Genetic epidemiology of glioblastoma multiforme: confirmatory and new findings from analyses of human leukocyte antigen alleles and motifs.

BACKGROUND: Human leukocyte antigen (HLA) class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM). METHODOLOGY/PRINCIPAL FINDINGS: As an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio=0.41, p=0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio=2.71, p=0.02). CONCLUSIONS/SIGNIFICANCE: HLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations.

Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression.

BACKGROUND: CTLA4 in the chromosome 2q33 region encodes cytotoxic T-lymphocyte (CTL) associated antigen 4, which downregulates CTL responses. We examined the relationships between common CTLA4 variants and several outcomes of HIV-1 infection in adults and adolescents. METHODS: We studied 765 HIV-1-infected persons: 558 Caucasian seroconverters from three cohorts (MACS, ACS, and DCG) and 207 infected adolescents (mostly female) from another cohort (REACH) of mixed ethnicity. Single nucleotide polymorphisms in CTLA4 promoter (-1147C/T, -658C/T, -318C/T), coding sequence (49A/G) and the 3' untranslated region (CT60A/G) were resolved by PCR-based techniques. Repeated measures and survival analyses were used to test allelic and haplotypic associations with HIV-1 viral load (VL) and time to AIDS, respectively. RESULTS: Individuals carrying -318T or the (-1147) T-(-318) T haplotype had elevated HIV-1 VL in MACS and REACH but reduced VL in DCG and ACS participants. Time-dependent associations of CTLA4-318T with VL were observed in MACS and REACH (P = 0.03-0.09). In Cox regression models adjusted for age and established contributory markers in CCR5 and HLA class I genes, CTLA4-318T was associated with rapid progression to AIDS in MACS (relative hazard 1.69; 95% confidence interval, 1.15-2.49; P < 0.01) as opposed to a non-significant slower disease progression in ACS and no appreciable association in DCG. CONCLUSIONS: Association of CTLA4 genotypes with clinical and virological outcomes following HIV-1 infection appeared to vary with time and among the cohorts. Further analyses in conjunction with other biologically and positionally related genes, such as CD28 and ICOS, may help explain the disparate findings.

Positive and negative associations of human leukocyte antigen variants with the onset and prognosis of adult glioblastoma multiforme.

Associations of genetic factors with malignant gliomas have been modest. We examined the relationships of human leukocyte antigen (HLA) and related polymorphisms to glioblastoma multiforme in adult Caucasians (non-Hispanic Whites) from the San Francisco Bay area. For 155 glioblastoma multiforme patients and 157 control subjects closely matched by ethnicity, age, and gender, PCR-based techniques resolved alleles at HLA-A, -B, -C, and -DRB1 loci along with short tandem repeat polymorphisms of MICA exon 5 and TNFb. By multivariable logistic regression, B*13 and the B*07-Cw*07 haplotype were positively associated with glioblastoma multiforme (P=0.01 and <0.001, respectively), whereas Cw*01 was the only variant showing a negative association (P=0.05). Among glioblastoma multiforme patients, progression to death after diagnosis was slower in those with A*32 (relative hazard, 0.45; P<0.01) and faster in those with B*55 (relative hazard, 2.27; P<0.01). Thus, both the occurrence and the prognosis of glioblastoma multiforme could be associated with specific but different HLA genotypes. B*07 and the B*07-Cw*07 haplotype are much more common in Caucasians than other ethnic groups in the U.S., which may partially explain the higher incidence of glioblastoma multiforme in Caucasians.

HLA-B, -DRB1/3/4/5, and -DQB1 gene polymorphisms in human immunodeficiency virus-related Kaposi's sarcoma.

Polymorphisms of genes in the human leukocyte antigen (HLA) complex, particularly those encoding HLA-DR, have been suggested as markers of susceptibility to Kaposi's sarcoma (KS). We conducted a case-control study comparing 147 homosexual men who developed KS after infection by human immunodeficiency virus-1 (HIV-1) and human herpes virus 8 (HHV8) with 147 matched dually infected men without HIV-associated KS (HIV-KS) from the Multicenter AIDS Cohort Study. HLA-B, DRB1, DRB3, DRB4, DRB5, and DQB1 polymorphisms were examined by high-resolution DNA-based methods. Differences in distributions of genetic variants were tested by conditional logistic regression. Previously reported relationships with HLA-DRB1 alleles could not be confirmed. Instead, other associations were observed. In univariate analysis, KS was weakly associated with B*2702/5 (odds ratio (OR)=0.40, 95% confidence interval (CI)=0.18-0.91). Similar or stronger associations, positive or negative, were seen for haplotypes containing class II alleles: DRB1*1302-DQB1*0604 (OR=3.67, 95% CI=1.02-13.1), DRB4 (DR53) haplotype family members [OR=0.52, 95% CI=0.32-0.85], and DRB3 (DR52) haplotype family members (OR=1.69, 95% CI=1.07-2.67). The B*1402-DRB1*0102 haplotype, which invariably contains the V281L mutation in the 21-hydroxylase gene governing adrenal steroid biosynthesis, occurred in five cases and one control (OR=5.0, 95% CI=0.58-42.8). In a final multivariable analysis, only DRB1*1302-DQB1*0604 (OR=6.43, 95% CI=1.28-32.3, P=0.02) remained significantly associated with KS. Associations of HLA-DRB families with HIV-KS could reflect underlying immune dysregulation. The HLA B*1402-DRB1*0102 haplotype associated with increased risk of KS might represent an antigen-presenting pathway unfavorable for immune response to HHV8. Alternatively, the relationship might hold a clue to the predilection of KS for men because that haplotype harbors the mutant form of the 21-hydroxylase gene.