Abstract
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin (TMPO) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense TMPO variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 “T” risk allele frequency ranged from 21 to 68%, while the rs17028450 “T” minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models (OR = 2.48; p = 8 × 10–10 and OR = 1.59; p = 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models (p = 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of TMPO gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations.
Highlights
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a multifactorial disorder that results from complex interactions between genetic and environmental factors
The frequency of the derived “T” allele is lower than 2% in Asian, African and European populations, and 10.9 and 14.1% in Mexican American and Peruvian populations, respectively
NMOSD is a multifactorial disorder that results from complex interactions between genetic and environmental factors
Summary
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a multifactorial disorder that results from complex interactions between genetic and environmental factors. East Asians and populations with African ancestry have reported a higher prevalence of this disease (Hor et al, 2020). In Latin America, admixed populations with lower proportions of European ancestry have higher relative frequencies of NMOSD (Alvarenga et al, 2017). We performed a genome-wide association study (GWAS) identifying a NMOSD risk genetic variant within HLA class II region (rs9272219) that is in linkage disequilibrium with HLA DRB1∗16:02, previously associated with NMOSD in Southern Han Chinese, Japanese and Brazilian populations (Wang et al, 2011; Yoshimura et al, 2013; Kay et al, 2019; Romero-Hidalgo et al, 2020). A limited number of candidate gene association studies have reported associations of NMOSD with individual polymorphisms in a few genes involved in immune function, including PD-1, IL-17, IL-7R, CD226, and CD58 (Asgari et al, 2012; Liu et al, 2012; Wang et al, 2012; Kim et al, 2014; Zhuang et al, 2015)
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