背景:乳糜泻(CeD)是一种免疫介导的疾病,在食用麸质后在遗传易感个体中发展。HLA风险等位基因解释了40%的CeD的遗传成分,因此,人们一直在不断努力发现非HLA基因座,以解释剩余的遗传力.和大多数自身免疫性疾病一样,女性中CeD的患病率明显较高。这里,我们调查了X染色体对CeD性别偏倚的可能参与。
方法:我们对来自CeD免疫芯片的女性进行了X染色体全关联研究(XWAS)和基于基因的关联研究(7062例,5446个控件)。我们还构建了来自未刺激(n=226)和脂多糖(LPS)刺激(n=130)雌性供体的单核细胞中X染色体顺式表达数量性状基因座(eQTL)的数据库,并进行了基于摘要数据的MR(SMR)分析以整合XWAS和eQTL信息。我们询问了乳糜泻患者发病时外周血单核细胞(PBMC)中潜在致病基因(TMEM187)的表达,无麸质饮食,潜在的腹腔患者和非腹腔控制。
结果:基于XWAS和基因的分析确定了13个SNP和25个基因,分别,其中22个以前与CeD无关。X染色体顺式-eQTL分析发现18个基因在幼稚的雌性单核细胞中具有至少一个顺式-eQTL,在LPS刺激的雌性单核细胞中具有8个基因。其中2个是两种情况下常见的,6个是LPS刺激所特有的。SMR确定了女性幼稚单核细胞中TMEM187表达与CeD的潜在因果关系,受CeD相关的监管,eQTL-SNPsrs7350355和rs5945386。CeD风险等位基因与较低的TMEM187表达相关。使用来自LPS刺激的单核细胞的eQTL复制这些结果。与女性非乳糜泻对照相比,我们观察到女性CeD患者在发病时PBMC中TMEM187表达水平较高,但不是男性CeD个体。
结论:使用来自雌性单核细胞的X染色体基因型和基因表达数据,SMR已将TMEM187鉴定为CeD中的潜在因果候选者。需要进一步的研究来了解X染色体对女性CeD患病率较高的影响。
乳糜泻(CeD)是由遗传易感个体中的麸质消耗引发的免疫相关病症。女性的CeD患病率高于男性,但是这种差异的生物学解释尚未阐明。在这项研究中,我们调查了X染色体上的特定遗传变异是否与每个性别的CeD相关。令人惊讶的是,我们在女性中发现了13种遗传变异和25种与CeD显著相关的基因,但不是男人。此外,我们确定了X染色体上与单核细胞基因表达相关的遗传变异,一种在摄入麸质后在CeD中被激活的免疫细胞。将这些数据与我们之前的发现相结合,我们发现TMEM187基因的低表达可能与女性CeD风险的潜在增加有关.最后,验证实验证实,与非乳糜泻女性相比,女性CeD患者的血细胞中TMEM187水平更高,而在男性中没有看到这种差异。总之,我们的研究表明,X染色体基因TMEM187可能在CeD发育中起关键作用,提供对女性CeD患病率较高的见解。
Celiac disease (CeD) is an immune-mediated disorder that develops in genetically predisposed individuals upon gluten consumption. HLA risk alleles explain 40% of the genetic component of CeD, so there have been continuing efforts to uncover non-HLA loci that can explain the remaining heritability. As in most autoimmune disorders, the prevalence of CeD is significantly higher in women. Here, we investigated the possible involvement of the X chromosome on the sex bias of CeD.
We performed a X chromosome-wide association study (XWAS) and a gene-based association study in women from the CeD Immunochip (7062 cases, 5446 controls). We also constructed a database of X chromosome cis-expression quantitative trait loci (
eQTLs) in monocytes from unstimulated (n = 226) and lipopolysaccharide (LPS)-stimulated (n = 130) female donors and performed a Summary-data-based MR (SMR) analysis to integrate XWAS and eQTL information. We interrogated the expression of the potentially causal gene (TMEM187) in peripheral blood mononuclear cells (PBMCs) from celiac patients at onset, on a gluten-free diet, potential celiac patients and non-celiac controls.
The XWAS and gene-based analyses identified 13 SNPs and 25 genes, respectively, 22 of which had not been previously associated with CeD. The X chromosome cis-eQTL analysis found 18 genes with at least one cis-eQTL in naïve female monocytes and 8 genes in LPS-stimulated female monocytes, 2 of which were common to both situations and 6 were unique to LPS stimulation. SMR identified a potentially causal association of TMEM187 expression in naïve monocytes with CeD in women, regulated by CeD-associated, eQTL-SNPs rs7350355 and rs5945386. The CeD-risk alleles were correlated with lower TMEM187 expression. These results were replicated using
eQTLs from LPS-stimulated monocytes. We observed higher levels of TMEM187 expression in PBMCs from female CeD patients at onset compared to female non-celiac controls, but not in male CeD individuals.
Using X chromosome genotypes and gene expression data from female monocytes, SMR has identified TMEM187 as a potentially causal candidate in CeD. Further studies are needed to understand the implication of the X chromosome in the higher prevalence of CeD in women.
Celiac disease (CeD) is an immune-related condition triggered by gluten consumption in genetically susceptible individuals. Women present higher prevalence of CeD than men, but the biological explanation of such difference has not been elucidated. In this study, we investigated whether specific genetic variations on the X chromosome were associated with CeD in each sex. Surprisingly, we found 13 genetic variants and 25 genes significantly linked to CeD in women, but not in men. Additionally, we identified genetic variants on the X chromosome associated with gene expression of monocytes, a type of immune cells that is activated in CeD after gluten intake. Integrating these data with our previous findings, we found that lower expression of a gene termed TMEM187 might be associated with a potential increase in CeD risk in women. Finally, validation experiments confirmed higher TMEM187 levels in blood cells from female CeD patients compared to non-celiac women, while no such difference was seen in males. In summary, our study suggests that the X-chromosome gene TMEM187 may play a key role in CeD development, providing insights into the higher prevalence of CeD in females.