---
title: "rs28362336 in HCG27 Linked to Risk of Generalized Myasthenia Gravis and Alters HCG27 Regulation"
id: "plos-one-0-identification-of-rs28362336-as-a-risk-snp-for-generalized-myasthenia-gravis"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-0-identification-of-rs28362336-as-a-risk-snp-for-generalized-myasthenia-gravis"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069"
published_at: "2026-09-23T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# rs28362336 in HCG27 Linked to Risk of Generalized Myasthenia Gravis and Alters HCG27 Regulation
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-0-identification-of-rs28362336-as-a-risk-snp-for-generalized-myasthenia-gravis
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069)
- **Published At:** 2026-09-23T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study screened lncRNA-related regulatory SNPs in myasthenia gravis (MG) using GWAS data and a case–control cohort of 161 MG patients and 161 matched healthy controls. - Genotyping was performed by SNaPshot; machine learning (LASSO regression and random forest) was used to prioritize SNP-related risk factors. - Significant SNPs were identified on chromosomes 1, 6, 11, 17, and 18; subtype analysis showed associations that were not evident in the overall case–control comparison. - Subtype findings: **HCG27 rs9263872 (TT)**, **rs9263875 (GG)**, and **rs28362336 (GG)** were associated with **generalized myasthenia gravis (gMG)**; the rs9263875 G allele associated with gMG and HCG9 rs3823381 T allele associated with ocular MG (oMG). - Machine learning analysis highlighted **rs28362336** as a risk factor for MG. - Bioinformatics and ChIP-PCR revealed enrichment of enhancer-associated marks (H3K4me1, H3K27ac) and RNA polymerase II at the rs28362336 locus upstream of **HCG27**, consistent with enhancer activity. - Expression analysis (qRT-PCR) showed increased **HCG27** expression in MG patients overall and particularly in gMG patients with the rs28362336 GG genotype. - Fluorescence in situ hybridization localized **HCG27** in CD4+ T cells; functional assays showed HCG27 promoted CD4+ T-cell proliferation and inhibited apoptosis, suggesting a pro-proliferative, anti-apoptotic role. - The authors propose a functional axis in which the enhancer SNP rs28362336 modulates **HCG27** expression and thereby may contribute to MG pathogenesis and clinical subtype differences. - Data, methods, and multiomic evidence including ChIP-PCR and eQTL analyses were reported; details such as exact effect sizes, p-values, or full statistical outputs are presented in the original manuscript.
## Clinical Analysis & Structured Key Points
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Identification of rs28362336 as a risk SNP for generalized myasthenia gravis and its impact on HCG27 regulation * Zihong Chen, Roles Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0006-8558-072X ](https://orcid.org/0009-0006-8558-072X "ORCID Registry") ⨯ * Qingling Guo, Roles Methodology Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Liting Tian, Roles Formal analysis Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Jingnan Jin, Roles Formal analysis Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Xia Wang, Roles Methodology Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Chunyu Yu, Roles Investigation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Yichen Li, Roles Investigation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Jingjing Zhang, Roles Data curation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Yan Li, Roles Investigation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Yufan Zhao, Roles Data curation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Jiayi Zhang, Roles Data curation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Lanxin Zhang, Roles Formal analysis Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Lukuan Qiao, Roles Investigation Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China ⨯ * Jianjian Wang Roles Conceptualization, Resources, Supervision, Writing – review & editing * E-mail: wangjian_427@163.com Affiliation Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-5568-4612 ](https://orcid.org/0000-0001-5568-4612 "ORCID Registry") ⨯ # Identification of rs28362336 as a risk SNP for generalized myasthenia gravis and its impact on HCG27 regulation * Zihong Chen, * Qingling Guo, * Liting Tian, * Jingnan Jin, * Xia Wang, * Chunyu Yu, * Yichen Li, * Jingjing Zhang, * Yan Li, * Yufan Zhao ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: September 23, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0359069) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359069) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0359069) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0359069) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#abstract0) * [Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#sec001) * [Materials and methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#sec002) * [Results](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#sec017) * [Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#sec025) * [Conclusion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#sec026) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#sec027) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0359069) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069) ## Abstract Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junctions. Accumulating amounts of evidence have indicated that single nucleotide polymorphisms (SNPs) and long noncoding RNAs (lncRNAs) play critical roles in the pathogenesis of MG; however, research on MG-related lncRNA SNPs remains limited. Therefore, our study focused on MG-related lncRNA SNPs to explore their association with genetic susceptibility to MG. We screened regulatory SNPs using MG GWAS data and conducted a case‒control study including 161 patients and 161 controls. After SNaPshot genotyping, LASSO regression and random forest were used to identify SNP-related risk factors. We performed eQTL analysis and ChIP-PCR to identify the functional role and underlying mechanism of rs28362336. qRT-PCR was performed to measure HCG27 expression in MG patients and to further assess HCG27 expression in generalized MG (gMG) patients. Finally, fluorescence in situ hybridization was used to determine the subcellular localization of HCG27 in CD4 + T cells, and the effects of HCG27 overexpression or knockdown were evaluated by Western blot analysis and CCK-8 assays. Significant SNPs were identified on chromosomes 1, 6, 11, 17, and 18. Although no differences in genotype or allele frequency were observed between the cases and controls overall, subtype analysis revealed that HCG27 rs9263872(TT), rs9263875(GG), and rs28362336(GG) were associated with gMG risk. The rs9263875 G allele was associated with gMG, whereas the HCG9 rs3823381 T allele was associated with ocular MG (oMG). Machine learning analysis further revealed that rs28362336 is a risk factor of MG. Bioinformatics and ChIP-PCR revealed H3K4me1, H3K27ac, and Pol II enrichment at the rs28362336 locus, suggesting enhancer activity upstream of HCG27. HCG27 expression was increased in MG patients, particularly in gMG harboring the rs28362336 GG genotype. Finally, HCG27 promoted CD4 + T cell proliferation and inhibited apoptosis. This study revealed the associations of HCG27-related SNPs with gMG and the potential regulatory role of rs28362336 in HCG27 expression. Moreover, the upregulation of HCG27 in MG patients and its proliferation-promoting effect in CD4 + T cells suggest that HCG27 may contribute to MG pathogenesis. ## Figures ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g006) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g002) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.t001) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g003) ![Fig 4](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g004) ![Fig 5](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g005) ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g006) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g002) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.t001) **Citation:** Chen Z, Guo Q, Tian L, Jin J, Wang X, Yu C, et al. (2026) Identification of rs28362336 as a risk SNP for generalized myasthenia gravis and its impact on HCG27 regulation. PLoS One 21(9): e0359069. https://doi.org/10.1371/journal.pone.0359069 **Editor:** Xiaoen Wei, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, CHINA **Received:** June 27, 2026; **Accepted:** September 7, 2026; **Published:** September 23, 2026 **Copyright:** © 2026 Chen et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** Data is provided within the manuscript or supplementary information files. **Funding:** This work was supported by the Heilongjiang Chunyan Youth Science and Technology Talent team project (CYQN24009); Young Talents of Basic Research in Universities of Heilongjiang Province (YQJH2024129). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** The authors have declared that no competing interests exist. **Abbreviations:** MG, Myasthenia gravis; HCs, Healthy controls; lncRNAs, Long noncoding RNAs; SNPs, Single-nucleotide polymorphisms; PBMCs, Peripheral blood mononuclear cells; AChR, Acetylcholine receptor; LRP4, Low-density lipoprotein receptor-related protein 4; MuSK, Muscle-specific kinase; EOMG, Early-onset myasthenia gravis; LOMG, Late-onset myasthenia gravis; oMG, Ocular myasthenia gravis; gMG, Generalized myasthenia gravis; qRT‒PCR, Quantitative real-time PCR; HWE, Hardy‒Weinberg equilibrium; OR, Odds ratio; CI, Confidence interval; FISH, Fluorescence in situ hybridization; H3K27ac, Histone H3 lysine 27 acetylation; H3K4me, Histone H3 lysine 4 monomethylation; HLA, Human leukocyte antigen; MHC, Major histocompatibility complex; QMG, Quantitative myasthenia gravis; ML, Machine learning; RF, Random forest; ROC, Receiver operating characteristic; SLE, Systemic lupus erythematosus ## Introduction Myasthenia gravis (MG) is a chronic autoimmune disorder of neuromuscular junctions that is clinically characterized by fatigable muscle weakness [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref001)]. As the disease progresses, MG can lead to life-threatening exacerbations, notably myasthenic crisis. MG is a rare and complex condition triggered by the intricate interplay between genetic and environmental factors [[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref002)]. The underlying genetic pathogenesis is evidenced by the high disease concordance among identical twins [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref003)]. While associations with the major histocompatibility complex (MHC) locus have been recognized for more than 30 years, recent genome-wide association studies (GWAS) have identified numerous susceptibility variants, most of which reside in noncoding regions [[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref004),[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref005)]. These discoveries have revealed the complex genetic landscape of MG; however, the precise links between these variants and molecular pathogenesis remain elusive because of the inherent heterogeneity of MG. Increasing evidence suggests that many disease-associated variants identified by GWAS exert their pathogenic effects by modulating gene expression. Specifically, risk SNPs in noncoding regions are highly enriched in cis-regulatory elements, such as enhancers, which are characterized by specific histone modifications [[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref004)]. These “enhancer SNPs” can alter the binding affinity of transcription factors (TFs) in an allele-specific manner, thereby driving the dysregulation of downstream target genes [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref006)–[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref008)]. Among these targets, long noncoding RNAs (lncRNAs) have emerged as critical mediators of immune homeostasis [[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref009)]. Although lncRNA SNPs have been increasingly implicated in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis [[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref010),[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref011)], their systematic involvement in the regulatory landscape of MG remains poorly understood [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref012),[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref013)]. Within the genetic architecture of MG, the MHC on chromosome 6p21.3 is the most critical susceptibility locus [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref014),[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref015)]. This region is dense with not only HLA protein-coding genes but also numerous noncoding elements whose functions are only beginning to be decoded. Among these, HCG27 and HCG9 are two prominent lncRNAs situated within this high-risk cluster. While HCG27 has been linked to immune dysregulation in SLE patients [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref016)], its expression and pathogenic role in MG patients remain largely unexplored. Crucially, the clinical transition from ocular MG (oMG) to generalized MG (gMG) suggests a divergent molecular basis that may be governed by specific genetic variants within these MHC-located lncRNAs [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref017)–[19](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref019)]. However, systematic investigations into how these lncRNA SNPs contribute to the immunopathological heterogeneity of MG subtypes are currently lacking. To bridge this gap, we employed an integrative approach combining large-scale GWAS dataset screening with SNaPshot minisequencing to identify functional lncRNA SNPs in an MG cohort. We used machine learning (ML) algorithms, specifically LASSO regression and random forest (RF), to identify risk factors of disease, such as the rs28362336 genotype in HCG27. By incorporating multiomic evidence and ChIP validation, we aimed to elucidate the “functional SNP–transcription factor binding–target gene regulation” axis [[20](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref020)]. Our findings not only clarify the cis-regulatory mechanisms through which HCG27 modulates T-cell functions but also provide genetic markers that may facilitate the clinical stratification and personalized management of MG patients. ## Materials and methods ### Study subjects An age-, sex-, and ethnicity-matched case–control study was designed to assess the association between candidate lncRNA-related SNPs and MG susceptibility ([Fig 1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone-0359069-g001)). A total of 161 patients with MG were recruited at the Second Affiliated Hospital of Harbin Medical University between June 2024 and February 2025 and were included for genotyping. During the same period, 161 healthy controls (HCs) who underwent routine physical examinations at the same hospital were also recruited. Among the patients with MG, 131 were AChR-Ab-positive, while the antibody status of the remaining 30 patients was unknown. HCs had no personal or family history of autoimmune diseases or neuromuscular disorders. In this study, the diagnosis of MG was based on standard clinical criteria of characteristic fatigable weakness and electrophysiological and/or pharmacological abnormalities [[21](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.ref021)]. The exclusion criteria for the case group included serious cardiopulmonary diseases, severe infections, pregnancy, perinatal infections, malignancies other than thymoma, and other autoimmune diseases. Finally, 322 individuals were genotyped, including 161 MG patients and 161 HCs ([S1 Table](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359069#pone.0359069.s002)). [![thumbnail](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359069.g001)](https://journals.plos.org/plosone/article/figure/image?size=medium&id=10.1371/journal.pone.0359069.g001 "Click for larger image") Download: * [PNG larger image](https://journals.plos.org/plosone/article/figure/image?download&size=large&id=10.1371/journal.pone.0359069.g001) * [TIFF original image](https://journals.plos.org/plosone/article/
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