title: Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with B-cell chronic lymphocytic leukemia in the Polish population.
abstract: Abnormal expression of the costimulatory molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), CD28, and inducible co-stimulator (ICOS) leads to disturbances of immune response and an increased risk of cancer. An extended study was undertaken to evaluate the association among the polymorphisms CTLA-4c.49A>G, CTLA-4g.319C>T, CTLA-4g.*642AT(8_33), CD28c.17+3T>C, and ICOSc.1554+4GT(8_15) and susceptibility to B-cell chronic lymphocytic leukemia (B-CLL) in the Polish population. The study revealed increased frequency of the CTLA-4g.319C>T [T] allele and the CTLA-4g.319C>T [T] phenotype in B-CLL patients compared with healthy controls (p = 0.003, odds ratio [OR] = 1.73; and p = 0.009, OR = 1.74, respectively). The presence of the CD28c.17+3T>C [C] allele and the CD28c.17+3T>C [C] phenotype increased the OR of B-CLL to 1.59 (p = 0.007) and 1.74 (p = 0.007), respectively. Either CTLA-4g.319C>T or CD28c.17+3T>C was associated with time to Rai stage progression. The distributions of the alleles and genotypes of the ICOS gene significantly differed between patients and controls (p = 0.0009 and p = 0.006, respectively). Individuals possessing short alleles were 2.02 times more prone to B-CLL than others (p = 0.001), whereas carriers of long alleles were protected from B-CLL (p = 0.02, OR = 0.62). The haplotype association study and multivariate analysis confirmed the association of CTLA-4g.319C>T and ICOSc.1554+4GT(8_15) gene polymorphisms with B-CLL. The polymorphic sites CTLA-4c.49A>G and CTLA-4g.*642AT(8_33) did not correlate with B-CLL. Our results are the first in the literature to report that gene polymorphism of the costimulatory molecules CTLA-4, CD28, and ICOS contributes to susceptibility to B-CLL.
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Science, Wroclaw, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Suwalska
authors.forename: E
authors.initials: E
authors.lastname: Pawlak
authors.forename: L
authors.initials: L
authors.lastname: Karabon
authors.forename: A
authors.initials: A
authors.lastname: Tomkiewicz
authors.forename: T
authors.initials: T
authors.lastname: Dobosz
authors.forename: D
authors.initials: D
authors.lastname: Urbaniak-Kujda
authors.forename: K
authors.initials: K
authors.lastname: Kuliczkowski
authors.forename: D
authors.initials: D
authors.lastname: Wolowiec
authors.forename: A
authors.initials: A
authors.lastname: Jedynak
authors.forename: I
authors.initials: I
authors.lastname: Frydecka
mesh_terms: D000368:Aged; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D000943:Antigens, Differentiation / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D011044:Poland; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein