Features of KIR gene polymorphisms in unpaid blood donors with occult hepatitis B infection

Zhang Tao; Mao Wei; Wang DongFang; Jiang YuLin; Yang DanRong; Yin Dan; Yang Hu; Ou YangXiongYan; Tan QianQian

doi:10.3969/j.issn.1001-5256.2020.01.016

Volume 36 Issue 1

Jan. 2020

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Article Navigation > Journal of Clinical Hepatology > 2020 > 36(1): 70-75

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Features of KIR gene polymorphisms in unpaid blood donors with occult hepatitis B infection

DOI: 10.3969/j.issn.1001-5256.2020.01.016

Institute of Blood Transfusion,Chongqing Blood Center

Research funding:

Received Date: 2019-07-05
Published Date: 2020-01-20

Abstract

Abstract

Objective To investigate the KIR gene polymorphisms and their features in unpaid blood donors with occult hepatitis B infection(OBI). Methods A total of 105 unpaid blood donors with OBI were screened out from the unpaid blood donors in Chongqing Blood Center from 2016 to 2019. Peripheral blood samples were collected for DNA extraction and KIR genotyping. KIR genotype ID and haplotype were determined based on a comparative analysis of the KIR genotype database published on the international allele website. Genotype frequency was calculated according to the equation of genotype frequency( F) = ,in which f represented the proportion of a phenotype of KIR gene. The chi-square test was used for comparison of categorical data between groups. Results All 105 OBI blood donors had the KIR genes 2 DL4,3 DL2,3 DL3,and pseudogene 3 DP1. The KIR genes 2 DL1,2 DL3,3 DL1,2 DS4,and pseudogene 2 DP1 had an F value of > 70%,among which the KIR gene 2 DS4 with exon 5 deletion had an F value of 26. 32%. The KIR genes with low frequency(< 30%)were 2 DL2,2 DL5,2 DS1,2 DS2,2 DS3,2 DS5,and 3 DS1. Compared with the Han population in Chongqing,Hebei,and Jiangsu and the Tibetan population in Lasa,the OBI blood donors had a significantly lower frequency of the KIR 2 DL3 gene(χ~2= 9. 598,12. 236,13. 719,and 10. 974,all P < 0. 05). There were significant differences in the frequencies of 2 DL2,2 DL5,2 DS2,and 2 DS3 between the OBI blood donors and the Uyghur population in Urumqi(χ~2= 16. 215,6. 981,19. 498,and 11. 819,all P < 0. 05). There were significant differences in the frequencies of 2 DL2,2 DS1,2 DS2,2 DS3,and 2 DS4 between the OBI blood donors and the Caucasians(χ~2= 22. 477,3. 877,34. 937,6. 909,and 4. 271,all P < 0. 05). Compared with the Han population in Chongqing,the OBI blood donors had a significant increase in the frequency of KIR 2 DS4* del(χ~2= 12. 911,P < 0. 05). Compared with the population with chronic HBV infection,the OBIblood donors had significant reductions in the frequencies of 2 DS2 and 2 DS3(χ~2= 13. 005 and 8. 289,P < 0. 05) and significant increases in the frequencies of 2 DS4 and 3 DL1(χ~2= 10. 032 and 3. 865,P < 0. 05). Compared with the population with ankylosing spondylitis,the OBI blood donors had significant reductions in the frequencies of 2 DL3 and 2 DS3(χ~2= 7. 851 and 16. 504,P < 0. 05). Compared with the gays with HIV-AIDS,the OBI blood donors had significant increases in the frequencies of 2 DS4 and 3 DL1(χ~2= 15. 491 and 4. 475,P <0. 05). There were significant differences in the frequencies of 2 DL1,2 DL2,2 DL3,2 DL4,2 DL5,2 DS4,3 DL2,3 DL3,and 2 DP1 between the OBI blood donors and the population with sporadic acute hepatitis E(χ~2= 4. 448,30. 934,17. 942,15. 638,4. 227,13. 802,32. 667,35. 653,and 36. 566,P < 0. 05). A total of 21 KIR genotypes were found,among which genotype AA1 had the highest frequency of 49. 52%,followed by genotype Bx2(18. 1%). Conclusion OBI blood donors have unique features of KIR gene polymorphisms. KIR2 DL3 is a potential protective gene for OBI,while KIR 2 DS4 * del is a potential susceptibility gene for OBI.
- occult hepatitis b infection,
- genes,
- receptors,KIR

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门静脉高压是失代偿期肝硬化患者的主要临床表现之一，其导致的食管胃静脉曲张破裂出血、肝性脑病、顽固性腹水等并发症是患者死亡的重要原因^[1]。大量研究表明肝静脉压力梯度(hepatic venous pressure gradient, HVPG)可反映门静脉高压的严重程度。2021年Baveno Ⅶ国际共识^[2]推荐，对于病毒性肝炎相关肝硬化和酒精性肝硬化患者，HVPG值为诊断门静脉高压的金标准。Baveno Ⅶ国际共识^[2]和美国肝病学会2016版指导意见^[3]均明确指出和强调了HVPG对门静脉高压危险分层的作用和预后预测价值，HVPG≥20 mmHg提示肝硬化静脉曲张出血患者的止血治疗失败率和死亡风险升高^[4]。然而，HVPG测定是一项有创性操作，且对操作者技术水平和医疗设备有一定要求，并在测定过程中可能引起一过性的心律失常和迷走神经反应等不良反应，这些不足在很大程度上限制了HVPG的临床应用和推广。

近年来，非侵入性测量肝组织弹性的方法得到了发展。许多研究^[5-7]已证实肝炎患者和肝硬化代偿期患者的肝脏硬度(liver stiffnes, LS)与HVPG相关，但对于肝硬化失代偿期患者仍欠缺研究，LS对肝硬化食管胃静脉曲张破裂出血二级预防的患者预测能力尚不明确。此外，以往的大多数研究使用瞬时弹性成像(transient elastography, TE)来评估LS，少有研究探讨声脉冲辐射力成像技术(acoustic radiation force impulse, ARFI)检测的LS值的预测作用。因此，通过ARFI测量门静脉高压患者LS和脾脏硬度(spleen stiffness, SS)，验证LS、SS与HVPG的相关性，在临床上具有重要意义。

1. 资料与方法

1.1 研究对象

选取2013年4月—2021年6月在南京鼓楼医院消化内科同时接受HVPG测定及ARFI测量LS、SS的病毒性或酒精性失代偿期肝硬化患者。

1.2 纳入标准

(1) 确诊病毒性肝炎相关肝硬化或酒精性肝硬化失代偿期；既往食管胃底静脉曲张破裂出血病史。(2)年龄18~75岁。(3)在本院行经颈静脉HVPG测定，并于术前3 d内行ARFI测定LS、SS。术前3 d检验血常规、凝血功能、肝功能、肾功能，腹部彩超评估肝右叶斜径、脾肋间直径、门静脉血流速度(portal vein flow rate, PVF)、脾静脉直径(splenic vein diameter, SVD)，术前或术后1周内的内镜评估食管胃底静脉曲张程度。

1.3 排除标准

(1) 合并肝癌或肝外肿瘤；(2)严重的心、肺、肝、肾功能不全，或严重出血性疾病或局部、全身感染、甲状腺功能低下、雷诺综合征、周围血管疾病等；(3)脾脏切除患者；(4)严重门静脉血栓患者；(5)计划怀孕或已怀孕或哺乳的妇女。

1.4 观察指标

根据既往研究^[1]，HVPG≥20 mmHg提示早期再出血及高治疗失败率，故在本研究中，根据术中测定的HVPG值，将纳入患者分为严重门静脉高压组(SPH组，HVPG≥20 mmHg)和非严重门静脉高压组(非SPH组，HVPG＜20 mmHg)。收集纳入患者的临床资料，包括性别、年龄、既往史、HVPG值、LS、SS、血常规、凝血功能、肝功能、肾功能，腹部彩超评估肝右叶斜径、脾肋间直径、SVD、PVF、内镜下静脉曲张程度等指标。

1.5 统计学方法

应用SPSS 22.0软件进行统计分析。符合正态分布的计量资料以x ±s表示，2组间比较采用t检验；不符合正态分布的计量资料以M(P₂₅~P₇₅)表示，2组间比较采用Mann-Whitney U秩和检验。计数资料2组间比较采用χ²检验。相关性分析采用Pearson检验。用Pearson r系数评估不同无创检测指标与HVPG的相关性强度。若r＜0.3，提示弱强度相关；若0.3≤r≤0.5，提示中等强度相关；若r＞0.5，说明高强度相关。采用Logistic回归分析不同无创检测指标与SPH发生风险之间的关系。绘制不同无创指标预测HVPG≥20 mmHg发生的受试者工作特征曲线(ROC曲线)并计算曲线下面积(AUC)、敏感度、特异度、最大约登指数及对应的临界值，以评估各指标对SPH的预测价值。P＜0.05为差异有统计学意义。

2. 结果

2.1 基线资料比较

共纳入符合条件的受试者88例，其中SPH组24例，非SPH组64例。两组患者的年龄、性别、白细胞计数、血红蛋白、血小板计数、凝血酶原时间、谷丙转氨酶、谷草转氨酶、白蛋白、血钠、血肌酐、Child-Pugh肝功能分级等比较，差异均无统计学意义(P值均＞0.05)(表 1)。

表 1 受试者基线资料

Table 1. Baseline of the patients included

指标	所有患者(n=88)	非SPH组(n=64)	SPH组(n=24)	统计值	P值
男/女(例)	65/23	48/16	17/7	χ²=0.157	0.79
年龄(岁)	53.93±11.39	54.35±12.08	53.54±9.68	t=0.132	0.90
病因(病毒性/酒精性，例)	76/12	56/8	20/4	χ²=0.257	0.73
肝右叶斜径(cm)	12.20±1.48	12.56±1.28	12.57±1.66	t=-1.245	0.22
内镜下静脉曲张程度(轻/中/重，例)	4/19/65	3/14/47	1/5/18	χ²=0.025	0.99
白细胞计数(×10⁹/L)	2.25(1.70~3.30)	1.90(1.55~3.30)	2.50(2.05~3.20)	Z=-1.918	0.06
血红蛋白(g/L)	86.64±26.66	82.35±25.97	86.64±26.66	t=0.124	0.90
血小板计数(×10⁹/L)	59.49±33.65	60.10±28.95	57.35±30.83	t=0.367	0.72
凝血酶原时间(s)	14.89±2.74	14.35±1.64	15.90±3.10	t=-1.772	0.08
国际标准化比值	1.31±0.20	1.25±0.15	1.39±0.26	t=-1.525	0.07
谷丙转氨酶(U/L)	22.75(16.40~29.40)	24.75(15.90~29.00)	18.75(15.85~29.40)	Z=-0.932	0.35
谷草转氨酶(U/L)	26.75(21.25~35.55)	26.80(22.35~36.25)	23.15(20.10~31.50)	Z=-1.466	0.14
总胆红素(μmol/L)	16.90(11.00~22.35)	15.85(10.10~20.10)	18.70(13.10~31.70)	Z=-1.743	0.08
白蛋白(g/L)	35.43±4.77	36.43±4.45	33.96±5.31	t=1.155	0.25
血肌酐(μmol/L)	67.14±19.23	64.15±14.74	64.29±21.46	t=0.787	0.43
血钠(mmol/L)	141.20±2.60	141.16±3.13	141.23±2.84	t=-0.137	0.89
腹水(有/无，例)	30/58	25/39	5/19	χ²=2.581	0.13
Child-Pugh评分	6.85±1.32	6.40±1.05	7.25±1.29	t=-1.982	0.05
Child-Pugh分级(A/B/C，例)	37/48/3	31/32/1	6/16/2	χ²=5.517	0.06

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2.2 不同无创测定指标与HVPG的相关性分析

相关分析结果显示HVPG与LS呈中等强度正相关(r=0.458，P＜0.001)；而SS(r=0.117，P=0.300)、PVF(r=0.010，P=0.940)、SVD(r=-0.090，P=0.420)与HVPG不相关。

2.3 SPH组和非SPH组不同无创测定指标的比较

结果显示，两组间LS比较差异有统计学意义(P＜0.05)，而SS、PVF、SVD两组间比较，差异均无统计学意义(P值均＞0.05)(表 2)。

表 2 SPH组和非SPH组不同无创测定指标的比较

Table 2. The comparison of different noninvasive indexes between SPH group and non-SPH group

指标	所有患者(n=88)	非SPH组(n=64)	SPH组(n=24)	t值	P值
LS(m/s)	2.00±0.43	1.88±0.34	2.33±0.50	-3.970	＜0.01
SS(m/s)	3.48±0.53	3.46±0.56	3.54±0.46	-0.612	0.54
PVF(m/s)	27.56±9.53	27.65±9.59	27.33±9.58	0.139	0.89
SVD(cm)	1.19±0.30	1.18±0.30	1.22±0.30	-0.430	0.67

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2.4 SPH发生风险的Logistic回归分析

将LS、SS、PVF、SVD根据中位数水平转化为二分类变量，采用Logistic回归分析不同LS、SS、PVF、SVD、肝功能(Child-Pugh分级)水平下SPH的发生风险。结果显示，以低LS组为参考，在调整各危险因素后，高LS组SPH发生风险为低LS组的3.941倍(95%CI：1.245~12.476，P=0.020)(表 3)。

表 3 SPH发生风险的Logistic回归分析

Table 3. Logistic regression analysis of SPH risk

无创指标	OR	95%CI	P值
LS	3.941	1.245~12.476	0.020
SS	0.840	0.281~2.507	0.754
PVF	0.542	0.192~1.527	0.246
SVD	1.452	0.497~4.241	0.496
Child-Pugh分级
B级	0.184	0.011~3.192	0.245
C级	0.402	0.027~5.948	0.507
注：LS≤1.925 m/s赋值为0，LS＞1.925 m/s赋值为1；SS≤3.50 m/s赋值为0，SS＞3.50 m/s赋值为1；PVF≤25.85 m/s赋值为0，PVF＞25.85 m/s赋值为1；SVD≤1.12 cm赋值为0，SVD＞1.12 cm赋值为1；Child-Pugh分级以Child-Pugh A级为参考。

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2.5 不同无创指标预测SPH的ROC曲线

绘制不同无创指标预测SPH的ROC曲线(图 1)。其中LS预测SPH发生的AUC为0.751，最佳临界值为2.295 m/s，敏感度为54.17%，特异度为90.63%。

图 1 不同无创指标预测SPH发生风险的ROC曲线

Figure 1. ROC curve of different non-invasive index to predict the risk of SPH

下载: 全尺寸图片幻灯片

3. 讨论

由于失代偿期肝硬化患者存在显著的高死亡风险，因此精确评估、风险分层、个体化干预显得尤为重要^[8]。对于失代偿期肝硬化患者，基于HVPG的风险分层进行个体化干预治疗在Baveno Ⅶ共识^[2]中被推荐，即HVPG≥20 mmHg可考虑早期经颈静脉肝内门体分流术，而对于低危患者首选非选择性β受体阻滞剂联合内镜治疗进行二级预防。然而，HVPG检查属于有创操作，有一定技术难度，且患者接纳程度相对较低。因此，对无创指标的预测诊断模型的探索非常必要。近年来国内外学者在门静脉高压的预测诊断模型研究方面进行了诸多探索，其中比较有代表性的包括门静脉影像学模型、血流动力学评分模型等，但多数仍处于研究阶段且缺乏外部验证，不能广泛应用于临床^[9]。

近几年来，随着超声技术的发展，LS和SS主要测量方式包括TE、实时弹性成像、ARFI。许多研究表明，LS和SS可能是评估肝硬化失代偿期风险的潜在的无创指标^{[2, 10]}。既往研究^[11]表明原发性硬化性胆管炎患者随着时间推演肝纤维化的程度增加，LS逐渐增加，且LS与发生并发症的风险呈正相关。既往一项国外Meta分析^[12]发现：TE测得的LS在诊断临床显著门静脉高压方面具有出色的诊断性能，AUC为0.93；TE测得的LS诊断食管静脉曲张的AUC为0.84。Baveno Ⅶ共识^[2]提出，应用TE检测LS可能有助于对门静脉高压患者的门静脉压力进行评估。与此同时，既往有大样本临床研究^[13-14]得出结论：结合LS、血小板计数和脾脏直径的评分(即LSPS评分，TE测得LS×脾肋间直径/外周血血小板计数)在门静脉高压的诊断中也具有较高的预测价值；国内研究^[15]表明肝脾硬度联合血清学检测对重度食管胃底静脉曲张具有较好的预判价值。

目前TE已被广泛用于LS和SS的评估，但TE在技术上存在局限性，其在大量腹水、肥胖、肋间隙狭窄的患者中应用受限。欧洲超声医学与生物学联合会(EFUSUMB)指南^[16]提出，TE不能用于肝周腹水患者。而失代偿期肝硬化患者多发生腹水，因此，尽管TE在代偿性肝硬化患者中表现良好，但在失代偿期肝硬化患者中存在不确定性。

ARFI是一种新兴的、以超声为基础的无创评估组织弹性的方法。其检测原理为利用调制的聚焦超声波束向指定区域发射短程、低频的声脉冲波，使受检组织产生微小形变，通过追踪感兴趣区域内产生的横向剪切波的传播速度，从而将组织弹性转化为一个简单的速度值。组织的硬度越大，相应剪切波的速度值也越大^[17]。ARFI目前是一种具有良好应用前景的无创、快速、简单、客观、易重复的检测肝脏纤维化程度的手段。可在测量组织弹性的同时进行常规B超检査，无需更换仪器，较TE更为方便。同时，ARFI受到腹水及肝脏脂质沉积等影响较小。既往研究^[18]表明，通过ARFI测得的LS在诊断显著纤维化或肝硬化方面具有与TE相似的准确性，并且不需要单独的设备，亦不易受肝周腹水的影响。在失代偿期肝硬化患者中与TE相比具有一定的优势，几乎可以在每一例患者中清晰地显示解剖结构和进行成功的测量^[17]。

既往本课题组小样本研究^[19]表明，在不区分病因的情况下，提示ARFI测得的LS与HVPG呈中等强度相关(r=0.449，P＜0.05)。Baveno Ⅶ共识^[2]中提出HVPG是反映病毒性肝炎相关失代偿期肝硬化或失代偿期酒精性肝硬化合并门静脉高压患者门静脉压力的金标准。因此本研究纳入人群为乙型肝炎肝硬化失代偿期或酒精性肝硬化失代偿期合并门静脉高压患者。本研究评估了LS对病毒性肝炎相关肝硬化失代偿期和酒精性肝硬化失代偿期合并门静脉高压患者的诊断价值，并将其与门静脉压力值金标准HVPG进行比较。根据Pearson相关分析、Logistic回归分析及ROC曲线结果分析后认为，在临床较为常用的评估门静脉压力的无创指标中，LS对评估肝硬化型门静脉高压患者的门静脉压力具有较好的预测价值。但本研究也存在一定的不足之处，如本研究为回顾性研究，样本量较小且为单中心研究，LS临床诊断价值未来仍需多中心、大样本量的前瞻性研究进一步证实。

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Features of KIR gene polymorphisms in unpaid blood donors with occult hepatitis B infection

DOI: 10.3969/j.issn.1001-5256.2020.01.016

Abstract

1. 资料与方法

1.1 研究对象

1.2 纳入标准

1.3 排除标准

1.4 观察指标

1.5 统计学方法

2. 结果

2.1 基线资料比较

2.2 不同无创测定指标与HVPG的相关性分析

2.3 SPH组和非SPH组不同无创测定指标的比较

2.4 SPH发生风险的Logistic回归分析

2.5 不同无创指标预测SPH的ROC曲线

3. 讨论

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