Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer

Engelmark, Malin T.; Beskow, Anna H.; Magnusson, Jessica; Erlich, Henry A.; Gyllensten, Ulf

doi:10.1093/hmg/ddi464

Cited by 21 publications

(32 citation statements)

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“…7,11,[26][27][28][29] Also, in an affected sib-pair study, we have found further evidence that the class II region rather than the region containing the HLA class I loci is linked to cervical carcinoma in situ. 30 A high viral load of HPV 16 several years before diagnosis markedly increases the risk of CIS development. 6 Similarly, the risk of CIS has been shown to increase with higher viral loads of other high-risk types, although not to the magnitude seen for HPV 16.…”

Section: Discussionmentioning

confidence: 99%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Intl Journal of Cancer

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Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection. ' 2005 Wiley-Liss, Inc.Key words: HLA; human papillomavirus; viral load; cervical carcinoma HPV is the major etiologic risk factor for cervical carcinoma and is found in the majority of cervical tumors. Although infection with oncogenic forms of HPV are common among young women, less than 1% of those infected develop cervical carcinoma. [1][2][3] Both the length of the infection and a high viral load several years before diagnosis have been shown to increase the risk of developing cervical dysplasia and carcinoma in situ (CIS). [4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers. A plausible hypothesis is that HLA is involved in the cellular immunity against HPV. Also, HLA alleles making carriers more susceptible to HPV infections are likely to be less efficient in triggering immunity and inducing viral clearance. As a consequence, carriers of susceptibility alleles harbor higher HPV load than carriers of more efficient alleles. The relation between viral load and carcinoma development has been most extensively studied for HPV 16, presumably because it is the most prevalent HPV type in cervical tumors throughout most of the world. 1 We have previously examined the effect of HPV 18/45 and HPV 31 viral load on the risk for cervical CIS. 14 Our results showed that higher viral load of HPV 18/45 or HPV 31 increases the risk of CIS, although the risk magnitude is less than that observed for HPV 16. Therefore, it is possible that HLA alleles could influence carcinoma development by affecting viral load also for other HPV types besides HPV 16.A meta analysis demonstrated a protective effect of the DRB1*1301 and DQB1*0603 alleles against development of cervical carcinoma in 18 ...

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Section: Discussionmentioning

confidence: 99%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Intl Journal of Cancer

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“…These families were identified by cross-linking the Swedish Cancer Registry and the National Family Registry. 4 The 1306 cases included in this study correspond to 641 small families (617 sib-pairs, 4 families with 3 sisters and 20 families with a pair of sisters and a mother). The mean age of diagnosis was 31 years.…”

Section: Methodsmentioning

confidence: 99%

“…Biotinylated PCR products were hybridized to the array and detected by the formation of a colored precipitate catalyzed by streptavidin-conjugated horseradish peroxidase according to previously described methods. 4,56 Genotypes were determined by a pattern recognition algorithm implemented in StripScan (version 5.7.1; Roche Molecular Systems). The majority of the polymorphisms at non-HLA loci were genotyped using TaqMan genotyping assays (Applied Biosystems, Foster City, CA, USA) and the 7900 HT Fast Real Time PCR system (Applied Biosystems) according to the manufacturer's instructions.…”

Section: Genotypingmentioning

confidence: 99%

“…The MHC region harbors genes encoding the human leukocyte antigen (HLA) class I and II molecules, as well as genes encoding other proteins involved in peptide display, the complement system and cytokines. Cervical cancer has been linked to the HLA class II region, 4 and a summary of association studies showed that DQB1*03 increased susceptibility in 16 of 27 studies, the DRB1*1501/DQB1*0602 haplotype increased susceptibility in 9 of 21 and DQB1*0603 decreased the susceptibility in 18 of 19 studies. 5 In the Swedish population, previous studies demonstrate significant association only with DQB1*0602.…”

Section: Introductionmentioning

confidence: 99%

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

Ivansson

Magnusson

et al. 2008

Genes Immun

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Cervical cancer has been associated with specific human leukocyte antigen (HLA) haplotypes/alleles and with polymorphisms at the nearby non-HLA loci TNF, LTA, TAP1 and TAP2. Distinguishing effects of individual loci in the major histocompatibility complex (MHC) region are difficult due to the complex linkage disequilibrium (LD) pattern characterized by high LD, punctuated by recombination hot spots. We have evaluated the association of polymorphism at HLA class II DQB1 and the TNF, LTA, TAP1 and TAP2 genes with cervical cancer risk, using 1306 familial cases and 288 controls. DQB1 was strongly associated; alleles *0301, *0402 and *0602 increased cancer susceptibility, whereas *0501 and *0603 decreased susceptibility. Among the non-HLA loci, association was only detected for the TAP2 665 polymorphism, and interallelic disequilibrium analysis indicated that this could be due to LD with DQB1. As the TAP2 665 association was seen predominantly in non-carriers of DQB1 susceptibility alleles, we hypothesized that TAP2 665 may have an effect not attributable to LD with DQB1. However, a logistic regression analysis suggested that TAP2 665 was strongly influenced by LD with DQB1. Our results emphasize the importance of large sample sizes and underscore the necessity of examining both HLA and non-HLA loci in the MHC to assign association to the correct locus.

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“…However, previous studies showed that HPV16 E6 variants appeared to be correlated with distinct MHC class II haplotypes. 7,8 Engelmark et al 9 reported that the HLA class II genes represented a major genetic susceptibility region to cervical cancer in contrary to the class I gene that did not appear to have a significant impact on predisposition to the disease. Cervical cancer has been found to be associated with several class II alleles or antigens, such as the HLA-DQw3 antigen [10][11][12][13] and the DRB1*1501, DRB1*04 and DRB1*11 alleles.…”

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confidence: 99%

Polymorphic amino acids at codons 9 and 37 of HLA‐DQB1 alleles may confer susceptibility to cervical cancer among Chinese women

Chen

et al. 2006

Intl Journal of Cancer

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Cervical cancer is strongly associated with the infection by oncogenic forms of human papillomavirus (HPV). Although most women are able to clear HPV infection, some develop persistent infections that may lead to cancer, implying genetic susceptibility factors for malignant progression. To verify whether HLA class II DQB1 polymorphism is related to cervical cancer in Chinese population, HLA-DQB typing was carried out by PCR-SBT for 258 patients with cervical cancer and 284 healthy controls, and the allele frequencies were calculated. In this study, HLA-DQB1*060101 and DQB1*0602 alleles were significantly higher in the HPV16 infected patients with cervical cancer compared with healthy controls (v 2 5 31.7452, p < 0.0001; v 2 5 12.7838, p c 5 0.0066), but DQB1*050201 allele was significantly lower (v 2 5 26.2187, p < 0.0001). This result indicates that HLA-DQB1*060101 and DQB1*0602 may confer susceptibility to cervical cancer, and DQB1*050201 may contribute to the resistance to the development of cervical cancer among Chinese women. Sequence analysis reveals that DQB1*060101 allele encodes Leu at position 9 and Asp at position 37, unique to the susceptibility to cervical cancer, whereas the other DQB1 alleles encode Phe or Tyr and Ile or Tyr at the same two positions, respectively. This finding implies that polymorphic amino acids at the putative antigen binding residues 9 and 37 of HLA-DQB1 alleles may play an important role in the development of cervical cancer. ' 2006 Wiley-Liss, Inc.Key words: cervical cancer; HLA; polymorphism; human papillomavirus; susceptibility Cervical cancer is the second most common cancer in women, accounting for 9.8% of all new cancer cases worldwide (371,200 new cases per year), with a disproportionate share of the mortality associated with this disease occurring in developing countries. 1 Human papillomavirus (HPV) is the major etiologic factor in cervical cancer and is found in the majority of cervical tumors. 2 Infections are common but only a small fraction progresses into persistent infection and cancer, suggesting that other factors are needed for the pathogenesis. 3 One potential cofactor may be the host cellular immune response to HPV infection, mediated by HLA-restricted T lymphocytes. To date, there are more than 100 different HPV genotypes. There are 40 known genital HPVs, which are further divided into high-risk (oncogenic: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82, et al.) and low risk (e.g. 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, et al.) types. 4,5 HPV 16 is the most common type associated with cervical cancer worldwide, with little geographic variation. 6 Naturally occurring HPV-16 variants differ in certain biologic properties and might result in differences in pathogenicity. However, previous studies showed that HPV16 E6 variants appeared to be correlated with distinct MHC class II haplotypes. 7,8 Engelmark et al. 9 reported that the HLA class II genes represented a major genetic susceptibility region to cervical cancer in contrary to the clas...

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Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer

Cited by 21 publications

References 0 publications

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

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

Polymorphic amino acids at codons 9 and 37 of HLA‐DQB1 alleles may confer susceptibility to cervical cancer among Chinese women

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