Ramos Paula S, Marion Miranda C, Langefeld Carl D, Buyon Jill P, Clancy Robert M
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA.
Arthritis Rheum. 2012 Dec;64(12):4060-5. doi: 10.1002/art.34663.
The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the RNPs SSA/Ro and SSB/La, enhanced by as-yet-unknown factors that likely involve dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biologic functions.
Using data from our genome-wide association study of 116 Caucasian children with cardiac-NL and 3,351 Caucasian controls, we tested for enrichment of single-nucleotide polymorphism (SNP) associations in genes with candidate biologic functions related to fibrosis, immune function, apoptosis, T cell function, cell infiltration, innate immune cell function, interferon, Toll-like receptors, and calcium channels. After linkage disequilibrium pruning and exclusion of the extended HLA region, a total of 15,103 SNPs in 3,068 genes remained.
A highly significant enrichment of P values was observed for genes related to fibrosis (P = 2.27 × 10(-9) ), apoptosis (P = 7.67 × 10(-7) ), and innate immune cell (P = 2.53 × 10(-6) ), immune (P = 5.01 × 10(-4) ), T cell (P = 2.23 × 10(-4) ), and interferon functions (P = 1.64 × 10(-3) ). The most significant non-HLA associations included the sialyltransferase gene ST8SIA2 (rs1487982; odds ratio 2.20 [95% confidence interval 1.52-3.19], P = 3.37 × 10(-5) ), the integrin gene ITGA1 (rs2432143; odds ratio 2.31 [95% confidence interval 1.54-3.45], P = 4.54 × 10(-5) ), and the complement regulator gene CSMD1 (rs7002001; odds ratio 2.41 [95% confidence interval 1.57-3.72], P = 6.33 × 10(-5) ).
This study identified novel candidate genes associated with cardiac-NL and highlights the value of studying this cohort for advancing knowledge regarding the genetic etiology of this syndrome. Identification of causal alleles is expected to provide critical insight into the molecular mechanisms responsible for linking maternal autoantibodies to cardiac scarring in these fetuses/neonates.
新生儿狼疮心脏表现（心脏型新生儿狼疮）的发病机制推测涉及母体针对核糖核蛋白SSA/Ro和SSB/La的自身抗体，某些未知因素增强了这些抗体的作用，这些因素可能涉及胎儿炎症反应和纤维化反应的失调。本研究旨在提高检测具有候选生物学功能基因中特定关联的能力。
利用我们对116例患心脏型新生儿狼疮的白种儿童和3351例白种对照进行的全基因组关联研究数据，我们检测了与纤维化、免疫功能、细胞凋亡、T细胞功能、细胞浸润、固有免疫细胞功能、干扰素、Toll样受体和钙通道等候选生物学功能相关的基因中，单核苷酸多态性（SNP）关联的富集情况。经过连锁不平衡修剪并排除扩展的HLA区域后，3068个基因中共有15103个SNP保留下来。
观察到与纤维化（P = 2.27×10⁻⁹）、细胞凋亡（P = 7.67×10⁻⁷）、固有免疫细胞（P = 2.53×10⁻⁶）、免疫（P = 5.01×10⁻⁴）、T细胞（P = 2.23×10⁻⁴）和干扰素功能（P = 1.64×10⁻³）相关的基因的P值有高度显著的富集。最显著的非HLA关联包括唾液酸转移酶基因ST8SIA2（rs1487982；比值比2.20 [95%置信区间1.52 - 3.19]，P = 3.37×10⁻⁵）、整合素基因ITGA1（rs2432143；比值比2.31 [95%置信区间1.54 - 3.45]，P = 4.54×10⁻⁵）和补体调节基因CSMD1（rs7002001；比值比2.41 [95%置信区间1.57 - 3.72]，P = 6.33×10⁻⁵）。
本研究鉴定出与心脏型新生儿狼疮相关的新候选基因，并强调了研究该队列对于推进关于该综合征遗传病因学知识的价值。确定因果等位基因有望为将母体自身抗体与这些胎儿/新生儿心脏瘢痕形成联系起来的分子机制提供关键见解。
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