Abstract
目的
分析类风湿关节炎(rheumatoid arthritis, RA)患者的风湿病家族史特征及其临床意义。
方法
采用现场问卷调查方法,共调查890例RA患者,其中资料完整者803例,内容包括患者的性别、年龄、吸烟史、饮酒史、身高、体重、风湿病家族史、临床及血清学特征、疼痛和疾病总体评价、多维健康评估问卷等,并根据RA患者有无家族史进行分组比较。
结果
本研究中,RA患者发病年龄为(45.09 ±14.50)岁,男女比例1 ∶3.5。有风湿病(包括RA、脊柱关节炎、干燥综合征、系统性红斑狼疮、系统性硬化症)家族史的患者123例(123/803, 15.32%), 其中一级亲属患病者占有家族史者73.98%(91/123),二级亲属患病者占有家族史者17.89%(22/123),一级+二级亲属均患病10例(8.13%)。家族史疾病种类以RA为主,为70.73%(87/123),其他风湿性疾病为21.95%(27/123),RA合并其他风湿病占7.32%(9/123)。根据有无家族史,对两组RA患者的人口学特征和临床指标进行比较,结果显示:在有家族史患者中,发病年龄提前6.04年[(39.97±13.68)岁 vs.(46.01 ±14.46)岁],类风湿因子阳性率高(78.48% vs. 66.67%), 差异具有统计学意义(P<0.05)。校正性别、体重指数及抗环瓜氨酸肽抗体等混杂因素后,有家族史患者的发病年龄提前4.54年(β = -4.54;95%CI:-8.70, -0.38;P < 0.05)。进一步分层分析发现,在吸烟RA患者中,有家族史者发病年龄提前10.02年,差异具有统计学意义(β = -10.02;95%CI:-17.60, -2.43;P = 0.01);而在不吸烟RA患者中,有家族史者发病年龄提前3.27年,差异无统计学意义(β = -3.27;95%CI:-8.37, 1.82;P= 0.21)。
结论
风湿病家族史是RA发病提前的危险因素,与吸烟可能具有协同作用。
Keywords: 类风湿关节炎, 家族史, 发病年龄, 吸烟
Abstract
Objective
To determine the associations between the family history of rheumatic diseases and clinical features in patients with rheumatoid arthritis (RA).
Methods
In total, eight hundred and ninety patients with RA were enrolled. The demographic and clinical data were collected, including gender, age, height, body weight, age of disease onset, history of smoking and drinking, family history of rheumatic diseases, clinical and laboratory features, pain and global visual analogue scale (VAS), and multi-dimensional health assessment questionnaire (MDHAQ). Finally, 803 patients were completed the dataset and were included in the study.
Results
In this cohort, the male/female ratio was 1 ∶3.5, and the age of onset was (45.09±14.50) years. A total of 123 (15.32%) patients were accompanied with family history of rheumatic diseases, including RA, spondyloarthritis, Sjögren’s syndrome, systemic lupus erythematosus and systemic sclerosis. The percentages of first degree, second degree and both first and second degree relatives were 91 (73.98%), 22 (17.89%), and 10(8.13%) respectively. The most common disease was RA (70.73%), followed by other rheumatic diseases (21.95%), and RA combined with other rheumatic diseases (7.32%). The clinical and laboratory characteristics were compared between the patients with and without family history. The onset-age of the subjects was significantly different between those with and without family history of rheumatic diseases (39.97 ±13.68 vs. 46.01±14.46; P<0.01), which meant that the onset-age in patients with family history was 6.04 years earlier than that in patients without family history. The patients with family history had higher positive rate of rheumatoid factor (RF) compared with those without family history (78.48% vs. 66.67%, P<0.05). By adjusting with gender, body mass index (BMI), smoking and alcohol drinking, anti-cyclic citrullinated peptide (CCP) antibody and RF level, the age at disease onset in the patients with family history was 4.54 years earlier than that in the patients without family history (β=-4.54;95%CI:-8.70, -0.38;P<0.05). Further hierarchical regression analysis showed that, the age at onset of the RA patients with family history was 10.02 years earlier than that without family history among the smoking patients (β= -10.02;95%CI:-17.60, -2.43;P=0.01), while the age at onset of the RA patients with family history was 3.27 years earlier than that without family history among the never smoking patients (β=-3.27;95%CI:-8.37, 1.82;P=0.21).
Conclusion
The family history of rheumatic diseases is a risk factor for early onset of RA, and may interact with smoking.
Keywords: Rheumatoid arthritis, Family history, Age at onset, Smoking
类风湿关节炎(rheumatoid arthritis, RA)是以滑膜炎和进行性关节破坏为特征的全身性自身免疫病,可导致关节残疾和生活质量下降,预期寿命缩短3~10年,给社会带来巨大的经济负担[1]。目前普遍认为,RA是由遗传和环境因素之间的复杂相互作用导致的自身免疫病[2,3,4]。从20世纪50年代开始,以双胞胎、一级亲属、多病患家系等为研究对象的研究提示,RA的遗传度估计为20%~60%[5,6]。家族聚集性成为RA的强危险因素之一[7],家族聚集性是由家族内共有的遗传和环境因素引起的,而家族史代表了遗传和部分环境风险因素。家族患病风险可以用来评估RA的遗传性,这对于RA遗传病因学研究至关重要,但家族史的潜在临床用途仍不清楚,本研究采用现场问卷调查的研究方法,通过分析风湿病家族史分布特征及其与RA疾病临床特征及环境因素的相关性,探讨家族史在RA发病中的意义。
1. 资料与方法
1.1. 研究对象
对2015年12月至2016年8月就诊于北京大学人民医院的RA患者进行连续问卷调查,诊断符合1987年修订的美国风湿病学会(American College of Rheumatology, ACR)RA分类标准或2010年ACR/欧洲抗风湿病联盟(European League Against Rheumatism, EULAR)的RA分类标准。家庭中有多位RA患者仅以首位就诊者作为研究对象,其他成员列为亲属。本研究经北京大学人民医院医学伦理委员会批准,批件号:[2012]院伦审临医字第(12)号。研究共纳入患者890例,其中87例因数据不全予以排除,803例进行统计分析(90.2%,803/890)。
1.2. 调查方法
经患者知情同意后,由经过培训的风湿免疫科医生指导患者完成现场调查问卷并查阅病历。
1.3. 调查内容
调查内容包括:(1)性别、年龄、民族、身高、体重、吸烟和饮酒史;(2)风湿病家族史(一级亲属和二级亲属),包括RA、脊柱关节炎(spondyloarthritis, SpA)、干燥综合征(Sjögren’s syndrome, SS)、系统性红斑狼疮(systemic lupus erythematosus, SLE)、系统性硬化症(systemic sclerosis, SSc);(3)发病年龄、病程、关节肿胀数、关节压痛数、关节畸形数、疼痛和疾病总体评价视觉模拟评分(visual analogue scale, VAS)、多维健康评估问卷(multi-dimensional health assessment questionnaire, MDHAQ)等;(4)记录红细胞沉降率(erythrocyte sedimentation rate, ESR)、C反应蛋白(C-reactive protein, CRP)、类风湿因子(rheumatoid factor, RF)、抗环瓜氨酸肽(cyclic citrullinated peptide, CCP)抗体;(5)对每例患者计算疾病活动度评分(disease activity score in 28 joints, DAS 28):DAS28-ESR和DAS28-CRP。
1.4. 统计学分析
根据统计资料分布类型,临床资料、血清学检查结果采用描述性统计分析,连续性资料中符合正态分布的以 x±s表示,不符合正态分布的以M(P25,P75)表示。计数资料统计描述采用率、构成比表示。采用方差分析、卡方检验、Fisher精确概率检验或秩和检验进行组间比较,广义线性模型进行危险因素及交互作用分析,显著性水平为双侧0.05。所有统计资料应用R(3.4.3, http://www.R-project.org,The R Foundation)和易侕软件(, X&Y Solutions, Inc., Boston, MA)进行分析。
2. 结果
2.1. RA患者风湿病家族史分布特征
803例RA患者中,男性179例,女性624例,男女比为1 ∶3.5;年龄为(55.53±13.52)岁,发病年龄为(45.09±14.50)岁。汉族占 95.72%,少数民族占 4.28%(表1)。有风湿病家族史的患者123例(15.32%), 其中一级亲属患病91例(73.98%),二级亲属患病22例(17.89%), 一级+二级亲属均患病10例(8.13%,表1)。家族成员疾病种类以RA为主(70.73%),其他风湿性疾病占 21.95%, 其中:SpA占8.94%、SS占6.51%、SLE占5.69%、SSc占0.81%,RA合并其他风湿性疾病 7.32%。就家族史疾病种类而言,RA患者亲属所患风湿性疾病在一级亲属中分别为RA 70例(76.92%)、SpA 6例(6.59%)、SLE 5例(5.49%)、SS 5例(5.49%)、SSc 1例(1.10%)、RA合并其他风湿病4例(4.40%),二级亲属中分别为RA 15例(68.18%)、SpA 4例(18.18%)、SLE 1例(4.55%)、SS 2例(9.09%),一级+二级亲属中分别为RA 2例(20.00%)、SpA 1例(10.00%)、SLE 1例(10.00%)、SS 1例(10.00%)、RA合并其他风湿病5例(50%)。在各单病种中,均为一级亲属多于二级亲属,RA合并其他风湿病分布于一级亲属和一级+二级亲属中,二级亲属中所患病种最少。在一级和二级亲属中均是RA居多,其次SpA,而在一级+二级亲属中,则以RA合并其他风湿病最多,达到50%,其次是RA(表2)。
1.
RA患者一般情况及临床特征(n=803)
Clinical and demographic features of all participants (n=803)
| Items | Total (n=803) | Family history of rheumatic disease | ||
| No (n=680) | Yes (n=123) | P | ||
| RA, rheumatoid arthritis; MDHAQ, multi-dimensional health assessment questionnaire; VAS, visual analogue scale; TJC, tender joint count; SJC, swollen joint count; DJC, deformity joint count; BMI, body mass index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; DAS28, disease activity score in 28 joints; CCP, cyclic citrullinated peptide; RF, rheumatoid factor. | ||||
| Female,n (%) | 624 (77.71) | 519 (76.32) | 105 (85.37) | 0.05 |
| Han nationality,n (%) | 715 (95.72) | 614 (96.39) | 101 (91.82) | 0.03 |
| Age/years, x±s | 55.53±13.52 | 56.20±13.39 | 51.86±13.69 | <0.01 |
| Age at RA onset/years, x±s | 45.09±14.50 | 46.01±14.46 | 39.97±13.68 | <0.01 |
| History of smoking, n (%) | 222 (31.94) | 185 (31.46) | 37 (34.58) | 0.53 |
| History of drinking, n (%) | 210 (27.23) | 178 (27.30) | 32 (26.89) | 0.93 |
| Disease duration/years, M (P25, P75) | 7.00 (3.00,15.00) | 7.00 (3.00,14.00) | 10.00 (3.00, 16.00) | 0.12 |
| MDHAQ, M (P25, P75) | 2.0 (0.0, 6.0) | 2.0 (0.0, 6.0) | 2.0 (0.0, 6.0) | 0.32 |
| Pain VAS, M (P25, P75) | 3.0 (1.0, 6.0) | 3.0 (1.0, 5.0) | 3.0 (1.0, 6.0) | 0.15 |
| TJC,M (P25, P75) | 2.0 (0.0, 6.0) | 2.0 (0.0, 6.0) | 2.0 (0.0, 6.0) | 0.73 |
| SJC,M (P25, P75) | 1.0 (0.0, 4.0) | 1.0 (0.0, 4.0) | 2.0 (0.0, 4.0) | 0.37 |
| DJC,M (P25, P75) | 0.0 (0.0, 4.0) | 0.0 (0.0, 4.0) | 1.0 (0.0,7.0) | 0.15 |
| BMI/(kg/m2), x±s | 23.22±3.50 | 23.35±3.47 | 22.47±3.61 | 0.05 |
| CRP/(mg/L),M (P25, P75) | 4.68 (1.85, 11.72) | 4.88 (2.00, 12.03) | 3.40 (1.53, 10.54) | 0.07 |
| ESR/(mm/h), M (P25, P75) | 19.0 (10.0, 37.8) | 19.0 (11.0, 39.0) | 17.0 (8.3, 29.5) | 0.05 |
| DAS28-CRP,M (P25, P75) | 3.1 (2.2, 4.1) | 3.0 (2.2, 4.1) | 3.1 (2.1, 4.2) | 0.96 |
| DAS28-ESR,M (P25, P75) | 3.6 (2.7, 4.7) | 3.6 (2.7, 4.7) | 3.3 (2.5, 4.5) | 0.17 |
| Anti-CCP positive, n (%) | 509 (85.55) | 441 (85.96) | 68 (82.93) | 0.47 |
| RF-positive, n (%) | 394 (68.28) | 332 (66.67) | 62 (78.48) | <0.05 |
2.
RA患者风湿病家族史分布特征(n=123)
Characteristics of family history of rheumatic diseases in RA patients (n=123)
| Relatives | RA | SpA | SS | SLE | SSc | RA with others | Total, n (%) |
| RA, rheumatoid arthritis;SpA, spondyloarthritis; SS, Sjögren’s syndrome; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; Others, Sjögren’s syndrome, systemic lupus erythematosus, spondyloarthritis and systemic sclerosis. | |||||||
| First-degree relatives | 70 | 6 | 5 | 5 | 1 | 4 | 91 (73.98) |
| Second-degree relatives | 15 | 4 | 2 | 1 | 0 | 0 | 22 (17.89) |
| First- and second-degree relatives | 2 | 1 | 1 | 1 | 0 | 5 | 10 (8.13) |
| Total, n (%) | 87(70.73) | 11 (8.94) | 8 (6.51) | 7 (5.69) | 1(0.81) | 9 (7.32) | 123 (100.00) |
2.2. 风湿病家族史与RA环境因素的相关性
为评估环境因素对RA家族史的影响,本研究对RA患者的吸烟史、饮酒史和体重指数(body mass index, BMI)进行了分析,结果显示,有无风湿病家族史的RA患者在吸烟史、饮酒史和BMI方面差异均无统计学意义,提示风湿病家族史与三者无显著相关性(表1)。
2.3. 有无风湿病家族史RA患者临床特征的比较
本研究结果显示,有风湿病家族史RA患者发病年龄比无家族史患者发病年龄提前6.04年,差异具有统计学意义(39.97±13.68 vs. 46.01±14.46,P < 0.01)。此外,有风湿病家族史患者RF阳性率明显高于无家族史患者(78.48% vs. 66.67%,P < 0.05)。有无家族史RA患者在性别、病程、关节症状和抗CCP抗体等方面差异均无统计学意义,VAS、MDHAQ、ESR、CRP、DAS28-ESR和DAS28-CRP等病情活动度及功能指标方面差异亦无统计学意义(表1)。
2.4. 风湿病家族史对RA发病年龄的广义线性模型分析及交互作用分析
单因素分析结果显示,有风湿病家族史RA患者较无家族史患者发病年龄提前6.04年,差异有统计学意义(β =-6.04;95%CI:-8.79, -3.28;P < 0.01)。在校正性别、民族、BMI、吸烟史、饮酒史、抗CCP抗体及RF后,发病年龄提前4.54年,仍明显早于家族史阴性患者(β =-4.54;95%CI:-8.70, -0.38;P < 0.05,表3)。
3.
应用广义线性回归模型分析家族史对RA患者发病年龄的影响
The effect of family history on age at onset in RA patients
| Items | β(95%CI) | P |
| Adjusted model, adjusted by gender, body mass index, smoking and alcohol drinking, anti-cyclic citrullinated peptide antibody and rheumatoid factor level. | ||
| Non-adjusted | -6.04 (-8.79, -3.28) | <0.01 |
| Adjusted | -4.54 (-8.70, -0.38) | <0.05 |
分别按性别、民族、吸烟史、饮酒史、BMI、RF及抗CCP抗体分层,分析风湿病家族史对RA发病年龄的影响,结果显示家族史在每个因素分层分析中均对发病年龄有影响。在吸烟RA患者中,有家族史比无家族史者发病年龄提前10.02年,差异具有统计学意义(β=-10.02;95%CI:-17.60, -2.43;P=0.01);而在不吸烟RA患者中,有家族史比无家族史者发病年龄提前3.27年,差异无统计学意义(β=-3.27;95%CI:-8.37, 1.82;P=0.21)。进一步研究家族史与性别、吸烟史、饮酒史、BMI、RF、抗CCP抗体对RA发病年龄的交互作用,提示吸烟与家族史对发病年龄的影响有交互作用趋势(P= 0.09,表4)。
4.
RA发病年龄的危险因素分层及与家族史交互作用分析
Stratification analysis of risk factors for age at onset of RA and interaction with family history
| Variable | n | β (95%CI) | P (β) | P (interaction) |
| RA, rheumatoid arthritis; CI, confidence interval; BMI, body mass index; RF, rheumatoid factor; CCP, cyclic citrullinated peptide. | ||||
| Gender | 0.20 | |||
| Male | 179 | 1.81(-8.81, 12.43) | 0.74 | |
| Female | 624 | -6.78(-11.37, -2.20) | <0.01 | |
| Nation | 0.96 | |||
| Han | 715 | -5.42(-9.71, -1.13) | 0.01 | |
| Minority | 32 | -10.29(-39.73, 19.14) | 0.51 | |
| Drinking | 0.10 | |||
| No | 561 | -7.32(-12.13, -2.51) | <0.01 | |
| Yes | 210 | 0.89(-7.88, 9.66) | 0.84 | |
| Smoking | 0.09 | |||
| No | 473 | -3.27(-8.37, 1.82) | 0.21 | |
| Yes | 222 | -10.02(-17.60, -2.43) | 0.01 | |
| BMI/(kg/m2) | 0.12 | |||
| <24 | 337 | -8.83(-14.66, -3.00) | <0.01 | |
| 24-28 | 145 | -2.81(-9.87, 4.25) | 0.44 | |
| >28 | 80 | 1.11(-10.52, 12.74) | 0.85 | |
| RF | 0.79 | |||
| Negative | 183 | -5.10(-14.20, 4.00) | 0.27 | |
| Positive | 394 | -5.78(-10.52, -1.03) | <0.05 | |
| Anti-CCP | 0.56 | |||
| Negative | 86 | -8.92(-20.83, 2.98) | 0.15 | |
| Positive | 509 | -4.75(-9.31, -0.19) | <0.05 | |
3. 讨论
本研究采用现场调查问卷的研究方法,分析了RA患者中常见的风湿病家族史与临床特征、病情活动度、血清学指标的相关性及其与吸烟、饮酒等环境因素之间的交互作用,以进一步明确风湿病家族史在RA发病中的意义。
RA具有家族聚集性,其家族史是RA发病的重要危险因素之一。RA的标准化发病率比(standar-dized incidence ratio, SIR)在患者子女中为3.02,在兄弟姐妹中为4.64,在双胞胎中为6.48,在多重病患家庭中为9.31[8]。本研究发现,803例RA患者中有家族史患者占 15.32%,其中一级亲属为73.98%,二级亲属为17.89%,一级+二级亲属为8.13%而且各单病种中都是一级亲属例数明显多于二级亲属,提示与家族史相关的RA患病风险随着亲属距离的增加而减少,进一步证实家族风险可以用来评估RA患病风险和遗传性。本研究还发现家族成员所患疾病种类除RA外,还有SpA、SLE、SS、SSc等风湿性疾病。RA与其他风湿性疾病重叠或合并的报道并不少见,同一家族中不同成员患有不同风湿性疾病亦非罕见,均提示RA家族性风险还与其他自身免疫病显著相关,多重病患家庭更倾向于患有多种风湿病。全基因组关联分析已证实RA与多种其他自身免疫病共享人类白细胞抗原(human leukocyte antigen, HLA)等易感基因[9],表明RA与其他自身免疫病可能存在共同的病因学及机制。
众所周知,遗传因素在RA家族聚集性中有重要作用,同时有大量研究表明,各种非遗传因素与家族聚集性的发生无关[10,11,12]。本研究中,分析有无家族史RA患者在吸烟史、饮酒史、BMI方面差异均无统计学意义,这与其他研究者的报道一致[12]。虽然RA以女性多发,但本研究结果显示,RA的家族风险在性别上并没有差异,在一项基于瑞典总人口的巢式病例对照研究中亦得出同样的结果[13]。
多项东亚人群的研究显示,HLA-DRB1*0101、*0405、*0901、*1001阳性均与发病年龄有相关性,携带DRB1*0405或DRB1*0901等位基因的患者,平均发病年龄分别提前4年或3年[14,15]。一项通过建立加权遗传风险评分(genetic risk score, GRS)并分组分析的研究,发现RA发病年龄提前与GRS的增加有关,表明早发型RA患者比晚发型可能具有更高的遗传风险因素“负荷”[16]。已有报道共享表位等位基因和吸烟在抗CCP抗体阳性RA患者发病中具有相互作用。有研究显示,在抗CCP抗体阴性RA患者中,HLA-DRB1 * 0405-* 0901杂合子与吸烟存在显著协同效应,提示家族史与吸烟在RA发病中具有协同作用,而这一协同作用与抗CCP抗体的产生无关[14]。本研究发现,家族史阳性比阴性患者平均早发病6.04年,在校正吸烟史、饮酒史、IBM、RF、抗CCP抗体等因素后,仍早发病4.54 年,且差异有统计学意义(P<0.05)。进一步危险因素分层分析,发现吸烟且家族史阳性的RA患者发病年龄显著提前10.02年,虽然交互作用分析差异无统计学意义,但可能与样本量较少有关,还需扩大样本进行队列研究进一步明确两者的交互作用,这些研究结果证实了RA发病中遗传与环境因素,尤其是吸烟,有协同作用。
早期研究认为,有家族史的RA患者中疾病活动性和骨侵蚀风险增加,而近期大多数研究提示,除发病年龄提前外,其他临床特征差异均无统计学意义[2]。本研究发现,有无家族史患者在发病年龄上有明显差异,但在其他临床特征、病情活动指标等方面差异均无统计学意义,与文献报道一致[17]。关于血清学指标与家族聚集性的关系,既往的研究结论不一,有报道提示有家族史的RA患者血清学阳性率更高,也有报道显示有无家族史RA患者血清学阳性率差异无统计学意义[18,19]。本研究中,家族史阳性RA患者具有更高的RF阳性率,而未发现抗CCP抗体与家族史之间的显著相关性,这可能与不同研究选取的研究人群、实验方法及样本量等不同有关。血清学与家族聚集性之间的关系还有待进一步研究明确。
本研究存在不足之处,如家族史皆由患者及其家属自述,尽管已结合病历记录并通过电话随访与患者多次核对,但仍有可能产生回忆偏倚和自我报告的不准确性。另外,下一步需要进行大样本多中心的病例对照研究,并对易感基因进行检测,以进一步明确家族史在RA发病中的意义。
综上所述,家族史是RA发病的重要风险因素之一,家族史阳性RA患者可能发病年龄提前,家族史与吸烟之间可能存在协同作用,共同参与RA发病。
本文编辑:刘淑萍
Biography
栗占国,教授,主任医师,博士生导师,北京大学人民医院临床免疫中心/风湿免疫科主任,风湿免疫研究所所长,北京大学医学部风湿免疫学系主任,北京大学临床免疫中心主任,973首席科学家,国家杰出青年科学基金获得者,CMB杰出教授及吴杨医药奖获得者,享受国务院特殊津贴。
现任中国免疫学会临床免疫分会主任委员,中华医学会风湿病学分会名誉主任委员,国际风湿病联盟和亚太风湿病联盟前主席,WHO骨关节肌肉疾病委员会委员,Clinical Rheumatology和International Journal of Rheumatic Diseases副主编,《中华风湿病学杂志》总编,《北京大学学报(医学版)》副主编,Lancet Rheumatology、 Annals of the Rheumatic Diseases及Nature Reviews Rheumatology等期刊编委。
长期从事风湿免疫病临床工作,主要研究方向为类风湿关节炎、系统性红斑狼疮和干燥综合征等的发病机制及免疫治疗,发现了新的致病分子及机制,建立了多种新型无创诊断和免疫治疗方法,并转化应用于临床。在Nature Medicine及Immunity等发表SCI论文240余篇,其中影响因子8.96~41.06的论文36篇。主编(译)及参编《类风湿关节炎》《风湿免疫学高级教程》等风湿病学专著30余本。
Funding Statement
西藏自治区自然科学基金项目(XZ2017ZR-ZYZ02)和山西省青年科技研究基金面上项目(2015021180)
Supported by Tibet Autonomous Region National Science Foundation(XZ2017ZR-ZYZ02)and General Program of Shanxi Youth Science and Technology Research Foundation (2015021180)
Contributor Information
李 茹 (Ru LI), Email: doctorliru123@163.com.
栗 占国 (Zhan-guo LI), Email: li99@bjmu.edu.cn.
References
- 1.Worthington J. Investigating the genetic basis of susceptibility to rheumatoid arthritis. J Autoimmun. 2005;25(Suppl):16–20. doi: 10.1016/j.jaut.2005.09.011. [DOI] [PubMed] [Google Scholar]
- 2.Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016;12(6):335–343. doi: 10.1038/nrrheum.2016.52. [DOI] [PubMed] [Google Scholar]
- 3.Lawrence. JS. Heberden Oration, 1969. Rheumatoid arthritis-nature ornurture ? Ann Rheum Dis. 1970;29(4):357–379. doi: 10.1136/ard.29.4.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Somers EC, Antonsen S, Pedersen L, et al. Parental history of lupus and rheumatoid arthritis and risk in offspring in a nationwide cohort study: does sex matter? Ann Rheum Dis. 2013;72(4):525–529. doi: 10.1136/annrheumdis-2011-201165. [DOI] [PubMed] [Google Scholar]
- 5.Laufer VA, Chen JY, Langefeld CD, et al. Integrative approaches to understanding the pathogenic role of genetic variation in rheumatic diseases. Rheum Dis Clin North Am. 2017;43(3):449–466. doi: 10.1016/j.rdc.2017.04.012. [DOI] [PubMed] [Google Scholar]
- 6.Generali E, Ceribelli A, Stazi MA, et al. Lessons learned from twins in autoimmune and chronic inflammatory diseases. J Autoimmun. 2017;83(9):51–61. doi: 10.1016/j.jaut.2017.04.005. [DOI] [PubMed] [Google Scholar]
- 7.Wordsworth P, Bell J. Polygenic susceptibility in rheumatoidarthritis. Ann Rheum Dis. 1991;50(6):343–346. doi: 10.1136/ard.50.6.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hemminki K, Li X, Sundquist J, et al. Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis Rheum. 2009;60(3):661–668. doi: 10.1002/art.24328. [DOI] [PubMed] [Google Scholar]
- 9.Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376–381. doi: 10.1038/nature12873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Polderman, TJ, Benyamin B, de Leeuw CA Meta-analysis of the heritability of human traits based on fifty years of twin stu-dies. Nat Genet. 2015;47(7):702–709. doi: 10.1038/ng.3285. [DOI] [PubMed] [Google Scholar]
- 11.Khoury MJ, Beaty TH, Liang KY. Can familial aggregation of disease be explained by familial aggregation of environmental risk factors? Am J Epidemiol. 1988;127(3):674–683. doi: 10.1093/oxfordjournals.aje.a114842. [DOI] [PubMed] [Google Scholar]
- 12.Jiang X, Frisell T, AsklingJ, et al. To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors? Arthritis Rheum. 2015;67(2):352–362. doi: 10.1002/art.38927. [DOI] [PubMed] [Google Scholar]
- 13.Frisell T, Holmqvist M, Källberg H, et al. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 2013;65(11):2773–2782. doi: 10.1002/art.38097. [DOI] [PubMed] [Google Scholar]
- 14.Bang SY, Lee HS, Lee KW, et al. Interaction of HLA-DRB1*0901 and *0405 with smoking suggests distinctive mechanisms of rheumatoid arthritis susceptibility beyond the shared epitope. J Rheumatol. 2013;40(7):1054–1062. doi: 10.3899/jrheum.121280. [DOI] [PubMed] [Google Scholar]
- 15.Lee HS, Lee KW, Song GG, et al. Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA-DRB1*0405 and *0901. Arthritis Rheum. 2004;50(11):3468–3475. doi: 10.1002/art.20608. [DOI] [PubMed] [Google Scholar]
- 16.Chibnik LB, Keenan BT, Cui J, et al. Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset. PLoS One. 2011;6(9):e24380. doi: 10.1371/journal.pone.0024380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Frisell T, Saevarsdottir S, Askling J. Does a family history of RA influence the clinical presentation and treatment response in RA? Ann Rheum Dis. 2016;75(6):1120–1125. doi: 10.1136/annrheumdis-2015-207670. [DOI] [PubMed] [Google Scholar]
- 18.Kurko J, Besenyei T, Laki J, et al. Genetics of rheumatoid arthritis: a comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):170–179. doi: 10.1007/s12016-012-8346-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Diaz FJ, Rojas-Villarraga A, Salazar JC, et al. Anti-CCP antibo-dies are associated with early age at onset in patients with rheumatoid arthritis. Joint Bone Spine. 2011;78(2):175–178. doi: 10.1016/j.jbspin.2010.07.014. [DOI] [PubMed] [Google Scholar]