Role of the Human Endogenous Retrovirus HERV-K18 in Autoimmune Disease Susceptibility: Study in the Spanish Population and Meta-Analysis

<div><p>Background</p><p>Human endogenous retroviruses (HERVs) are genomic sequences that resulted from ancestral germ-line infections by exogenous retroviruses and therefore are transmitted in a Mendelian fashion. Increased HERV expression and antibodies to HERV antigens have been found in various autoimmune diseases. HERV-K18 in chromosome 1 was previously associated with type one diabetes and multiple sclerosis (MS). The etiology of these complex conditions has not been completely elucidated even after the powerful genome wide association studies (GWAS) performed. Nonetheless, this approach does not scrutinize the repetitive sequences within the genome, and part of the missing heritability could lie behind these sequences. We aimed at evaluating the role of HERV-K18 in chromosome 1 on autoimmune disease susceptibility.</p><p>Methods</p><p>Two HERV-K18 SNPs (97Y/C and 154W/Stop substitutions) conforming three haplotypes were genotyped in Spanish cohorts of multiple sclerosis (n = 942), rheumatoid arthritis (n = 462) and ethnically matched controls (n = 601). Our findings were pooled in a meta-analysis including 5312 autoimmune patients and 4032 controls.</p><p>Results</p><p>Significant associations of both HERV-K18 polymorphisms in chromosome 1 with MS patients stratified by HLA-<i>DRB1*15∶01</i> were observed [97Y/C p = 0.02; OR (95% CI) = 1.5 (1.04–2.17) and 154W/Stop: p = 0.001; OR (95% CI) = 1.6 (1.19–2.16)]. Combined meta-analysis of the previously published association studies of HERV-K18 with different autoimmune diseases, together with data derived from Spanish cohorts, yielded a significant association of the HERV-K18.3 haplotype [97Y–154W: p_M-H = 0.0008; OR_M-H (95% CI) = 1.22 (1.09–1.38)].</p><p>Conclusion</p><p>Association of the HERV-K18.3 haplotype in chromosome 1 with autoimmune-disease susceptibility was confirmed through meta-analysis.</p></div

Role of HERV-K18 haplotypes A) Meta-analysis of case-control studies in different autoimmune disease cohorts; B) Spanish data stratified by HLA susceptibility alleles (<i>DRB1*15∶01</i> in MS and shared epitope in RA).

<p>Role of HERV-K18 haplotypes A) Meta-analysis of case-control studies in different autoimmune disease cohorts; B) Spanish data stratified by HLA susceptibility alleles (<i>DRB1*15∶01</i> in MS and shared epitope in RA).</p

Genotypic frequencies of polymorphisms within the HERV-K18 sequence in autoimmune disease Spanish patients and controls.

1<p>GG vs AG+AA: MS 1501⁺ vs 1501⁻: p = 0.01; MS 1501⁺ vs. Controls: p = 0.02, OR (95%CI) = 1.50 (1.04–2.17).</p>2<p>GG vs AG+AA: MS 1501⁺ vs 1501⁻: p = 0.0009; MS 1501⁺ vs. Controls: p = 0.001, OR (95%CI) = 1.60 (1.19–2.16).</p

Strategy used for the selection of studies finally included in the meta-analysis.

<p>Strategy used for the selection of studies finally included in the meta-analysis.</p

Frequency of the different <i>DRB1*03:01</i>-containing haplotypes in <i>DRB1*15:01</i> positive (+) and negative (−) multiple sclerosis (MS) patients and in controls; and case-control study for the total MS patients.

<p>% are referred to the total number of haplotypes analysed in each group (last row).</p><p>AH 18.2 includes haplotypes carrying <i>DRB1*03:01</i>, <i>DQB1*02:01</i>, <i>TNF -376A</i>, <i>TNF a1b5</i> and <i>B*18</i>. AH 8.1 includes haplotypes carrying <i>DRB1*03:01</i>, <i>DQB1*02:01</i>, <i>TNF -308A</i>, <i>TNF a2b3</i> and <i>B*8</i>. Haplotypes with all the remaining allelic combinations in those loci or markers are included as “non-conserved” haplotypes.</p>1<p>Excluding the <i>HLA-DRB1*15:01</i>-containing haplotypes.</p

Meta-analysis of HERV-Fc1 association studies with bout-onset MS.

<p>Forest plot including all the available cohorts (A), and after eliminating heterogeneity by removing the Southern Spanish cohort (B).</p

TRAILR-1 expression levels among Responders and Non Responders to IFN beta therapy, in different PBMC subsets.

<p>Expression level is represented as relative expression compared to the reference gene GAPDH, using the ΔΔCt method. TRAILR-1 expression levels between responder and non responder patients to IFN beta therapy in each of the assessed cell subsets were compared by a Mann Whitney test.</p

Demographic characteristics of the MS patients included in the study.

<p>Demographic characteristics of the MS patients included in the study.</p

Scheme of the HERV-Fc1 position and polymorphisms in the locus.

<p>The figure depicts from top to bottom: Chr X scale; chromosomal position as indicated in B37/gh19 (Position); SNPs genotyped in the IMSGC-WTCCC2 GWAS (GWAS SNPs); statistically significant SNPs with p≤0.05 (Significant SNPs); position of rs391745 (Studied SNP); HERV-Fc1 retrovirus copy position (Virus Position) and common polymorphisms mapping at this locus (Common SNPs).</p

Molecular dynamics simulations of Glu228Ala SNP in TRAILR-1.

<p>A and C corresponds to the superimposed structures of the 50s and 90s loops respectively in the initial (green) and final (orange) model of the <b>wild type</b> of TRAILR-1 (Glutamatic acid at position 228). B and D corresponds to the superimposed structures of the loops in the initial (green) and final (brown) model of the <b>mutant type</b> of TRAILR-1 (Alanine at position 228).</p