López-Isac Elena, Bossini-Castillo Lara, Simeon Carmen P, Egurbide María Victoria, Alegre-Sancho Juan José, Callejas Jose Luis, Roman-Ivorra José Andrés, Freire Mayka, Beretta Lorenzo, Santaniello Alessandro, Airó Paolo, Lunardi Claudio, Hunzelmann Nicolas, Riemekasten Gabriela, Witte Torsten, Kreuter Alexander, Distler Jörg H W, Schuerwegh Annemie J, Vonk Madelon C, Voskuyl Alexandre E, Shiels Paul G, van Laar Jacob M, Fonseca Carmen, Denton Christopher, Herrick Ariane, Worthington Jane, Assassi Shervin, Koeleman Bobby P, Mayes Maureen D, Radstake Timothy R D J, Martin Javier
Arthritis Res Ther. 2014 Jan 9;16(1):R6. doi: 10.1186/ar4432.
A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.
Sixty-six non-HLA SNPs showing a P value <10⁻⁴ in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays.
We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10⁻⁶, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10⁻⁶, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10⁻⁷; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.
Our results suggest a role of PPARG gene in the development of SSc.
最近一项包含法国系统性硬化症（SSc）队列的全基因组关联研究（GWAS）报告了几个非HLA单核苷酸多态性（SNP），在发现阶段显示出名义上的关联。我们旨在通过采用后续策略来识别先前被忽视的易感变异。
在本研究的第一步中，分析了在法国SSc GWAS发现阶段P值<10⁻⁴的66个非HLA SNP，进行了一项荟萃分析，该分析合并了两个已发表的SSc GWAS的数据。第一阶段共纳入2921例SSc患者和6963例健康对照。根据第一步的结果，选择两个SNP，即PPARG rs310746和CHRNA9 rs6832151，在复制队列（1068例SSc患者和6762例健康对照）中进行基因分型。基因分型采用TaqMan SNP基因分型检测法进行。
在本研究的第一步中，我们观察到PPARG rs310746（PMH = 1.90×10⁻⁶，OR，1.28）和CHRNA9 rs6832151（PMH = 4.30×10⁻⁶，OR，1.17）基因变异与SSc存在名义上的关联。在复制阶段，我们观察到PPARG rs310746存在关联趋势（P值 = 0.066；OR，1.17）。对本研究中纳入的所有队列进行的总体Mantel-Haenszel荟萃分析显示，PPARG rs310746与SSc仍存在关联，P值具有名义上的非全基因组显著性（PMH = 5.00×10⁻⁷；OR，1.25）。在复制阶段或总体汇总分析中均未观察到CHRNA9 rs6832151存在关联的证据。
我们的结果提示PPARG基因在SSc的发生发展中起作用。
