García-Ortiz Humberto, Barajas-Olmos Francisco, Flores-Huacuja Marlen, Morales-Rivera Monserrat I, Martínez-Hernández Angélica, Baca Vicente, Contreras-Cubas Cecilia, Orozco Lorena
Immunogenomics and Metabolic Diseases Laboratory, National Institute of Genomic Medicine, SS, Mexico City, Mexico.
Department of Rheumatology, Hospital de Pediatría, CMN Siglo XXI IMSS, Mexico City, Mexico.
Front Med (Lausanne). 2023 Jan 12;9:1044856. doi: 10.3389/fmed.2022.1044856. eCollection 2022.
Here we aimed to investigate the association of the Xq28 risk haplotype (H1) with susceptibility to childhood-onset systemic lupus erythematosus (SLE), and to compare its frequency and genetic structure in the Mexican population with those in other continental populations.
We genotyped 15 single-nucleotide variants (SNVs) that form the H1 haplotype, using TaqMan real-time PCR. The association analysis [case-control and transmission disequilibrium test (TDT)] included 376 cases and 400 adult controls, all of whom were mestizos (MEZ). To identify risk alleles in Mexican Indigenous individuals, SNVs were imputed from whole-exome sequencing data of 1,074 individuals. The allelic frequencies determined in MEZ and Indigenous individuals were compared with those of the continental populations from the 1,000 Genomes database phase 3. Linkage disequilibrium (LD) analysis of risk alleles was performed on all populations. Interleukin-1 receptor associated kinase 1 () and methyl CpG binding protein 2 () mRNA levels were determined using real-time PCR.
Case-control analysis revealed genetic association with childhood-onset SLE for all 15 SNVs (OR = 1.49-1.75; = 0.0095 to 1.81 × 10) and for the Xq28 risk haplotype (OR = 1.97, = 4 × 10). Comparing with individuals of European ancestry (0.14-0.16), the frequencies of the risk alleles were significantly higher in the MEZ individuals (0.55-0.68) and even higher in Indigenous individuals (0.57-0.83). LD analysis indicated a differential haplotype structure within the Indigenous groups, which was inherited to the MEZ population as a result of genetic admixture. Individuals homozygous for the Xq28 risk haplotype exhibited decreased levels of both and transcripts.
We found that the H1 risk haplotype differs in its conformation in the Mexican population. This difference could be attributed to positive selection within the Indigenous population, with its inheritance now having an autoimmune health impact in both the Mexican Indigenous and MEZ populations.
本研究旨在探讨Xq28风险单倍型（H1）与儿童期系统性红斑狼疮（SLE）易感性之间的关联，并比较墨西哥人群与其他大陆人群中该单倍型的频率和遗传结构。
我们使用TaqMan实时PCR对构成H1单倍型的15个单核苷酸变异（SNV）进行基因分型。关联分析[病例对照和传递不平衡检验（TDT）]纳入了376例病例和400名成年对照，所有个体均为梅斯蒂索人（MEZ）。为了确定墨西哥原住民个体中的风险等位基因，从1074名个体的全外显子测序数据中推算出SNV。将在MEZ和原住民个体中确定的等位基因频率与千人基因组数据库第3阶段中大陆人群的频率进行比较。对所有人群进行风险等位基因的连锁不平衡（LD）分析。使用实时PCR测定白细胞介素-1受体相关激酶1（）和甲基CpG结合蛋白2（）的mRNA水平。
病例对照分析显示，所有15个SNV与儿童期SLE存在遗传关联（OR = 1.49 - 1.75； = 0.0095至1.81×10），Xq28风险单倍型也存在关联（OR = 1.97， = 4×10）。与欧洲血统个体（0.14 - 0.16）相比，风险等位基因频率在MEZ个体中显著更高（0.55 - 0.68），在原住民个体中甚至更高（0.57 - 0.83）。LD分析表明，原住民群体内部存在不同的单倍型结构，由于基因混合，这种结构遗传给了MEZ人群。Xq28风险单倍型纯合个体的和转录本水平均降低。
我们发现H1风险单倍型在墨西哥人群中的构象不同。这种差异可能归因于原住民群体中的正选择，其遗传现在对墨西哥原住民和MEZ人群的自身免疫健康都有影响。
