Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations

Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). Methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. Conclusion: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.Peer Reviewe

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio

TRAIL/TRAIL Receptor System and Susceptibility to Multiple Sclerosis

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.8×10−4, OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.12×10−5, OR = 0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS

IL2RA/CD25 Gene Polymorphisms: Uneven Association with Multiple Sclerosis (MS) and Type 1 Diabetes (T1D)

[Background] IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. [Methods and Results] Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3′- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. [Conclusions] These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.Financial support for the study was provided by the Ministerio de Educación y Ciencia (grants PN-SAF2006-02023 and TIN2007-67418-C03-03) and Junta de Andalucía (P07-CVI-02551) to A. Alcina and Servicio Andaluz de Salud de la Junta de Andalucía (grant PI0168/2007) to F. Matesanz. María Fedetz is a holder of a fellowship from Fundación IMABIS. Dorothy Ndagire is a holder of AECI-Ministerio de Asuntos Exteriores fellowship

Factors associated with internalizing or somatic symptoms in a cross-sectional study of school children in grades 1-10

<p>Abstract</p> <p>Background</p> <p>School related factors that may contribute to children's subjective health have not been extensively studied. We assessed whether factors assumed to promote health and factors assumed to have adverse effects were associated with self-reported internalizing or somatic symptoms.</p> <p>Methods</p> <p>In a cross-sectional study, 230 boys and 189 girls in grades 1-10 from five schools responded to the same set of questions. Proportional odds logistic regression was used to assess associations of school related factors with the prevalence of sadness, anxiety, stomach ache, and headache.</p> <p>Results</p> <p>In multivariable analyses, perceived loneliness showed strong and positive associations with sadness (odds ratio, 1.94, 95% CI 1.42 to 2.64), anxiety (odds ratio, 1.78, 95% CI 1.31 to 2.42), and headache (odds ratio, 1.47, 95% CI 1.10 to 1.96), with consistently stronger associations for girls than boys. Among assumed health promoting factors, receiving necessary help from teachers was associated with lower prevalence of stomach ache in girls (odds ratio, 0.51, 95% CI 0.30 to 0.87).</p> <p>Conclusions</p> <p>These findings suggest that perceived loneliness may be strongly related to both internalizing and somatic symptoms among school children, and for girls, the associations of loneliness appear to be particularly strong.</p

Social inequalities in changes in health-related behaviour among Slovak adolescents aged between 15 and 19: A longitudinal study

<p>Abstract</p> <p>Background</p> <p>Lower socioeconomic position is generally associated with higher rates of smoking and alcohol consumption and lower levels of physical activity. Health-related behaviour is usually established during late childhood and adolescence. The aim of this study is to explore changes in health-related behaviour in a cohort of adolescents aged between 15 and 19, overall and by socioeconomic position.</p> <p>Methods</p> <p>The sample consisted of 844 first-year students (42.8% males, baseline in 1998 – mean age 14.9, follow-up in 2002 – mean age 18.8) from 31 secondary schools located in Kosice, Slovakia. This study focuses on changes in adolescents' smoking, alcohol use, experience with marijuana and lack of physical exercise with regard to their socioeconomic position. Four indicators of socioeconomic position were used – adolescents' current education level and employment status, and the highest education level and highest occupational status of their parents. We first made cross tabulations of HRB with these four indicators, using McNemar's test to assess differences. Next, we used logistic regression to assess adjusted associations, using likelihood ratio tests to assess statistical significance.</p> <p>Results</p> <p>Statistically significant increases were found in all health-related behaviours. Among males, the most obvious socioeconomic gradient was found in smoking, both at age 15 and at 19. Variations in socioeconomic differences in health-related behaviour were more apparent among females. Although at age 15, almost no socioeconomic differences in health-related behaviour were found, at age 19 differences were found for almost all socioeconomic indicators. Among males, only traditional socioeconomic gradients were found (the lower the socioeconomic position, the higher the prevalence of potentially harmful health-related behaviour), while among females reverse socioeconomic gradients were also found.</p> <p>Conclusion</p> <p>We confirmed an increase in unhealthy health-related behaviour during adolescence. This increase was related to socioeconomic position, and was more apparent in females.</p

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth