*3.1. Genetic Evidence for lncRNA Involvement in Endometriosis*

Genome-wide association studies (GWAS) have been conducted for many diseases including endometriosis [24,25]. This powerful approach surveys single-nucleotide polymorphisms (SNPs) throughout the genome in a large cohort of individuals to identify variants and genomic regions associated with an increased chance of developing the disease. SNPs identified in GWAS studies often occur in intergenic regions, and therefore, it has been speculated that they may affect the regulation of nearby genes [26]. One mechanism by which this could work is via changing the sequence of an lncRNA and, thereby, affecting its regulatory function [27].

Genome-wide DNA sequencing technology has identified genetic variations in lncRNA loci that may affect the pathogenesis of endometriosis. The rs10965235 SNP located on chromosome 9p21.3 is associated with severe endometriosis in a Korean patient cohort and lies within the *CDKN2B-AS* gene locus [28]. This indicates that disruption of lncRNA function by the SNP is a possible mechanism through which this variant may predispose patients to endometriosis. The rs3820282 SNP located within a *WNT4* intron on chromosome 1p36.12 is associated with endometriosis and appears to affect an enhancer–promoter interaction resulting in the downregulation of *LINC00339* and upregulation of *CDC42* [29]. This indicates another possible mechanism for lncRNA regulation, whereby dysregulation of *CDC42* due to the risk of an SNP affecting enhancer competition with the *LINC00339* promoter leads to predisposition to endometriosis. Recently, genetic variations at the rs1838169 and rs17720428 SNPs sites on chromosome 12q13.3 in *HOTAIR* have been shown to be frequently detected in patients with endometriosis [30]. These variants appear to increase the stability of the lncRNA, resulting in reduced levels of *HOXD10* and *HOXA5* transcripts regulated by *HOTAIR*. A variant of the rs591291 SNP located on chromosome 11q13.1 in the promoter region of *MALAT1* was associated with an increase in endometriosis risk in a Chinese population, indicating that a change in the *MALAT1* expression level may affect endometriosis risk, although this was not examined in this study [31]. Finally, the rs710886 SNP in *PCAT1* has been associated with increased risk of developing endometriosis [32]. This SNP appears to disrupt sponging by *PCAT1* of *miR-145*, affecting the expression of *FASCIN1*, *SOX2*, *MSI2*, *SERPINE1*, and *JAM-A*, and the proliferative and invasive ability of endometriosis stem cells. Together, these studies indicate that genetic variants associated with endometriosis may predispose patients to the disease by disrupting the lncRNA gene regulatory function via diverse mechanisms.
