 0.4133, 95% CI, 0.10-1.8 and p = 0.3297, OR = 2257, 95% CI, 0.55-914, respectively, for the heterozygous genotype and the polymorphic minor allele). Conclusion: An analysis of recent publications on the genetics of endometriosis showed a discrepancy in the results obtained in different populations. In the Sardinian population, the results obtained do not show a significant association between the investigated variants of the genes and a greater risk of developing endometriosis, although several other studies in the literature have shown the opposite. Anyway, the data underline the importance of evaluating genetic variants in different populations. In fact, in different ethnic groups, it is possible that specific risk alleles could act differently in the pathogenesis of the disease.

Hematological phenotypes in children according to the α-globin genotypes.

Limited information is available on the hematological characterization of the α-thalassemia carrier in pediatric age. The objective of this report was to evaluate the red cell indices according to the α-globin genotype in a cohort of children evaluated in Sardinia. Moreover, we verified the frequency of different α-globin genotypes in this cohort. A total of 453 subjects were investigated for hematological indices and for the most common α-globin defects present in Sardinia. Of them, 352 with HbA2≤3.2%, and no iron deficiency anemia were taken into consideration to evaluate the red cell indices according to the α-globin genotype in pediatric age. A total of 11 different α-genotypes were detected, confirming the wide heterogeneity of α-thalassemia in Sardinia. Moreover, our results showed that the hematological parameters in normal children may be conditioned by the clinically occult coinheritance of mild α-thalassemia alleles as already described in the adult population while microcytosis and hypocromia in children without iron deficiency should suggest the coexistence of two α-globin defects. We concluded that recognizing the α-globin gene mutations for a particular population with their particular red cell indices may help pediatricians to perform a correct diagnosis distinguishing among physiological and pathological types of microcytosis and hypocromia.

A genetic score for the prediction of beta-thalassemia severity.

Clinical and hematologic characteristics of beta(ß)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 ß-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R(2)=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P<0.001) and with transfusion dependency status (Area Under the Receiver Operating Characteristic Curve=0.774; P<0.001). Finally, an automatized on-line calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the present results could be helpful in the management of patients, both as a predictive score for screening and a standardized scale of severity to overcome the major-intermedia dichotomy and support clinical decisions.

Natural history of hepatitis C in thalassemia major: a long-term prospective study.

BACKGROUND: Transfusion-acquired hepatitis C virus (HCV) remains an important problem among patients with thalassemia. In this study, we evaluated the natural history of post-transfusional hepatitis C in thalassemia major, paying special attention to spontaneous viral clearance, to factors influencing the chronicity rate and fibrosis progression. DESIGN AND METHODS: A prospective study to evaluate the incidence and etiology of transfusion-related hepatitis was started in 1980. In patients who developed hepatitis C, HCV RNA, ALT, and ferritin were measured over time. The correlation between interleukin-28B gene polymorphisms and viral clearance was also analyzed. RESULTS: Seventy-three of 135 patients (62.2%) acquired HCV. An extended follow-up (22 to 30 yr) with HCV RNA assessment was available in 52 patients. Of them, 23 (44.2%) cleared the virus. The proportion of IL-28B genotypes was different between the subjects who cleared the virus and the subjects who did not. Fibrosis progression was similar in HCV RNA-positive and HCV RNA-negative patients. Liver iron was the only factor associated with the fibrosis. CONCLUSIONS: In thalassemia patients with HCV infection, liver iron does not play a major role in influencing the chronicity rate, whereas it is significantly associated with the fibrosis.

Genetic modifiers of ß-thalassemia and clinical severity as assessed by age at first transfusion.

BACKGROUND: The clinical and hematologic features of ß-thalassemia are modulated by different factors, resulting in a wide range of clinical severity. The main factors are the type of disease-causing mutation and the ability to produce α-globin and γ-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of ß-thalassemia as assessed by the patients' age at first transfusion. DESIGN AND METHODS: We studied the effect of seven loci in a cohort of 316 Sardinian patients with ß(0)-thalassemia. In addition to characterizing the ß-globin gene mutations, α-globin gene defects and HBG2:g.-158C>T polymorphism, we genotyped two different markers in the BCL11A gene and three in the HBS1L-MYB intergenic region using single nucleotide polymorphism microarrays, imputation and direct genotyping. We performed Cox proportional hazard analysis of the time to first transfusion. RESULTS: According to the resulting model, we were able to explain phenotypic severity to a large extent (Harrell's concordance index=0.72; Cox & Snell R(2)=0.394) and demonstrated that most of the model's discriminatory ability is attributable to the genetic variants affecting fetal hemoglobin production (HBG2:g.-158C>T, BCL11A and HBS1L-MYB loci: C-index=0.68, R(2)=0.272), while the remaining is due to α-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population. CONCLUSIONS: This detailed analysis clarifies the impact of genetic modifiers on the clinical severity of the disease, measured by time to first transfusion, by determining their relative contributions in a homogeneous cohort of ß(0)-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with ß-thalassemia.