Association Between HLA DQBl * 03 and Cervical Intra-epithelial Neoplasia

Abstract

Background: Cervical intraepithelial neoplasia (CIN) and cervical cancer have been shown to be strongly associated with infection by human papillomavirus (HPV). However, other factors may be contributory in the progression from normal epithelium to CIN and cervical cancer, since not all women with HPV infection develop disease. Recently, it was demonstrated that there is a high risk for cervical cancer and CIN in women with HLA DQB1 * 03 (RR = 7.1, p < 0.0009) (1). Subsequent reports have been conflicting, due to sample size, genetic heterogeneity and differences in the techniques employed for the detection of HLA DQB1 * 03. Materials and Methods: DNA from cervical smears of 178 women with CIN and 420 controls with normal cervical cytology was analyzed by polymerase chain reaction (PCR) with type-specific primers for HPV 16, 18, 31, and 33. The DNA from test and control samples were also analyzed by a novel PCR technique, which mutates the first base of codon 40 (DQ alleles) from T to G to create an artificial restriction site for an enzyme Mlu I that distinguish DQB1 * 03 from other alleles and are confirmed by digestion of amplified DNA with Mlu I. Further analysis of individual DQB 1 * 03 alleles was performed using PCR and allele-specific primers. Results: One hundred forty-four (34%) out of 420 controls (all HPV 16, 18, 31, or 33 negative and normal cytology), 37/66 (56%) of CIN I and 72/112 (64%) of CIN III were positive for DQB1 * 03 (trend test, p < 0.001, X2 = 37.3). A significant association was observed between DQB1 * 03 and CIN (odds ratio 3.03; 95% CI 2.11-3.45). Of women with CIN, 131/ 178 (73.5%) had HPV (types 16, 18, 31, or 33) infection. There was a significant association between DQB1 * 03 and presence of HPV (odds ratio 3.43; 95% CI 2.25-5.10). Homozygosity for DQB1 * 03 was more strongly associated with CIN than heterozygosity (odds ratios 4.0 and 2.63, respectively); and for the presence of HPV (odds ratio 4.47; 95% CI 2.58-7.77). HLA DQB1 * 0301 was the most strongly associated allele with CIN and HPV (odds ratios 2.53 and 2.63, respectively). Conclusions: HLA DQB1 * 03 is associated significantly with CIN and may be permissive for HPV infection. Further analysis of class II HLA typing in CIN is necessary to evaluate this association.

Selected class I and class II HLA alleles and haplotypes and risk of high‐grade cervical intraepithelial neoplasia

“…10 In contrast, the DRB1*1501 and DQB1*0602 were only moderately correlated (r 5 0.60) and there was no correlation between HLA-B7 and DRB1*1501-DQB1*0602 in a study from Costa Rica. 19 In contrast to some previous studies 12,15,17,38 but in agreement with others, 10,11,13,19 there was no evidence of increased risk due to DRB1*1501-DQB1*0602. Only a single study examining the role of HLA and CIN has shown a significant protective effect for DRB1*1501-DQB1*0602.…”

“…The most consistent published evidence to date involves the HLA-DQB1*03 (DQ3) allele and HLA-DRB1*1501-DQB1*0602 haplotype. Increased risks (approximately 2-fold) for cervical cancer or malignant precursor lesions have been identified in different populations for HLA-DQB1*03 (DQ3) allele [7][8][9][10][11][12][13] or HLA-DRB1*1501-DQB1*0602 12,14-17 haplotype carriers. Other studies did not show any association with HLA-DQB1*03 [15][16][17][18][19] or HLA-DRB1*1501-DQB1*0602.…”

“…Other studies did not show any association with HLA-DQB1*03 [15][16][17][18][19] or HLA-DRB1*1501-DQB1*0602. 10,11,13,[18][19][20] One large study conversely reporting a significant protective association for the HLA-DRB1*1501-DQB1*0602 haplotype. 21 More consistent findings have been reported in favor of a protective effect (odds ratios (ORs) of approximately 0.3-0.4) for HLA alleles DRB1*13 and DQB1*0603, which are in linkage disequilibrium.…”

“…21 More consistent findings have been reported in favor of a protective effect (odds ratios (ORs) of approximately 0.3-0.4) for HLA alleles DRB1*13 and DQB1*0603, which are in linkage disequilibrium. [10][11][12][13][14][15]19,20 Two larger studies in distinct populations in the US and Costa Rica showed elevated risks of low-and high-grade cervical lesions and cancer in women who were carriers of both class I allele HLA-B7 and DQB1*0302. 19,21 The Biomarkers of Cervical Cancer Risk (BCCR) case-control study was designed to investigate the role of the several candidate alleles from Class I and Class II genes on the risk of preinvasive high grade cervical neoplasia in a Canadian population, after adjusting for the potential mediating or confounding effects of ethnicity and other known risk factors.…”

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

“…Other DQB1 alleles, such as the *03 (*0301), have shown an association in several other populations, 38 but previously no association in the Swedish population. There was no apparent difference between cases and controls for all *03 alleles taken together but when *0301 was examined separately, based on the suggestion that this allele confers most of the effect for the *03 group, 41 it seemed that *0301 was associated with susceptibility in the familial material. The association was not strengthened in the joint analysis, reflecting the fact that there was no association in the previous study.…”