Tiina M. Järvinen

Evidence for Genetic Association and Interaction Between the TYK2 and IRF5 Genes in Systemic Lupus Erythematosus

Objective. Several candidate genes have been implicated in susceptibility for systemic lupus erythematosus (SLE), a complex autoimmune disease. The proposed genes include members of the type I interferon (IFN) pathway and genes involved in immunological defense functions. Our aim was to systematically replicate 6 such genes, TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2. Methods. Single-nucleotide polymorphisms in TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2 were genotyped in 277 SLE patients and 356 healthy controls from Finland, giving a power of 42%–70% for different genes at published allele frequencies. Results. Significant association was seen for rs2304256 (p = 0.0001) and rs12720270 (p = 0.0031) in TYK2 and rs10954213 (p = 0.0043) in IRF5 in our samples, but not for the other genes. We found evidence for genetic interaction (p = 0.014) between rs2304256 in TYK2 and rs10954213 in IRF5, both members of the type I IFN pathway, strengthening the role of the type I IFN pathway in the pathogenesis of SLE. Conclusion. The IFN pathway genes IRF5 and TYK2 may act epistatically in increasing risk for SLE, but our lack of replication does not exclude effects of the other genes studied.

Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations.

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus

Please cite this paper as: Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Experimental Dermatology 2010; 19: 123–131.

Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population

OBJECTIVE A large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (n = 275) and control individuals (n = 356). METHODS We genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci. We further investigated gene-gene interactions between the loci included in the study. RESULTS The strongest evidence of association was found at the IRF5-TNPO3 locus, with the most significant P-value being 2.0 × 10(-7) and an odds ratio of 1.95 (95% CI 1.51, 2.50). Association between SLE and TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542 was also confirmed, although at a lower significance level and contribution to individual risk. No significant association was found with 1q25.1, PXK, ATG5, ICA1, XKR6, LYN and SCUBE1. Furthermore, no significant gene-gene interactions were detected. CONCLUSION Replication of previous GWAS findings across diverse populations is of importance to validate these associations and to get a better understanding of potential genetic heterogeneity between populations in SLE susceptibility. Our results attest the importance of B-cell receptor pathway and IFN signalling in SLE pathogenesis.

Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous than of Systemic Lupus Erythematosus

Background Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear. Principal Findings To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value  = 4.73×10−11, OR  = 3.20, 95% CI  = 2.23–4.57). Significant association was also detected to SLE patients (P-value  = 8.29×10−6, OR  = 2.14, 95% CI  = 1.52–3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value  = 3.59×10−8, OR  = 3.76, 95% CI  = 2.29–6.18). Significance We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.

Genetic background and the risk of otitis media.

OBJECTIVE Otitis media is a multifactorial disease where genetic background may have an important role. For genome-wide association studies, it is important to understand the degree of heritability. The objective of this study was to estimate the heritability of recurrent acute otitis media and chronic otitis media with effusion. METHODS Children operated because of recurrent or chronic otitis media at the Helsinki University Central Hospital, Finland, as well as their families were recruited during 2008-2009. A cohort of 2436 subjects was enrolled consisting of 1279 children and their parents. The study subjects answered a questionnaire concerning their otitis media history and treatment, as well as tobacco exposure, allergy and asthma history. Heritability estimates were calculated for recurrent acute, chronic and any episodes of otitis media using software especially designed for estimating heritability in family cohorts. RESULTS Altogether 901 subjects suffered from recurrent otitis media and 559 from chronic otitis media with effusion. The heritability estimates in our cohort were 38.5% for recurrent (P=7.3 × 10(-9)), 22.1% for chronic (P=4.6 × 10(-3)) and 47.8% for any otitis media (P=1.5 × 10(-11)). CONCLUSIONS Our results demonstrate a moderately strong and statistically significant genetic component for both recurrent acute otitis media and chronic otitis media with effusion. These results highlight the importance of unraveling the genetic factors for otitis media that are still poorly known.

Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE)

Background Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families. Principal Findings Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P –value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103–1.513) and rs2297926 (P –value = 0.003, OR = 1.349, 95% CI 1.109–1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans. Significance Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE.

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families.

Children with type 1 diabetes (T1D) susceptibility HLA genotypes are shown to have an increased birthweight. We investigated to what extent T1D-predisposing HLA haplotypes were associated with increased birthweight. A total of 1255 Finnish children comprising those with T1D and their non-diabetic siblings were investigated. A total of 342 children and their non-diabetic parents were HLA genotyped. Birthweight data were obtained from the national Medical Birth Registry. The population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 was associated with high birthweight (P=0.0280) in families with a diabetic offspring. Other T1D-predisposing HLA haplotypes showed nonsignificant tendency with high birthweight. More infants with a birthweight ⩾4000 g were born in families with a T1D offspring than in the general Finnish population (P=0.0139). The previously observed direct association between birthweight and T1D risk may be mediated through the modulating effects that T1D susceptibility HLA genes have on weight. High birthweight and subsequent weight gain may accelerate the ongoing pancreatic autoimmune process in genetically susceptible individuals. The high proportion of infants having a birthweight ⩾4000 g in families with a diabetic offspring raises a concern of potential adverse health outcomes that high birthweight can have.

Dr. Hellquist, et al reply

To the Editor: We read with interest the letter of Suarez-Gestal, et al 1, and we believe that it is useful to briefly discuss possible causes of differences between our study2, which reported an interaction between the TYK2 and IRF5 genes, and the report of Suarez-Gestal, et al. It is a common observation that replicating even single-gene association results in complex disorders is not always easy, and largely the same causes that may explain these differences also apply to gene-gene interaction studies. Some of the common causes for the different results include insufficient … Address correspondence to Dr. Hellquist; E-mail: anna.hellquist{at}ki.se