Sex bias in celiac disease: XWAS and monocyte eQTLs in women identify TMEM187 as a functional candidate gene

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2023-12-11 DOI:10.1186/s13293-023-00572-1
Alba Hernangomez-Laderas, Ariadna Cilleros-Portet, Silvia Martínez Velasco, Sergi Marí, María Legarda, Bárbara Paola González-García, Carlos Tutau, Iraia García-Santisteban, Iñaki Irastorza, Nora Fernandez-Jimenez, Jose Ramon Bilbao
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Abstract

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.
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乳糜泻的性别偏见:女性的 XWAS 和单核细胞 eQTL 确定 TMEM187 为功能性候选基因
乳糜泻(Celiac disease,CeD)是一种免疫介导的疾病,易感基因携带者在食用麸质食品后发病。HLA 风险等位基因可解释乳糜泻 40% 的遗传因素,因此人们一直在努力发掘可解释剩余遗传性的非 HLA 基因位点。与大多数自身免疫性疾病一样,女性的 CeD 患病率明显更高。在此,我们研究了 X 染色体对 CeD 性别偏向的可能影响。我们对 CeD 免疫片段(7062 例病例,5446 例对照)中的女性进行了全 X 染色体关联研究(XWAS)和基于基因的关联研究。我们还在未受刺激(n = 226)和受脂多糖(LPS)刺激(n = 130)的女性供体单核细胞中构建了一个 X 染色体顺式表达定量性状位点(eQTL)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。我们检测了乳糜泻患者发病时、无麸质饮食时、潜在乳糜泻患者和非乳糜泻对照组的外周血单核细胞(PBMC)中潜在致病基因(TMEM187)的表达情况。基于 XWAS 和基因的分析分别发现了 13 个 SNP 和 25 个基因,其中 22 个基因以前从未与乳糜泻相关联。X染色体顺式-eQTL分析发现,在天真雌性单核细胞中有18个基因具有至少一个顺式-eQTL,在LPS刺激的雌性单核细胞中有8个基因具有至少一个顺式-eQTL,其中2个基因在两种情况下都有,6个基因在LPS刺激下特有。SMR确定了TMEM187在女性幼稚单核细胞中的表达与CeD的潜在因果关系,该关系受CeD相关的eQTL-SNPs rs7350355和rs5945386调节。CeD 风险等位基因与较低的 TMEM187 表达相关。我们利用 LPS 刺激单核细胞的 eQTLs 复制了这些结果。我们观察到,与女性非糜烂性对照组相比,女性糜烂性结肠炎患者发病时的 PBMC 中 TMEM187 表达水平较高,而男性糜烂性结肠炎患者则没有。利用来自女性单核细胞的 X 染色体基因型和基因表达数据,SMR 发现 TMEM187 可能是 CeD 的致病候选基因。要了解 X 染色体对女性糜烂性胃炎发病率较高的影响,还需要进一步的研究。乳糜泻(Celiac disease,CeD)是一种与免疫相关的疾病,由基因易感者食用麸质引发。女性的乳糜泻发病率高于男性,但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 染色体上的特定基因变异是否与不同性别的 CeD 相关。令人惊讶的是,我们发现女性中有 13 个基因变异和 25 个基因与 CeD 有显著关联,而男性则没有。此外,我们还发现了与单核细胞基因表达相关的 X 染色体遗传变异,单核细胞是一种免疫细胞,摄入麸质后会激活 CeD。将这些数据与我们之前的研究结果相结合,我们发现名为 TMEM187 的基因表达较低可能与女性 CeD 风险的潜在增加有关。最后,验证实验证实,与非乳糜泻女性患者相比,女性乳糜泻患者血细胞中的 TMEM187 水平较高,而男性则没有这种差异。总之,我们的研究表明,X 染色体基因 TMEM187 可能在 CeD 的发展过程中起着关键作用,为女性 CeD 的高发病率提供了启示。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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