Susceptible and Protective Associations of HLA Alleles and Haplotypes with Cervical Cancer in South India

Background: Human leukocyte antigen (HLA) genes have been implicated in cervical cancer in several populations. Objectives: To study the predispositions of HLA alleles/haplotypes with cervical cancer. Materials and Methods: Clinically diagnosed and PAP smear confirmed cervical cancer patients (n 48) and age matched controls (n 47) were genotyped for HLA-A,-B,-DRB1* and DQB1* alleles by PCR-SSP methods. Results: The frequencies of alleles DRB1*04 (OR=2.57), DRB1*15 (OR=2.04), DQB1*0301 (OR=4.91), DQB1*0601 (OR=2.21), B*15 (OR=13.03) and B*07 (OR=6.23) were higher in cervical cancer patients than in the controls. The frequencies of alleles DRB1*10 (OR=0.22) and B*35 (OR=0.19) were decreased. Strong disease associations were observed for haplotypes DRB1*15-DQB1*0601 (OR=6.56; < 3.5.10-4), DRB1*14-DQB1*0501 (OR=6.51; <0.039) and A*11-B*07 (OR=3.95; <0.005). The reduced frequencies of haplotypes DRB1*10-DQB1*0501 (OR=0.45), A*03-B*35 (OR=0.25) and A*11-B*35 (OR= 0.06) among patients suggested a protective association. HLA-C* typing of 8 patients who possessed a unique three locus haplotype 'A*11-B*07-DRB1*04' (8/48; 16.66%; OR=6.51; <0.039) revealed the presence of a four locus haplotype 'A*11-B*07-C*01-DRB1*04' in patients (4/8; 50%). Amino acid variation analysis of susceptible allele DQB1*0601 suggested 'tyrosine' at positions 9 and 37 and tyrosine-non-tyrosine genotype combination increased the risk of cervical cancer. Conclusions: Strong susceptible associations were documented for HLA alleles B*15, B*07, DRB1*04, DRB1*15, DQB1*0301, DQB1*0601 and haplotypes DRB1*15-DQB1*0601 and DRB1*14-DQB1*0501. Further, protective associations were evidenced for alleles B*35 and DRB1*10 and haplotypes A*11-B*35 and DRB1*10-DQB1*0501 with cervical cancer in South India.     

Multiple low-frequency and rare HLA-B allelic variants are associated with reduced risk in 1,105 nasopharyngeal carcinoma patients in Hunan province,southern China

In our study, 1,105 cases of nasopharyngeal carcinoma (NPC) and 1,430 normal controls recruited from Hunan province, southern China were typed for human leukocyte antigen (HLA)-B locus by Sanger sequencing exons 2–4. Besides confirming the NPC association with HLA-B*46:01 allele, HLA-A*02:07-B*46:01 and HLA-A*33:03-B*58:01 haplotypes (all positive), and HLA-B*13 lineage (negative), all of which were relatively common, strong negative associations were observed for five low-frequency and rare alleles or lineages, including HLA-B*07, -B*27:04, -B*39, -B*51:02 and -B*55:02, with odds ratio (OR) ranging from 0.16 to 0.3 (all p_corrected < 0.05). These strong protective associations were independent of linkage disequilibrium (LD) between HLA-A and HLA-B loci. Further analysis indicated a single amino acid change from histidine to tyrosine at residue 171 is probably crucial for the mutant allele, HLA-B*51:02, to mediate resistance to NPC. A subset of NPC cases (n = 821) and normal controls (n = 1,035) were tested for antivirus capsid antigen immunoglobulin A (anti-VCA IgA), which differed drastically between the two groups [67.7% vs. 5.5%, OR (95% confidence interval) = 36 (26.55–48.81), p < 0.0001]. HLA-B allelic variation did not associate with seropositivity for anti-VCA IgA in either group. Results from our study show, more clearly than previously, the existence of a cluster of low-frequency and rare HLA-B variants conferring low, or very low risk to NPC, a phenomenon not observed in other ethnic groups. Our data shed new insights into genetic susceptibility to NPC in southern Chinese populations. Future independent studies are warranted to replicate the findings reported in our study.     

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

Human leukocyte antigen (HLA)-G acts as negative regulator of the immune responses and its expression in tumor cells may enable them to escape immunosurveillance. The purpose of this study was to investigate the influence of HLA-G polymorphism on risk of high-grade cervical intraepithelial neoplasia (HG-CIN) and cervical cancer in a Canadian population. The authors have analyzed 1,372 women from participants recruited between 2001 and 2009 in the ongoing Biomarkers of Cervical Cancer Risk case-control study. A total of 539 women with histologically confirmed HG-CIN and invasive cancer formed the case series, and 833 women with normal cytology served as controls. Cervical specimens were tested for human papillomavirus (HPV) DNA using the MY09/11 PCR protocol and HLA-G alleles where determined using a direct DNA sequencing procedures. HLA-G polymorphisms were not associated with HG-CIN or HPV infection. However, the risk for invasive cancer was significantly increased with the homozygous genotypes HLA-G*01:01:02 [odds ratio (OR) = 3.52, 95% confidence interval (CI): 1.43-8.61, p = 0.006], -G*01:06 (OR = 19.1, 95% CI: 2.29-159, p = 0.005) and -G* 3'UTR 14-bp insertion (OR = 2.17, 95% CI: 1.10-4.27, p = 0.020), whereas, the heterozygotic form of the G*01:01:01 wild-type allele was significantly associated with a reduced risk of invasive cancer (OR = 0.31, 95% CI: 0.16-0.59, p < 0.0001) after adjusting for age, HPV infection and ethnicity. These associations were also observed with progression of disease from HG-CIN to invasive cancer among HPV-positive women. These results suggest that HLA-G polymorphism is an independent risk factor for the development of invasive cervical cancer.     

HLA-B*07 is a high risk allele for familial cervical cancer

Aim: The purpose of this study was to investigate 50 women from eight families with familial cervical cancer in Wufeng County, Hubei Province, China, a region with a high incidence of cervical cancer. Eighty-nine healthy women, of similar age, location and ethnicity, were selected as a control group. Methods: Blood samples were collected from both groups, and HLA-A, HLA-B, and HLA-DRB1 genotypes were profiled with the Multi-Analyte Profiling system (xMAP) (Luminex HLA-SSO) using a WAKFlow HLA typing kit. Results were analyzed with Luminex HLA typing software and showed good stability, reproducibility and specificity. Results: We found several high risk alleles in women with familial cervical cancer, that associated with the highest risk being HLA-B*07 (OR = 8.7, 95% CI = 1.8-41.1). Conclusions: HLA-B*07 is a high risk allele for cervical cancer, and has strong potential for use as a molecular biomarker.     

Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk

Variation in human major histocompatibility genes may influence the risk of squamous cell cervical cancer (SCC) by altering the efficiency of the T-cell-mediated immune response to human papillomavirus (HPV) antigens. We used high-resolution methods to genotype human leukocyte antigen (HLA) class I (A, B, and Cw) and class II (DRB1 and DQB1) loci in 544 women with SCC and 542 controls. Recognizing that HLA molecules are codominantly expressed, we focused on co-occurring alleles. Among 137 allele combinations present at >5% in the case or control groups, 36 were significantly associated with SCC risk. All but one of the 30 combinations that increased risk included DQB1*0301, and 23 included subsets of A*0201-B*4402-Cw*0501-DRB1*0401-DQB1*0301. Another combination, B*4402-DRB1*1101-DQB1*0301, conferred a strong risk of SCC (odds ratio, 10.0; 95% confidence interval, 3.0-33.3). Among the six combinations that conferred a decreased risk of SCC, four included Cw*0701 or DQB1*02. Most multilocus results were similar for SCC that contained HPV16; a notable exception was A*0101-B*0801-Cw*0701-DRB1*0301-DQB1*0201 and its subsets, which were associated with HPV16-positive SCC (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). The main multilocus associations were replicated in studies of cervical adenocarcinoma and vulvar cancer. These data confirm that T helper and cytotoxic T-cell responses are both important cofactors with HPV in cervical cancer etiology and indicate that co-occurring HLA alleles across loci seem to be more important than individual alleles. Thus, certain co-occurring alleles may be markers of disease risk that have clinical value as biomarkers for targeted screening or development of new therapies.     

Meningioma: is there an association with human leukocyte antigens?

The expression of human leukocyte antigen (HLA) alleles plays an important role in the development and recurrence of benign and malignant diseases. Association of single HLA alleles or haplotypes with neoplastic processes has been investigated previously, and correlation between HLA and solid tumors, such as head and neck cancers or uterine cervical squamous epithelial lesions, were reported. However, there is no published data on the influence of the HLA system on the development of symptomatic cerebral meningioma, a mostly benign intracranial tumor of mesenchymal origin in adults. The present investigation is comparing the frequency of single HLA alleles and haplotypes in 81 adult Caucasian patients with symptomatic central nervous system meningiomas to that of 157 area- and race-matched healthy controls. Both standard serological and molecular genetic (PCR) techniques were used for HLA typing. Our results suggest an association between single HLA alleles and occurrence of clinically symptomatic meningioma. Patients with HLA-A*02 had a 2.5-fold increased risk of meningioma (P = 0.02), and those with HLA-DQB1*05 had a 1.8-fold increased risk of meningioma (P = 0.05). Conversely, HLA-A*01, -B*08, and -DRB1*03 were associated with a 0.4-, 0.5-, and 0.5-fold, respectively, decreased risk of meningioma (P = 0.008, P = 0.05, and P = 0.04). Moreover, the occurrence rate of combinations and estimated haplotypes containing these HLA alleles was strikingly different in meningioma patients compared with controls: significantly increased for the haplotypes HLA-A*02:DRB1*04 (P = 0.02, relative risk = 2.5) and HLA-A*02:DRB1*04:DQB1*0302,DQB1*05 (P = 0.03, RR = 7.5), and significantly decreased for the haplotype HLA-A*01:B*08:DRB1*03 (P = 0.01, relative risk = 0.2). In conclusion, these data suggest that some single HLA alleles and haplotypes may protect from or predispose to developing symptomatic central nervous system meningioma during adult life. These associations may be indicative of the involvement of the immune system in the host antitumor surveillance, recognition, and destruction of de novo arising human tumor cells.     

Association between human leukocyte antigen polymorphism and human papillomavirus 16-positive vulval intraepithelial neoplasia in British women

Polymorphisms in human leukocyte antigen (HLA) genes have been implicated in the risk for developing human papillomavirus (HPV)-associated cervical neoplasia. By comparison with local cadaver controls typed for HLA class I (n = 946) and II (n = 144) antigens, HPV-16-positive high grade vulval intraepithelial neoplasia patients (n = 42) showed significantly different frequencies of HLA-A2 [odds ratio (OR), 2.1; confidence interval (CI), 1.4-3.9], HLA-B7 (OR, 2.6; CI, 1.4-4.7), HLA-DRB1*01(01/02/04) (OR, 0.1; CI, 0.03-0.5), HLA-DRB1*11 (OR, 3.3; CI, 1.4-7.1), HLA-DRB1*13 (OR, 0), HLA-DQB1*05 (OR, 0.2; CI, 0.05-0.6), and HLA-DQB1*03032 (OR, 4.6; CI, 1.5-14.0). With the exception of HLA-B7 and HLA-DRB1*11, these significant differences were also seen comparative to local HPV-16-positive cervical carcinoma patients (n = 114), suggesting a specific immunogenetic contribution that is independent of HPV-16 infection in high-grade vulval intraepithelial neoplasia. Such factors are important to the development of HPV vaccines for treatment of cervical and vulval neoplasia.     

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

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 (chi(2) = 31.7452, p < 0.0001; chi(2) = 12.7838, p(c) = 0.0066), but DQB1*050201 allele was significantly lower (chi(2) = 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.     

HLA and MICA associations with head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive tumour arising from the epithelial lining of the upper aerodigestive tract. The precise mechanisms involved in the pathogenesis of HNSCC have not been elucidated. Previous studies observed aberrant HLA expression patterns on HNSCC tumour cells and this study focused on the allelic polymorphism of HLA genes and the MHC class I chain related gene A (MICA) and HNSCC. We investigated whether associations with HLA and/or MIC alleles or haplotypes are involved in the pathogenesis of HNSCC and could explain the observed HLA expression patterns. Patients and controls were typed for HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 with sequence specific priming (SSP), supplemented with sequencing based typing (SBT). MICA allelic polymorphism was included and MICA allele assignment was based upon the combination of high resolution SBT of exons 2-4 in combination with repeat analysis and nucleotide polymorphism of exon 5. HLA-B *35 (p=0.014, OR=0.31) and HLA-B *40 (p=0.013, OR=2.9) were significantly associated in respectively the metastasized patients and the oral cavity patients. In addition, the HLA-B *40-DRB1 *13 haplotype (p=0.016, OR=4.1) was more often observed in the oral cavity patient group. The biological significance of the prevalence of specific HLA haplotypes in patients with oral cavity HNSCC and metastasizing HNSCC requires further investigation.     

HLA-DRB1,-DQA1 and -DQB1 Allele and Haplotype Frequencies in Female Patients with Early Onset Breast Cancer

Based on the reports, few HLA class II alleles are associated with susceptibility or protection in breast cancer. Here we investigate the association between HLA class II alleles and breast cancer in Iranian women. 100 patients with pathologically proven breast cancer who referred to Cancer Institute were randomly selected and compared with a group of 80 healthy blood donor subjects. The patients were studied in two groups, group 1 includes patients aging 40?years or younger and group 2 include patients aging over 40?years. HLA class II alleles were determined by amplification of DNA followed by HLA-typing using sequence-specific primer (SSP) for each allele. In group 1, the most frequent alleles were HLA-DQA1*0301 (P?=?0.002, OR?=?3.3) and HLA-DQB1*0302 (P?=?0.04, OR?=?2.8). In group 2, the following alleles increased significantly than those in controls including HLA-DQA1*0301 (P?=?0.001, OR?=?3.4) and HLA-DRB1*0301 (P?=?0.04, OR?=?2.3). In complete group of patients, the frequency of HLA-DQA1*0301 (P?=?0.001, OR?=?3.4) and HLA-DRB1*1303 (P?=?0.02, OR?=?2.3) increased significantly than those in control group. HLA-DQA1*0505, HLA-DQA1*0101, HLA-DRB1*1301and HLA-DRB1*0101 alleles showed negative association with breast cancer. Our findings suggest that HLA-DQA1*0301 allele is mainly associated with increased risk of breast cancer including early-onset of the disease. HLA-DQA1*0505 and HLA-DRB1*1301 are involved in protection. We conclude that specific alleles of HLA class II influence breast cancer risk.     

中国南方汉族急性淋巴细胞白血病患者572例的HLA基因和单倍型分析

 目的　研究HLA-A、B、DRB1基因和单倍型与中国南方汉族急性淋巴细胞白血病（ALL）的疾病相关性。方法　应用最大似然性方法分别计算南方汉族ALL患者组572例和5645名南方汉族健康供者HLA-A、B、DRB1基因和单倍型频率,采用χ2检验方法比较其分布差异。结果　ALL组HLA-A33、B58和DRB1*17基因频率均低于对照组[HLA-A33（7.15 %比9.3 %,OR＝0.73,P＜0.05）、B58（5.93 %比8.75 %,OR＝0.64,P＜0.05）和DRB1*17（5.15%比6.30 %,OR＝0.82,P＜0.05）];A3、B51和DRB*12基因频率均高于对照组[A3（2.1 %比1.26 %,OR＝1.7,P＜0.05）,B51（7. 25 %比5.78 %,OR＝1.3,P＜0.05）和DRB*12（16.13 %比12.99 %,OR＝1.35,P＜0.05）];HLA-A33-B58-DRB1*17单倍型频率低于对照组（2.46 %比4.14 %,OR＝0.35,P＜0.05）,A2-B51- DRB1*12单倍型频率高于对照组（1.24 %比0.89 %,OR＝1.66,P＜0.05）。结论　携带有A33-B58-DRB1*17单倍型个体可能与降低ALL的发病风险有相关性,A3基因和A2-B51- DRB1*12可能与增加ALL发病风险有弱相关性。     

Decreased frequency of HLA-DRB 1*13 alleles in Frenchwomen with HPV-positive carcinoma of the cervix

Specific types of human papillomaviruses (HPV) are associated with most cases of pre-invasive and invasive neoplasia of the uterine cervix. HLA phenotype influences susceptibility and resistance to viral infections and may therefore influence the course of HPV-associated tumors. Some data suggest that specific HLA class-II alleles may be associated with protection from or susceptibility to papillomavirus-associated lesions, but these results are still controversial. Using molecular probes, we looked for associations between specific DQAI, DQBI, DRBI HLA class-II alleles, HPV types and cervical cancer. The analysis was performed on a population of 126 patients with invasive cervical cancer. For HLA typing, 165 healthy individuals were taken as controls. The DRBI * 1301/02 allele frequency significantly decreased in patients (11%) as compared to controls (29%). This difference in frequency was dependent on the HPV-positive status of tumors and was no longer significant in the group of HPV-negative lesions. The same trends were observed with the DRBI * 1301/02-DQAI * 0103-DQBI * 0603 haplotype frequency. An increase in the frequency of the DRBI * 1401/07 and DRBI * 03 alleles was observed in patients under 40. Contrary to what has been reported in the literature, no increase in the DRBI * 15 allele frequency was observed in our series and only a slight increase in the DQBI * 03 frequency was found in patients (70%) compared to controls (58%). In our study, no positive correlations between cervical cancer in Frenchwomen and specific HLA DR-DQ haplotypes has been found. In contrast, a negative correlation between DRBI * 1301/02 alleles and HPV-positive tumors has been observed. This may suggest a protective effect of DR13 against HPV-associated lesions of the cervix. © 1996 Wiley-Liss, Inc.     

N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk.

N-Acetyltransferase 1 (NAT1), encoded by the polymorphic NAT1 gene, has been shown to be one of the major enzymes in human breast tissue that activates aromatic and heterocyclic amines. Humans are mainly exposed to these carcinogens through cigarette smoking and consumption of well-done meat. To test the hypothesis that variations in the NAT1 gene are related to breast cancer risk, particularly among women who smoke or consume high levels of well-done meat, a nested case-control study was conducted in a prospective cohort study of 41,837 postmenopausal Iowa women. Information on cigarette smoking and other breast cancer risk factors was obtained at the baseline survey conducted in 1986. DNA samples and information on the consumption of well-done meat were obtained, in the case-control study, from breast cancer cases diagnosed from 1992 to 1994 and a random sample of cancer-free cohort members. Genomic DNA samples obtained from 154 cases and 330 controls were assayed for 11 NAT1 alleles (NAT1*3, *4, *5, *10, *11, *14, *15, *16, *17, *19, and *22). The NAT1*4 allele was the predominant allele observed in this study population, accounting for 73.2% (72.4% in cases versus 73.8% in controls) of the total alleles analyzed. Compared to controls, breast cancer cases had a slightly higher frequency of the NAT1*10 allele (18.8% in cases versus 17.3% in controls) and a substantially higher frequency of the NAT1*11 allele (3.6% versus 1.2%). In multivariate analyses, we found a 30% [95% confidence interval (CI) = 0.8-1.9] elevated risk of breast cancer associated with the NAT1*10 allele and a nearly 4-fold (95% CI = 1.5-10.5) elevated risk associated with the NAT1*11 allele. The positive association of breast cancer with the NAT1*11 allele was more evident among smokers [odds ratio (OR) = 13.2, 95% CI = 1.5-116.0] and those who consumed a high level of red meat (OR = 6.1, 95% CI = 1.1-33.2) or consistently consumed their red meat well done (OR = 5.6, 95% CI = 0.5-62.7). The association of the NAT1*10 allele with breast cancer was mainly confined to former smokers (OR = 3.3, 95% CI = 1.2-9.5). These findings are consistent with a role for the NAT1 gene in the etiology of human breast cancer.     

人类白细胞抗原Ⅰ、Ⅱ类等位基因及单倍体多态性与中国南方汉族白血病的相关性

目的探讨人类白细胞抗原(HLA)Ⅰ类(A、B、C)、Ⅱ类(DRB1、DQB1、DPB1)等位基因和单倍体多态性与中国南方汉族急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)以及慢性粒细胞白血病(CML)的相关性。方法收集深圳市血液中心845例中国南方汉族白血病患者(323例ALL、350例AML及172例CML)和745名中国南方汉族健康献血者的外周血样本。应用聚合酶链反应反向序列特异性寡核苷酸探针杂交(PCR-rSSO)及测序分型(PCR-SBT)方法对HLA-A、-B、-C、-DRB1、-DQB1和-DPB1进行基因分型,鉴定HLA等位基因前4位数。采用Arlequin 3.5软件分析HLA单倍体;从HLA低分辨水平(等位基因前2位数)及高分辨水平(等位基因前4位数)分别统计分析HLA等位基因和单倍体多态性与3种白血病的相关性。结果经Bonferroni校正,ALL组A*02(36.22%比28.26%,χ²=13.41,PC<0.01)及其单倍体A*02-B*46-C*01(15.35%比10.23%,χ²=10.90,PC=0.02)、DRB1*12(15.79%比11.10%,χ²=9.02,PC=0.03)、A*02:03(9.75%比5.32%,χ²=14.25,PC=0.002)及其单倍体A*02:03-B*38:02-C*07:02(3.80%比1.51%,χ²=10.41,PC=0.02)的频率均高于对照组,是ALL易感因素;AML组A*11-B*15-C*08-DRB1*15-DQB1*06-DPB1*02的频率高于对照组(1.34%比0.07%,χ²=12.54,PC=0.003),是AML易感单倍体;CML组A*02(36.63%比28.26%,χ²=9.33,PC=0.02)及其单倍体A*02-B*15-C*04(2.17%比0.29%,χ²=11.74,PC=0.02)、DRB1*03:01-DQB1*02:01-DPB1*02:01(1.86%比0.14%,χ²=13.10,PC=0.01)的频率均高于对照组,是CML易感因素;CML组DRB1*13的频率低于对照组(1.45%比5.25%,χ²=9.29,PC=0.03),是CML拮抗基因。结论在HLA低分辨及高分辨水平发现了白血病易感或拮抗HLA等位基因和单倍体,可为探究中国南方汉族白血病发病机制并制订有效治疗策略提供参考。     

HLA genotyping in Japanese patients with multiple myeloma receiving bortezomib: An exploratory biomarker study of JCOG1105 (JCOG1105A1)

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.     

新疆维吾尔族女性乳腺癌与HLA-DRB1基因多态性的关系及临床意义

目的:研究新疆维吾尔族女性乳腺癌的发生与人类白细胞抗原(HLA) DRB1等位基因多态性的关系,探讨乳腺癌的遗传易感性。方法:分别收集维吾尔族女性乳腺癌患者和健康人外周血标本196和230例,提取细胞基因组DNA,采用序列特异性引物聚合酶链反应(PCR- SSP)和毛细管电泳测序(CE)的方法进行HLA-DRB1基因多态性鉴定。结果：乳腺癌患者外周血DNA的HLA-DRB1*01多态性频率显著高于健康对照(χ²=10.180,OR=4.550,P<0.05),HLA-DRB1*16多态性低于对照(χ²=4.792,OR=0.492,P<0.05),而其他位点多态性两组间的差异无统计学意义(P>0.05)。结论:维吾尔族女性乳腺癌的发生可能与HLA-DRB1等位基因多态性存在密切关系,对于揭示乳腺癌发病机制及临床诊断提供了客观依据。     

维吾尔族霍奇金淋巴瘤与HLA-DRB1、DPA1基因多态性的相关性研究

目的：探索人类白细胞抗原（HLA）DRB1和DPA1低分辨等位基因型与维吾尔族霍奇金淋巴瘤（HL）易感性的关系。方法：采用病例-对照研究（1∶2）和DNA直接测序分型（SBT）法,对40例维吾尔族HL患者和80名健康体检者进行HLA-DRB1及DPA1基因分型,分析其与HL发病的相关性。结果：对于HLA-DRB1和DPA1基因,病例组分别检出12和3个低分辨等位基因,对照组中分别检出13和4个低分辨等位基因;HLA-DRB1、DPA1基因座位上等位基因频率分布均满足Hardy-Weninberg遗传平衡检验（P > 0.05）。维吾尔族HL中HLA-DRB1*15、DPA1*03、DPA1*02-DRB1*13基因表达均高于维吾尔族健康对照组（P均<0.05）;而HLA-DRB1*07基因频率低于维吾尔族健康对照组（P < 0.05）。结论：HLA-DRB1、DPA1基因多态性可能与维吾尔族HL的发病存在关联,在揭示HL的发病机制方面有研究价值。     

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

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 = 381) were women with histologically-confirmed HG-CIN attending colposcopy clinics and controls (N = 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] = 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 = 0.17; 95%CI: 0.05-0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR = 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.     

HLA-B等位基因与新疆地区鼻咽癌相关性及其临床意义

目的 探讨HLA-B等位基因多态性与新疆地区鼻咽癌的关系及其临床意义。方法 纳入226例患者作为鼻咽癌组,207例健康志愿者作为健康对照组。采用PCR-SSP法对HLA-B等位基因进行检测。采用χ²检验两组之间、汉族和维吾尔族之间、鼻咽癌不同临床特征之间HLA-B等位基因频率差异。Kaplan-Meier法计算生存率并Logrank单因素分析与HLA-B等位基因频率关系。结果 鼻咽癌组HLA-B*46等位基因频率高于健康对照组(P=0.000),且HLA-B*46等位基因频率在汉族存在差异性(P=0.000),而维吾尔族未发现差异性(P>0.05)。<30岁组HLA-B*44等位基因频率高于≥30岁组(P=0.029);分化型非角化性癌和T₁+T₂期HLA-B*48等位基因频率分别高于未分化型非角化性癌和T₃+T₄期(P=0.029)。鼻咽癌5年OS、DFS、DMFS、LRFS率与HLA-B*46(P=0.118~0.502)、HLA-B*44(P=0.761~0.804)及HLA-B*48(P=0.308~0.727)表达状态无关。结论 HLA-B*46等位基因可能为新疆地区汉族鼻咽癌的易感基因,而HLA-B*44可能与较早发病年龄有关,HLA-B*48可能与病理类型及T分期有关。故HLA-B等位基因可能与鼻咽癌发生、发展有关。     

Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan

BACKGROUND: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC. METHODS: We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred. RESULTS: We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4). CONCLUSIONS: The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.