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

Abstract

Human leukocyte antigens (HLAs) present foreign antigens to the immune system and may be important determinants of cervical neoplasia. Previously published associations between HLA and cervical neoplasia exhibit considerable variation in findings. The biomarkers of cervical cancer risk (BCCR) case-control study addressed the role of specific HLA alleles as cofactors in the development of high-grade cervical intraepithelial neoplasia (HG-CIN) based on the most consistent evidence from published literature. Cases (N 5 381) were women with histologically-confirmed HG-CIN attending colposcopy clinics and controls (N 5 884) were women from outpatient clinics with normal cytological screening smears. Subjects were mainly of French-Canadian descent. Cervical specimens were tested for human papillomavirus (HPV) DNA and HLA genotypes by PGMY L1 consensus primer PCR and a PCR sequence-specific primer method, respectively. Unlike other studies, the DQB1*03 and DRB1*13 allele groups were not associated with risk of HG-CIN. The B7-DRB1*1501-DQB1*0602 haplotype was associated with a 41% overall reduction in HG-CIN risk (odds ratio [OR] 5 0.59; 95% confidence interval [CI]: 0.36-0.96), and an 83% reduction in risk of HG-CIN among HPV 16 or HPV 18-positive subjects (OR 5 0.17; 95%CI: 0.05-0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR 5 8.44, 95%CI: 1.12-63.73). In conclusion, the B7-DRB1*1501-DQB1*0602 haplotype was protective against HG-CIN, especially in individuals infected with oncogenic HPV, but the mechanism of the association seems to involve multiple steps in the natural history of HPV and CIN. ' 2008 Wiley-Liss, Inc.Key words: cervical intraepithelial neoplasia; human leukocyte antigen; human papillomavirus; case-control study After breast cancer, cervical cancer is the second most common cancer in women worldwide, with 493,000 new cases and over 273,000 deaths annually. 1 It is well established that the cervical infection caused by one of up to 18 oncogenic human papillomaviruses (HPV) is the main causal factor in cervical cancer, with HPV 16 alone accounting for over half of all cases. 2 In fact, HPV infection can be considered a necessary intermediate step in cervical carcinogenesis. 3 On the other hand, despite the presence of asymptomatic cervical HPV infection in 5-50% of women of reproductive age, 4,5 only a small fraction of infected women will develop cervical cancer. Thus, HPV infection alone is not a sufficient cause of cervical cancer, which underscores the need to identify cofactors that may mediate risk of persistent HPV infection or progression to cervical dysplastic changes and overt neoplasia. The human leukocyte antigens (HLA) mediate the presentation of HPV antigens to the immune system and thus may either predispose to or protect against development of HPV-associated cervical neoplasia. 6 Previous case-control studies examining the relationship have suggested that certain HLA polymorphisms are associated with risk of neoplastic tran...

Association between human leukocyte antigen class II alleles and human papillomavirus-mediated cervical cancer in Indian women

“…These results are in concordance with cervical cancer studies on Swedish women [23,27], southwestern Hispanic women from the United States [28], Norwegian women [29] and northeastern Brazilian women [30]. Conversely, a significant protective association for the DRB1*15-DQB1*06 haplotype was observed in U.S. and Chinese populations with respect to cervical precancer [31,32] and cancer cases [33], respectively. Other reports indicated no association for the DRB1*15-DQB1*06 haplotype with respect to cervical cancer/precancer [34,35].…”

“…No association was established for the DQB1*03 allele, either with cervical precancer/cancer or with HPV infection, consistent with prior studies in a Canadian population [32], ethnically admixed Costa Rican women [36], Norwegian women [29], northeastern Brazilian women [30], Senegalese women [51], and Swedish women [27]. However, various studies have indicated an association of the DQB1*03 allele with the risk of development of cervical cancer [23,28,29,34,37,40,47,52].…”

“…In haplotypic association with DQB1*06, the DRB1*13-DQB1*06 haplotype emerged as protective toward either susceptibility to cervical cancer (p c ϭ 0.01, OR 0.15) or HPV infection (p c Ͻ 0.002, OR 0.13), in favor of previous studies on different populations in the United States [34], the United Kingdom [47], Sweden [23,27], France [52], Hispanics in the United States [28], Costa Rica [36], and Spain [49]. However, no association was reported for high-grade CIN for the DRB1*13 allele [32]. The DRB1*13 allele was associated with a cumulative risk of HPV infection, including infection with oncogenic HPV/HPV16 in the McGill-Concordia Cohort Study on Montreal women [54], as well as a study by Maciag et al on Brazilian women in the Ludwig-Mc Gill cohort [55].…”

HLA-G polymorphisms in women with squamous intraepithelial lesions harboring human papillomavirus

“…Whether the amount of sHLA-G production and magnitude of HLA-G membrane expression or the balance between HLA molecules on the cervical cell surface that produce inhibitory or stimulatory signals for NK cells is necessary to modulate the outcome of the infection are questions that need to be further explored. Although other HLA class I and class II classical genes have been associated with SIL, [44][45][46][47] the results of the present study indicate that HLA-G polymorphisms as well as the HPV type are associated with SIL. To clarify the function of HLA-G alleles in SIL susceptibility, it would be interesting to conduct a longitudinal study on normal women exhibiting HPV infection with no SIL to determine whether these alleles are associated with elimination or persistence of HPV infection.…”

Human leukocyte antigen G polymorphism is associated with an increased risk of invasive cancer of the uterine cervix

“…The specifics of this study have been described in detail elsewhere. 13 The authors have analyzed 539 cases with histologically confirmed disease and 833 controls recruited between January 2001 and April 2009. The ethics review boards of the authors' institutions approved the protocol and consent procedures, and all subjects provided written informed consent.…”