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LBX1 基因座与法裔加拿大青少年特发性脊柱侧凸相关性的复制研究。

A Replication Study for Association of LBX1 Locus With Adolescent Idiopathic Scoliosis in French-Canadian Population.

机构信息

Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine, University Hospital, Research Center, Montreal, QC, Canada.

Program of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.

出版信息

Spine (Phila Pa 1976). 2018 Feb 1;43(3):172-178. doi: 10.1097/BRS.0000000000002280.

DOI:10.1097/BRS.0000000000002280

PMID:28604496

Abstract

STUDY DESIGN

A case-control association study.

OBJECTIVES

To investigate the relationship between LBX1 (lady bird homeobox1) polymorphisms and adolescent idiopathic scoliosis (AIS) in French-Canadian population.

SUMMARY OF BACKGROUND DATA

It is widely accepted that genetic factors contribute to AIS. Although the LBX1 locus is so far the most successfully replicated locus in different AIS cohorts, these associations were replicated mainly in Asian populations, with few studies in Caucasian populations of European descent.

METHODS

We recruited 1568 participants (667 AIS patients and 901 healthy controls) in the French-Canadian population. Genomic data were generated using the Illumina Human Omni 2.5M BeadChip. An additional 121 AIS cases and 51 controls were genotyped for specific single-nucleotide polymorphisms (SNPs) by multiplex polymerase chain reaction using standard procedures. BEAGLE 3 was used to impute the following markers: rs7893223, rs11190878, and rs678741 against the 1000-genomes European cohort phased genotypes given that they were absent in our genome wide association studies (GWAS) panel. Resulting genotypes were combined then used for single marker and haplotyped-based association.

RESULTS

Four markers showed association with AIS in our cohort at this locus; rs11190870 the most studied marker, rs7893223, rs594791, and rs11190878. When we restricted the analysis to severe cases only, four additional SNPs showed associations: rs11598177, rs1322331, rs670206, and rs678741. In addition, we analyzed the associations of the observed haplotypes and dihaplotypes formed by these SNPs. The haplotype TTAAGAAA and its homozygous dihaplotype showed the highest association with our severe group and was the highest risk haplotype. The haplotype CCGCAGGG was significantly more associated with the control group, and its homozygous or heterozygous dihaplotype was less frequent in the severe group compared with the control group, suggesting that CCGCAGGG may represent a protective haplotype.

CONCLUSION

We have replicated the association of the LBX1 locus with AIS in French-Canadian population, a novel European descent cohort, which is known for its unique genetic architecture.

LEVEL OF EVIDENCE

摘要

研究设计

病例对照关联研究。

目的

探讨 LBX1（鸟翼蝶同源盒 1）多态性与法国裔加拿大人群青少年特发性脊柱侧凸（AIS）的关系。

背景资料概要

遗传因素与 AIS 密切相关，这一观点已被广泛接受。尽管迄今为止，LBX1 基因座是不同 AIS 队列中复制最成功的基因座，但这些关联主要在亚洲人群中得到复制，而在欧洲裔白种人群中的研究较少。

方法

我们在法国裔加拿大人群中招募了 1568 名参与者（667 名 AIS 患者和 901 名健康对照者）。使用 Illumina Human Omni 2.5M BeadChip 生成基因组数据。通过多重聚合酶链反应（PCR）使用标准程序对另外 121 名 AIS 病例和 51 名对照进行了特定单核苷酸多态性（SNP）的基因分型。使用 BEAGLE 3 将 rs7893223、rs11190878 和 rs678741 这三个标记物进行了单倍型内插，这些标记物在我们的全基因组关联研究（GWAS）面板中缺失，但是基于它们存在于 1000 基因组欧洲队列的相位基因型中。然后，将生成的基因型组合起来，用于单标记和基于单体型的关联分析。

结果

在我们的队列中，该基因座的四个标记与 AIS 相关；rs11190870 是研究最多的标记，rs7893223、rs594791 和 rs11190878。当我们仅将分析限制在严重病例时，另外四个 SNP 显示出相关性：rs11598177、rs1322331、rs670206 和 rs678741。此外，我们分析了观察到的单体型及其由这些 SNP 形成的双单体型的关联。TTAAGAAA 单体型及其纯合二单体型与我们的严重组相关性最高，是最高风险单体型。CCGCAGGG 单体型与对照组显著相关，且其纯合或杂合二单体型在严重组中比对照组中少见，表明 CCGCAGGG 可能代表一种保护单体型。