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外周血白细胞SLC45A4AHSP基因甲基化与乳腺癌关系的病例对照研究

付庆臻 李大鹏 符金铭 刘宇鹏 孙鸿儒 张磊 张显玉 庞达 赵亚双

付庆臻, 李大鹏, 符金铭, 刘宇鹏, 孙鸿儒, 张磊, 张显玉, 庞达, 赵亚双. 外周血白细胞SLC45A4和AHSP基因甲基化与乳腺癌关系的病例对照研究[J]. 中华疾病控制杂志, 2024, 28(1): 56-63. doi: 10.16462/j.cnki.zhjbkz.2024.01.009
引用本文: 付庆臻, 李大鹏, 符金铭, 刘宇鹏, 孙鸿儒, 张磊, 张显玉, 庞达, 赵亚双. 外周血白细胞SLC45A4AHSP基因甲基化与乳腺癌关系的病例对照研究[J]. 中华疾病控制杂志, 2024, 28(1): 56-63. doi: 10.16462/j.cnki.zhjbkz.2024.01.009
FU Qingzhen, LI Dapeng, FU Jinming, LIU Yupeng, SUN Hongru, ZHANG Lei, ZHANG Xianyu, PANG Da, ZHAO Yashuang. Methylation of SLC45A4 and AHSP gene in peripheral blood leukocytes and the risks of breast cancer: a case-control study[J]. CHINESE JOURNAL OF DISEASE CONTROL & PREVENTION, 2024, 28(1): 56-63. doi: 10.16462/j.cnki.zhjbkz.2024.01.009
Citation: FU Qingzhen, LI Dapeng, FU Jinming, LIU Yupeng, SUN Hongru, ZHANG Lei, ZHANG Xianyu, PANG Da, ZHAO Yashuang. Methylation of SLC45A4 and AHSP gene in peripheral blood leukocytes and the risks of breast cancer: a case-control study[J]. CHINESE JOURNAL OF DISEASE CONTROL & PREVENTION, 2024, 28(1): 56-63. doi: 10.16462/j.cnki.zhjbkz.2024.01.009

外周血白细胞SLC45A4AHSP基因甲基化与乳腺癌关系的病例对照研究

doi: 10.16462/j.cnki.zhjbkz.2024.01.009
基金项目: 

国家自然科学基金 81172743

黑龙江省自然科学基金 ZD2021H001

详细信息
    通讯作者:

    赵亚双,E-mail: zhao_yashuang@263.net

  • 中图分类号: R181.3;R737.9

Methylation of SLC45A4 and AHSP gene in peripheral blood leukocytes and the risks of breast cancer: a case-control study

Funds: 

National Natural Science Foundation of China 81172743

Heilongjiang Provincial Natural Science Foundation of China ZD2021H001

More Information
  • 摘要:   目的  探究外周血白细胞溶质载体家族45成员4(solute carrier family 45 member 4,SLC45A4)和α血红蛋白稳定蛋白(α hemoglobin stabilizing protein,AHSP)基因甲基化与乳腺癌发病的关系。  方法  通过差异甲基化分析等方法在GSE51032、GSE104942和GSE89093数据集中筛选与乳腺癌发病潜在相关的基因。采用病例对照研究,纳入545例乳腺癌患者和524例非乳腺癌对照作为研究对象。使用MethylTarget靶向测序检测目标基因甲基化并分析其与乳腺癌的关系。  结果  本研究共筛选出4个基因,控制混杂因素后,SLC45A4AHSP高甲基化与乳腺癌关系的ORadj分别为0.218(95% CI:0.158~0.299)和0.535(95% CI:0.384~0.741)。在不同亚组中SLC45A4高甲基化与乳腺癌的关联仍有统计学意义,ORadj最高为0.427(95% CI:0.270~0.679),最低为0.153(95% CI:0.085~0.274),而AHSP高甲基化仅在管腔A型(Luminal A)、管腔B型(Luminal B)、雌激素受体阳性(estrogen receptor +, ER+)和≤60岁年龄组中与乳腺癌的关联有统计学意义。异质核糖核酸蛋白C(heterogeneous nuclear ribonucleoproteins C,HNRNPC)甲基化与乳腺癌的关系与公共数据结果相反,ORadj为0.747(95% CI:0.569~0.980),锌指蛋白425(zinc finger protein 425,ZNF425)甲基化与乳腺癌的关联无统计学意义(P=0.158)。  结论  外周血白细胞SLC45A4AHSP基因高甲基化可能是乳腺癌发病的保护因素。
  • 图  1  MethylTarget靶向测序2步PCR体系和反应条件

    PCR, 聚合酶链式反应。

    Figure  1.  The two-step PCR panel and reaction conditions of MethylTarget sequencing

    PCR, polymerase chain reaction.

    表  1  GEO数据集中基因甲基化差异及与乳腺癌的关系

    Table  1.   Gene methylation differences and association with breast cancer in the GEO datasets

    亚组Subgroup Δβ P值value OR值value (95% CI) P值value
    GSE51032
      DNMBP(cg02732134) -0.052 < 0.001 0.114(0.065~0.188) < 0.001
      NA(cg03252499) 0.069 < 0.001 3.948(2.663~5.959) < 0.001
      SLC45A4(cg07437919) -0.064 < 0.001 0.313(0.221~0.442) < 0.001
      AHSP(cg14387505) -0.057 < 0.001 0.358(0.253~0.504) < 0.001
      HNRNPC(cg22872033) 0.055 < 0.001 2.441(1.722~3.482) < 0.001
      ZNF425(cg25009327) -0.055 < 0.001 0.279(0.196~0.394) < 0.001
    GSE104942
      DNMBP(cg02732134) -0.012 0.155 0.571(0.322~1.001) 0.052
      NA(cg03252499) 0.020 0.040 2.302(1.283~4.166) 0.005
      SLC45A4(cg07437919) -0.024 0.003 0.288(0.158~0.515) < 0.001
      AHSP(cg14387505) -0.026 0.021 0.465(0.220~0.966) 0.041
      HNRNPC(cg22872033) 0.012 0.155 1.805(1.034~3.183) 0.039
      ZNF425(cg25009327) -0.019 < 0.001 0.250(0.112~0.516) < 0.001
    GSE89093
      DNMBP(cg02732134) -0.033 0.146 0.194(0.065~0.535) 0.002
      NA(cg03252499) 0.027 0.431 2.429(0.884~6.807) 0.086
      SLC45A4(cg07437919) -0.012 0.599 0.481(0.176~1.268) 0.144
      AHSP(cg14387505) -0.015 0.439 0.445(0.159~1.182) 0.110
      HNRNPC(cg22872033) 0.029 0.203 2.729(1.028~7.561) 0.047
      ZNF425(cg25009327) -0.012 0.698 0.407(0.142~1.098) 0.083
    注:①Δβ=β病例-β对照;②OR为甲基化水平每增加1个s与乳腺癌的关系。
    Note: ①Δβ=βcase-βcontrol; ②OR is the association between each 1 s deviation increase in methylation level and breast cancer.
    下载: 导出CSV

    表  2  病例组和对照组的基本信息

    Table  2.   Basic information of the cases and controls

    特征Features 病例组
    Case group
    对照组
    Control group
    χ2
    value
    P
    value
    年龄组/岁Age group/years 52(46.0, 58.0) 50(44.0, 60.0) -0.591 0.555
      ≤60 428(82.5) 386(77.2) 4.395 0.036
      >60 91(17.5) 114(22.8)
    BMI/(kg·m-2) 23.4(21.5, 25.7) 23.6(21.5, 26.0) 0.063 0.949
       < 18.5 15(2.9) 22(4.4) -0.005 0.996
      18.5~ < 24.0 274(52.8) 252(50.4)
      ≥24.0 230(44.3) 226(45.2)
    居住地Location 0.741 0.389
      城市City 99(19.1) 85(17.0)
      农村Rutal 420(80.9) 415(83.0)
    乳腺癌家族史Family history of breast cancer 23.969 < 0.001
      无No 478(92.1) 493(98.6)
      有Yes 41(7.9) 7(1.4)
    其他恶性肿瘤家族史Family history of other cancers 25.108 < 0.001
      无No 378(72.8) 428(85.6)
      有Yes 141(27.2) 72(14.4)
    月经初潮年龄/岁 Age at menarche/years -0.055 0.956
      ≥13 428(82.5) 413(82.6)
      12~<13 89(17.1) 85(17.0)
       < 12 2(0.4) 2(0.4)
    钼靶检查Mammography 8.935 0.003
      否No 453(87.3) 402(80.4)
      是Yes 66(12.7) 98(19.6)
    良性乳腺疾病史History of benign breast disease 52.082 < 0.001
      无No 345(66.5) 429(85.8)
      有Yes 174(33.5) 71(14.2)
    妇科手术史History of gynecological surgery 0.137 0.711
      无No 318(61.3) 312(62.4)
      有Yes 201(38.7) 188(37.6)
    绝经Status of menopause 0.732 0.392
      否No 228(43.9) 233(46.6)
      是Yes 291(56.1) 267(53.4)
    母乳喂养Breast feeding 0.382 0.536
      否No 57(11.0) 49(9.8)
      是Yes 462(89.0) 451(90.2)
    避孕药使用Usage of contraception pill 4.139 0.042
      否No 454(87.5) 457(91.4)
      是Yes 65(12.5) 43(8.6)
    激素类药物使用Usage of estrogen 1.652 0.199
      否No 498(96.0) 487(97.4)
      是Yes 21(4.0) 13(2.6)
    活产次数Number of live birth 8.506 0.004
      ≤1 336(64.7) 279(55.8)
      >1 183(35.3) 221(44.2)
    流产次数Number of abortion 14.242 < 0.001
      ≤1 391(75.3) 424(84.8)
      >1 128(24.7) 76(15.2)
    乳腺癌一级亲属人数First-degree relatives with a history of breast cancer 16.618 < 0.001
      0 490(94.4) 495(99.0)
      ≥1 29(5.6) 5(1.0)
    吸烟Smoking 0.053 0.819
      否No 449(86.5) 435(87.0)
      是Yes 70(13.5) 65(13.0)
    饮酒Drinking 0.042 0.838
      否No 465(89.6) 446(89.2)
      是Yes 54(10.4) 54(10.8)
    注:①采用秩和检验; ②以M(P25, P75) 或人数(占比/%)表示。
    Note: ① Rank-sum test; ② M(P25, P75) or number of people (proportion/%).
    下载: 导出CSV

    表  3  病例组和对照组的基本信息

    Table  3.   Basic information of the cases and controls

    亚组Subgroup β截断值分组 Group of βcut off value 病例组[人数(占比/%)]Case group[Number of people(proportion/%)] 对照组[人数(占比/%)]Control group[Number of people(proportion/%)] OR值value (95% CI) P值value ORadj值value(95% CI) P值value
    SLC45A4 总体Overall
    hypo 223(43.3) 77(15.6) 1.000 < 0.001 1.000 < 0.001
    hyper 292(56.7) 418(84.4) 0.241(0.178~0.324) 0.218(0.158~0.299)
    年龄组/岁Age group/years
    ≤60 hypo 187(44.0) 57(14.9) 1.000 < 0.001 1.000 < 0.001
    hyper 238(56.0) 326(85.1) 0.223(0.157~0.311) 0.186(0.128~0.267)
    >60 hypo 36(40.0) 20(17.9) 1.000 < 0.001 1.000 0.008
    hyper 54(60.0) 92(82.1) 0.326(0.169~0.614) 0.386(0.188~0.799)
    ER分组ER subgroup
    ER- hypo 64(52.5) 77(15.6) 1.000 < 0.001 1.000 < 0.001
    hyper 58(47.5) 418(84.4) 0.167(0.108~0.256) 0.160(0.100~0.255)
    ER+ hypo 111(33.9) 77(15.6) 1.000 < 0.001 1.000 < 0.001
    hyper 216(66.1) 418(84.4) 0.358(0.256~0.500) 0.308(0.214~0.440)
    分子分型分组Molecular types of subgroup
    Luminal A hypo 65(40.6) 77(15.6) 1.000 < 0.001 1.000 < 0.001
    hyper 95(59.4) 418(84.4) 0.269(0.181~0.401) 0.236(0.153~0.361)
    Luminal B hypo 46(27.5) 77(15.6) 1.000 0.001 1.000 < 0.001
    hyper 121(72.5) 418(84.4) 0.485(0.320~0.739) 0.427(0.270~0.679)
    HER-2 hypo 35(51.5) 77(15.6) 1.000 < 0.001 1.000 < 0.001
    hyper 33(48.5) 418(84.4) 0.174(0.101~0.296) 0.153(0.085~0.274)
    Basal_like hypo 29(53.7) 77(15.6) 1.000 < 0.001 1.000 < 0.001
    hyper 25(46.3) 418(84.4) 0.159(0.088~0.285) 0.156(0.081~0.297)
    AHSP 总体Overall
    hypo 322(77.6) 294(65.2) 1.000 < 0.001 1.000 < 0.001
    hyper 93(22.4) 157(34.8) 0.541(0.399~0.730) 0.535(0.384~0.741)
    年龄组/岁Age group/years
    ≤60 hypo 255(75.2) 213(61.7) 1.000 0.001 1.000 0.001
    hyper 84(24.8) 132(38.3) 0.532(0.382~0.737) 0.545(0.381~0.776)
    >60 hypo 67(88.2) 81(76.4) 1.000 0.049 1.000 0.243
    hyper 9(11.8) 25(23.6) 0.435(0.181~0.966) 0.574(0.216~1.414)
    ER分组ER subgroup
    ER- hypo 59(68.6) 294(65.2) 1.000 0.541 1.000 0.562
    hyper 27(31.4) 157(34.8) 0.857(0.516~1.393) 0.855(0.497~1.440)
    ER+ hypo 233(79.3) 294(65.2) 1.000 < 0.001 1.000 < 0.001
    hyper 61(20.7) 157(34.8) 0.490(0.346~0.687) 0.452(0.309~0.654)
    分子分型分组Molecular types of subgroup
    Luminal A hypo 118(83.7) 294(65.2) 1.000 < 0.001 1.000 < 0.001
    hyper 23(16.3) 157(34.8) 0.365(0.220~0.584) 0.337(0.197~0.554)
    Luminal B hypo 115(75.2) 294(65.2) 1.000 0.023 1.000 0.015
    hyper 38(24.8) 157(34.8) 0.619(0.405~0.930) 0.561(0.348~0.886)
    HER-2 hypo 35(71.4) 294(65.2) 1.000 0.383 1.000 0.316
    hyper 14(28.6) 157(34.8) 0.749(0.380~1.405) 0.699(0.336~1.379)
    Basal_like hypo 24(64.9) 294(65.2) 1.000 0.968 1.000 0.946
    hyper 13(35.1) 157(34.8) 1.014(0.489~2.017) 0.974(0.446~2.044)
    HNRNPC 总体Overall
    hypo 315(62.5) 271(55.3) 1.000 0.258 1.000 0.158
    hyper 189(37.5) 219(44.7) 0.742(0.576~0.956) 0.747(0.569~0.980)
    年龄组/岁Age group/years
    ≤60 hypo 255(61.0) 209(55.4) 1.000 0.112 1.000 0.117
    hyper 163(39.0) 168(44.6) 0.795(0.599~1.055) 0.794(0.594~1.059)
    >60 hypo 60(69.8) 62(54.9) 1.000 0.033 1.000 0.019
    hyper 26(30.2) 51(45.1) 0.527(0.289~0.945) 0.464(0.240~0.874)
    ER分组ER subgroup
    ER- hypo 75(64.7) 271(55.3) 1.000 0.068 1.000 0.022
    hyper 41(35.3) 219(44.7) 0.676(0.441~1.025) 0.594(0.377~0.922)
    ER+ hypo 199(61.4) 271(55.3) 1.000 0.084 1.000 0.158
    hyper 125(38.6) 219(44.7) 0.777(0.583~1.034) 0.810(0.603~1.084)
    分子分型分组Molecular types of subgroup
    Luminal A hypo 96(60.8) 271(55.3) 1.000 0.230 1.000 0.411
    hyper 62(39.2) 219(44.7) 0.799(0.553~1.149) 0.852(0.579~1.247)
    Luminal B hypo 103(62.0) 271(55.3) 1.000 0.130 1.000 0.276
    hyper 63(38.0) 219(44.7) 0.757(0.526~1.083) 0.803(0.540~1.189)
    HER-2 hypo 43(66.2) 271(55.3) 1.000 0.099 1.000 0.045
    hyper 22(33.8) 219(44.7) 0.633(0.362~1.079) 0.549(0.299~0.975)
    Basal_like hypo 32(62.7) 271(55.3) 1.000 0.310 1.000 0.355
    hyper 19(37.3) 219(44.7) 0.735(0.399~1.320) 0.738(0.381~1.391)
    注:ER, 雌激素受体。
    SLC45A4AHSPHNRNPC高低甲基化分组所依据的β截断值分别为0.961、0.743及0.025,hypo:<对应位点的β截断值,hyper:≥对应位点的β截断值;②ORadj为校正混杂因素后的OR,年龄亚组的校正因素为乳腺癌及其他恶性肿瘤家族史、钼靶检查、良性乳腺疾病史、避孕药使用、活产次数、流产次数及乳腺癌一级亲属人数,总体、ER和分型亚组的校正因素在年龄亚组的校正因素基础上增加年龄因素;表中数据存在缺失,缺失样本为测序深度低于100×的样本和乳腺癌分子分型缺失的样本。
    Note: ER, estrogen receptor.
    ①The β cut-off values for the methylation levels in SLC45A4, AHSP, and HNRNPC are 0.961, 0.743, and 0.025, respectively. ′Hypo′ refers to values below the corresponding β cut-off, while ′Hyper′ denotes values that are equal to or exceed the β cut-off; ②ORadj represents the OR adjusted for confounding factors. The age subgroup adjustments include family history of breast cancer and other cancers, mammography, history of benign breast diseases, contraceptive pill usage, number of live births, number of abortion, and the number of first-degree relatives with breast cancer. The overall, ER, and molecular type subgroups have additional adjustments for age on top of those used for the age subgroup. Some data in the table are missing. The missing samples are those with sequencing depths below 100× and those lacking molecular subtyping for breast cancer.
    下载: 导出CSV
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出版历程
  • 收稿日期:  2023-03-22
  • 修回日期:  2023-09-27
  • 网络出版日期:  2024-02-05
  • 刊出日期:  2024-01-10

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