Rapid method for detection of extra (TA) in the promoter of Bilirubin-UDP-Glucuronosyl transferase 1 gene associated with Gilbert Syndrome

Gilbert syndrome (GS) is an inherited form of chronic mild unconjugated hyperbilirubinemia (1)(2)(3), although many patients do not have a clear family history (4). Hepatic glucuronidation of bilirubin is catalyzed by isoenzyme 1A1 of UDP-glucuronosyl transferase (UGT1A1). The majority of GS subjects were found to be homozygous for an extra TA in the TATA-box in the promoter region of UGT1A1 (5)(6)(7). Transcription of the (TA)7 allele is reduced by at least 70% compared with the wild-type (TA)6 allele. Because bilirubin UGT1A1 is the only enzyme with substantial bilirubin glucuronidating activity in humans (8), the presence of this extra TA in both alleles can explain the impaired conjugation of bilirubin found in Caucasoid GS patients (6)

Prolactin and prolactin receptor gene polymorphisms in multiple sclerosis and systemic lupus erythematosus

Genes encoding for prolactin (PRL) and its receptor (PRLR) are possible candidates for multiple sclerosis (MS) and systemic lupus erythematosus (SLE) susceptibility. In fact: (1) a prolactin secretion dysfunction has been described in several autoimmune diseases including SLE and MS and their animal models; (2) both PRL and PRLR are structurally related to members of the cytokine/hematopoietin family and have a role in the regulation of the immune response; and (3) both PRL and PRLR genes map in genomic regions that showed linkage with autoimmunity. Prolactin maps on chromosome 6p, about 11-kb telomeric to HLA-DRB1 and PRLR in 5p12-13, which revealed evidence of linkage with MS in different populations. To evaluate a possible role of these two genes in SLE and MS we performed an association study of 19 PRL and PRLR single nucleotide polymorphisms (SNPs). These were directly searched by DHPLC in a panel of SLE and MS patients and selected from databases and the literature. The SNP allele frequencies were determined on patient and control DNA pools by primer-extension genotyping and HPLC analysis. Moreover a panel of HLA typed SLE and control individuals were individually genotyped for the PRL G-1149T polymorphism previously described to be associated with SLE. No statistically significant difference in the allele distribution was observed for any of the tested variations

Association of HLA class I markers with Multiple Sclerosis in the Italian and UK population: evidence of two independent protective effects

International audienceBackground: We recently confirmed the association with Multiple Sclerosis (MS) of HLA-A*02 and observed that the combined presence of HLA-Cw*05 significantly enhanced (3-fold) the protective effect of HLA A*02. Objectives and Methods: Since A*02-Cw*05 is carried by two HLA extended haplotypes characterized by the B*4402 and B*1801 alleles, respectively, we extended the association analysis to HLA-B*44 and -B*18 in our Italian sample (1445 MS cases and 973 controls) and verified these associations in a UK cohort (721 MS cases, 408 controls and 480 family trios). Results: A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR=0.27 p=3.3x10-5), was seen in the Italian samples and confirmed in UK family trios (OR=0.33 p=5.5x10-4) and in a combined cohort of UK families and case/controls (OR=0.53 p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR=0.38 p=6.5x10-7; UK: OR=0.60 p=0.0029) indicating that it was not secondary to linkage disequilibrium with B*44. At difference from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44 ) protection when adjusted for the remaining markers. Conclusions: We identified at least two independent protective effects which are tagged by A*02-Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalyzed factor characterizing the HLA extended haplotype/s carrying A*02 and Cw*05 or to a direct interaction between these allele

Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122Fondation pour la Recherche Médicale (ARS 2.09 Bertrand Fontaine), by Association pour la Recherche sur la Sclérose en Plaques, by Italian Foundation for Multiple Sclerosis, by INSERM, and by the French Ministry of Research (Centre d'Investigations Cliniques Pitié‐Salpétrière and Centre de Resources Biologiques