Population Genetics and Disease Predisposing Genes
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Abstracts S22 Population Genetics and Disease Predisposing Genes 33 34 HLA CLASS I AND CHEMOKINE GENE EXPRESSION A NEW HLA-DRB1 ALLELE: DRB1* 1152 IN RENAL CELL CARCINOMAS Giuseppina Ozzella, Palmina I. Monaco, Angela Iacona, Elide Calcagni, José María Romero, José Manuel Cózar, Julia Cantón, Antonio Garrido, Claudio Cortini, Daniela Piancatelli, Anna Aureli, Giuseppe Tufano, Teresa Cabrera, Pilar Jiménez, Susana Pedrinaci, Miguel Tallada, Antonina Piazza and Domenico Adorno. Federico Garrido, Francisco Ruiz-Cabello. Servicio Análisis Clínicos e C.N.R. Institute for Organ Transplantation, Rome - Italy Inmunologia, Hospital Universitario Virgen de las Nieves. Granada. Spain Searching for a potential related bone marrow donor, a new HLA- DRB1*11 allele, DRB1*1152, was identifi ed in three members of a Moroccan Berber Immune mechanisms have been suggested to play a role in the natural family. The doubtful presence of a new allele raised from some discrepancies disease course of RCC. The objective of this study was to examine factors among family members’ DRB1 low resolution typing. So, all members were that may be involved in the signifi cant survival benefi t of immunotherapy studied performing PCR SSP high resolution typing. Father’s DRB1 typing for RCC patients. A low frequency of total or HLA haplotype loss was surely permitted to assign DRB1*1104. It was not possible to defi ne the second found and, in parallel, the tumour tissue expressed more HLA classI/ allele because of an ambiguity between DRB1*1117 and some DRB1*14 alleles, B2m mRNA. These data signifi cantly differ from those reported in other due to a false positive reaction. HLA class II serological typing of father assigned epithelial tumours. Furthermore, chemokines and their receptors play key DR11, DR14. Instead, it seemed possible to assign DRB1*1117 allele to the roles in leukocyte traffi cking and are also implicated in cancer metastasis. patient and his matched brother, without any mismatch, just because father’s false positive reaction was now used to assign DRB1*1401 allele, inherited from We identifi ed a number of chemokines that were highly expressed in RCC mother. Sister’s high resolution typing permitted to assign, without any ambiguity, versus normal tissue. RT-PCR analysis showed expression of antiangiogenic DRB1*1104 inherited from father and DRB1*1401 from mother. All these agents I-TAC and IP-10, and proinfl ammatory chemokines MIP-1a and results supported the presence of a new DRB1*11 allele. Molecular cloning and RANTES in RCC tissues and very weak or undetectable expression in direct sequencing confi rmed that the new allele differs from DRB1* 1117 by one most of the normal kidney tissues. In contrast, the angiogenic SDF-1 was nucleotide substitution at position 265 (T to C) of exon 2, encoding an amino acid more strongly detected in the normal tissue. This chemokine production substitution of Tyrosine (TAC) to Histidine (CAC) at codon 60. The nucleotide pattern was correlated with a preferential recruitment of CD4+ Th1- sequence reported was submitted to GenBank database in March 2004 obtaining polarized effector memory cells that express CXCR3/CCR5, monocytes the accession number AY574194. The name DRB1* 1152 (HWS10002397) has been offi cially assigned by the WHO Nomenclature Committee for Factors of and NK cells. The composition of the tumour infi ltrate was different in HLA System in May 2004. more advanced tumours. In conclusion, upregulation of HLA class I gene Comparison of DRB1*1152 with all DRB1*14 allelic sequences on the IMGT expression in addition to chemokine expression in the tumour environment HLA database showed that the nucleotide substitution at codon 60 (CAC) was may contribute to the successful response of RCC to immunotherapy. shared with some DRB1*14 alleles. This may explain the class II serological typing that assigned in the father an erroneous DR14. 35 36 HLA ASSOCIATIONS WITH HIV-1 INFECTION IN BULGARIAN DISTRIBUTION OF HPA-GENES AND GENOTYPES IN THE PATIENTS POPULATION OF RUSSIAN UNRELATED DONORS Fani Martinova, Roumiana Markova, Ivailo Elenkov, Vera Popova, Larisa.L.Golovkina, Tatyana Makarik, Andrey B. Sudarikov Velislava Terzieva, Maria Yankova Hematologic Scientifi c Centre of Medical Science Russian Academy, Hospital “Pirogov”, NCIPD, Infect. Dis. Hospital, Sofi a, Bulgaria Moscow, Russia Due to the major role of the HLA locus in controlling the immune Race and populational distinctions in prevalence of HPA-genes (human response, associations between HLA genes and progression to AIDS have platelet antigens) are known. Defi nition of frequency allele variants and been extensively studied. The aim of the our study was to determine which genotypes HPA matters for immunogenetic and transfusion. The research HLA alleles from class I (HLA-A, -B) and class II (HLA-DRB1) were problem - studying of distribution of HPA-genes among Russians. A method presented in HIV-1 infected patients. of research - polymerase chain reaction with allele-specifi c primers of fi rm HLA-A, B and DRB1 alleles were tested in 17 patients with chronic HIV- “Protrans” for identifi cation of twelve allele genes “á” and “b” of loci 1 infection. 200 control healthy individual were tested too. Fifteen of the HPA-1,-2,-3,-4,-5 and -6. A material - DNA leukocytes of peripheral blood patients were under highly active antiretroviral therapy (HAART) (2NRTIs of 229 unrelated donors. Allele genes HPA- HPA-4A and HPA-6a met at and 1PI). all surveyed persons, HPA-1a - at 94,32 %, HPA-2a –at 98,25%, HPA-3a The HLA alleles were identifi ed using polymerase chain reaction (PCR)- - at 78,60 %, HPA-3b - at 70,74 % and HPA-5a – at 99,13 of Russians. amplifi ed DNA hybridized with sequence-specifi c probe (SSP). Allele genes HPA-1b,-2b,-5b met approximately identical frequency - at The frequencies of HLA class I antigens B*47 (p=0.0258, OR=13.665), 27,95 %, 21,83 % and 20,09 % of individuals. Frequencies of genotypes B*58 (p=0.0258, OR=13.665) and B*65 (p=0.0003) were increased in all are established: HPA-1a/a - 0,72, -1a/b - 0,22, -1b/b - 0,06; HPA-2a/a-0,78,- HIV-1 positive patients in comparison with the controls. The frequency of 2a/b-0,20; -2b/b-0,017; HPA-3a/a-0,297,-3a/b-0,49,-3b/b-0,214; HPA-5a/ the antigen B*35 was weakly and non-signifi cantly increased. HLA-B*7 a-0,8,-5a/b-0,19, 5b/b-0,009. Genotypes HPA-4b/b, HPA-6b/b have not and B*57 alleles were missing in all patients. been revealed. Gene frequencies have made 0,83 and 0,17 for HPA-1a and The frequencies of HLA class II antigens DRB1*01 and DRB1*13(*06) HPA-1b; 0,88 and 0,12 for HPA-2a and HPA-2b; 0,54 and 0,46 HPA-3a and have been found increased in patients. The frequency of DRB1*11(*05) has HPA-3b; 1,0 and 0 for HPA-4a, 6a and-4b,-6b; 0,895 and 0,105 for HPA-5a been established decreased in all patients in comparison with controls. and HPA-5b. The allele and genotypes frequencies of HPA at inhabitants Our fi ndings, although preliminary, suggest that HLA alleles infl uence of Russia are comparable to frequencies of genes in the East European resistance or susceptibility in a small cohort of HIV-1 infected Bulgarians, population. investigated up to now. Further studies are in progress to evaluate the correlation between host genetic profi les, progression to AIDS and the clinical outcome of the disease. Genes and Immunity Abstracts S23 37 38 HLA ALLELES AND HAPLOTYPES IN THE GALICIAN STUDY OF HLA ALELES IN MULTIPLE SCLEROSIS IN POPULATION: RELATEDNESS TO OTHER SPANISH AND CASTILLA Y LEON (SPAIN) EUROPEAN POPULATIONS Victoriano J Leon, Roberto Rodríguez-Perez1, Jesus.L.Cacho 1 , Alberto Torío, Pilar Sánchez, Rosario Couceiro, Maria J. Formoso, Clara Y.Chong1. Alonso. Laboratory of Immunology, Hosp. Juan Canalejo, La Coruña, Servicio de Bioquimica, 1 Servicio de Neurologia. Hospital Universitario Spain de Salamanca. Galicia is a region situated in Northwest Spain with a population of Celtic Introduction: Our Spanish region, Castilla y Leon, presents a tight origin. The geographical isolation and migratory patterns (high emigration population with more than 2 million of inhabitants which has not received rates throughout centuries and almost no immigration until recent years) has emigrants in the last centuries, instead of it the population has emigrated. preserved its language and cultural identity. Thus, everything becomes suitable for a population study of diseases that HLA class I and II alleles have been studied in 140 old ancestry unrelated appear in young people with Multiple Sclerosis (MS). We have chosen for Caucasian donors representative of the four different Galician provinces. our study the markers HLA A3, B7 and DR15 in patients with MS in our Allele and phenotype frequencies were estimated by ‘maximum-likelihood’ region. and phylogenetic trees were constructed from the allelic frequencies by Material and Methods: We have studied a series of 98 diagnosed patients the neighbor-joining method to obtain the genetic distances between with MS according to approaches of POSER, and 129 healthy controls populations. (HC). The DNA was extracted using the technique of Salting-Out. The The most frequent haplotypes were A1-B8-DRB1*0301-DQB1*0201 genes HLA were studied with Kits Dynal. It was also studied a well-defi ned (0.035), A2-B44-DRB1*0701-DQB1*0202 (0.025), A2-B49-DRB1*1302- genetic marker of EA as it is the Apo E, kit of Innogenetics. DQB1*0604 (0.021), A29-B44-DRB1*0701-DQB1*0202 (0.018), and A2- Results: The frequency of allele HLA A3 was 41% in MS (24% in HC), B18-DRB1*1104-DQB1*0301 (0.018).