Pullmann Rudolf, Bonilla Eduardo, Phillips Paul E, Middleton Frank A, Perl Andras
State University of New York, Syracuse, NY 13210, USA.
Arthritis Rheum. 2008 Feb;58(2):532-40. doi: 10.1002/art.23161.
Endogenous retroviral sequences represent a link between viral and genetic factors that may influence the development of systemic lupus erythematosus (SLE). The HRES-1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. We therefore undertook the present study to determine the haplotypes of the HRES-1 locus and their linkage to SLE.
One hundred six patients with SLE, 82 unrelated healthy Caucasian individuals, and 70 healthy members of 34 lupus families were examined. HRES-1 was amplified by polymerase chain reaction (PCR) and analyzed by sequencing and restriction enzyme mapping. Microsatellites were analyzed by PCR. Haplotype construction and transmission disequilibrium testing (TDT) were performed in lupus families.
Based on 4 single-nucleotide polymorphisms (SNPs) within a 935-base interval, we detected 6 HRES-1 haplotypes that were differentially segregated in unrelated Caucasian patients and control subjects (chi(2) = 16.86, P = 0.0048) and were in linkage disequilibrium (LD) with the D1S225 microsatellite (P = 0.0002). The microsatellites D1S225, D1S235, and D1S2785 (but not D1S229) were linked to SLE by TDT. Interestingly, LD between HRES-1 SNPs at bases 653 and 1259 was reduced in patients with SLE (P = 0.048). The HRES-1 653C/1259C-harboring alleles were associated with the presence of renal disease (P = 0.0021) and with the absence of lung disease (P = 0.0323), while the 956A allele was associated with the antiphospholipid syndrome in patients with SLE (P = 0.0036).
The HRES-1 locus represents a recombination hot spot at the 1q42 chromosomal region that influences the development and disease manifestations of SLE.
内源性逆转录病毒序列代表了可能影响系统性红斑狼疮（SLE）发病的病毒因素与遗传因素之间的联系。相对于先前与SLE相关的微卫星，HRES-1人类内源性逆转录病毒序列位于1q42染色体区域的中心位置。因此，我们开展了本研究以确定HRES-1基因座的单倍型及其与SLE的连锁关系。
对106例SLE患者、82名无亲缘关系的健康白种人个体以及34个狼疮家族的70名健康成员进行了检测。通过聚合酶链反应（PCR）扩增HRES-1，并进行测序和限制性酶切图谱分析。通过PCR分析微卫星。在狼疮家族中进行单倍型构建和传递不平衡检验（TDT）。
基于935个碱基区间内的4个单核苷酸多态性（SNP），我们检测到6种HRES-1单倍型，它们在无亲缘关系的白种人患者和对照受试者中存在差异分离（χ² = 16.86，P = 0.0048），并且与D1S225微卫星处于连锁不平衡（LD）状态（P = 0.0002）。微卫星D1S225、D1S235和D1S2785（但不包括D1S229）通过TDT与SLE连锁。有趣的是，SLE患者中653位和1259位碱基处的HRES-1 SNP之间的LD降低（P = 0.048）。携带HRES-1 653C/1259C的等位基因与肾脏疾病的存在相关（P = 0.0021），与肺部疾病的不存在相关（P = 0.0323），而956A等位基因与SLE患者的抗磷脂综合征相关（P = 0.0036）。
HRES-1基因座代表1q42染色体区域的一个重组热点，影响SLE的发病及疾病表现。
