The Association of Cancer Development in Patients with Systemic Lupus Erythematosus by Rose Michelle Coley MPH, Walden University, 2011 BS, University of Mount Olive, 2008 Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Public Health Walden University March 2016 Both cancer and autoimmune diseases have been associated with numerous factors that may independently lead to the development of either disease. When these factors overlap the difficulty in assessing association is compounded. The numerous factors that are thought to cause systemic lupus erythematosus (SLE), which leads to the development of cancer, makes the study of an association between the 2 diseases challenging. The purpose of this study was to examine whether the risk of cancer development increased in SLE patients compared to the risk in non-SLE patients. Researchers have not shown consistent relationships of cancer development in patients with SLE; however, consideration of the various factors that contribute to the diseases is necessary to measure an association between the 2 diseases. This study used the Clinical Practice Research database (CPRD), a large, population-based database to test the relationship between SLE and cancer. A matched retrospective cohort study among SLE (n=3025) and non-SLE (n=180555) patients was conducted using the propensity score methodology to help balance the differences between the comparison groups. The propensity score methodology created a similar distribution of observed baseline covariates between the 2 groups. With adjustment for age, the predictor variable of SLE indicates that a patient with SLE is still 2.7 times more likely to develop cancer than is a non-SLE patient. The study outcomes could promote positive social change by reinforcing current recommendations for cancer screenings in persons with SLE, which could enhance the ability to detect cancer early enough to decrease mortality because of cancer in persons with SLE.

<p>Systemisk lupus erythematosus, (SLE) ingår i gruppen reumatiska sjukdomar och är en av ca 80 diagnoser inom området reumatologi. SLE är en kronisk , inflammatorisk, autoimmun sjukdom som orsakar inflammation i olika delar av kroppens organ. SLE förekommer i båda könen och alla åldrar,men sjukdomen är sju gånger vanligare bland kvinnor än hos män. Det oförutsägbara förloppet av denna kroniska sjukdom, dess symtom och eventuellt bieffekter av behandling kan betydande påverka patientens fysiska och psykiska välbefinnande.</p><p>Tidigare studier har visade att patienter med diagnosen SLE hade ett behov av och efterfrågade kunskap om egenvård för att kunna nå en bättre livskvalitet. Förhoppningen var att om egenvård kommer i fokus i patientutbildningar för denna patientgrupp kan deras livskvalitet höjas.</p><p>Föreliggande studie kartlägger vilken kunskap kvinnliga patienter i Uppsala län med SLE uppfattar att de hade om egenvård, samt hur mycket kunskap de uppfattade att de önskade inom egenvårdsområden. Studien omfattade följande områden; smärta, fysisk träning, kronisk trötthet och stress. Vidare berörde studien viket intresse det fanns att deltaga i patientutbildning som berör SLE och egenvård. Studien begränsade sig till kvinnliga patienter av den anledningen att det är flest kvinnor med den diagnosen.</p><p>Det var 39 kvinnliga deltagare i denna studie. Deltagarna fick vis postenkäter besvara 12 frågor. Frågeformuläret var specifikt utformat för denna studie. Deltagarna ombads skatta i vilken grad de uppfattade att de hade kunskap och önskade kunskap inom olika egenvårdsområden.</p><p>Resultatet av denna studie visade att patienter med SLE önskar mer kunskap än vad de redan har om områden som berör egenvård. Över hälften som deltog var intresserade av att vara med i patientutbildning.</p>

<p>Linkage in the 2q37 region was evaluated using microsatellite markers in multi-case families from Sweden, Iceland and Norway. Both the two-point and the multipoint linkage analysis show highly significant LOD scores (Z=4.51 and 6.03, respectively). Linkage disequilibrium mapping indicates that some association exists in this region. The <i>PDCD1</i> gene was suggested as a candidate gene within the 2q37 locus due to its importance in immune regulation. Indeed, one haplotype, described by the presence of allele A of the PD1.3 SNP located within intron 4 of this gene, shows linkage to SLE in the Nordic families. The PD1.3A allele is also found to be strongly associated in familiar and sporadic cases of SLE in Europeans and Mexicans. Functional studies further support PD1.3A to be a susceptibility allele for SLE.</p><p>The 1q23 region, containing the genes for the low affinity Fcγ receptors, was fine mapped using single- and multi- case families of various origins. Genetic variants of those genes were analysed and association is found to both the risk alleles of <i>Fc</i>γ<i>RIIA</i> and <i>Fc</i>γ<i>RIIIA</i> in all families. In these families, a single haplotype carrying both risk alleles is predominantly transmitted to patients with SLE, suggesting a presence of linkage disequilibrium between those two genes. <i>Fc</i>γ<i>RIIA</i> and <i>Fc</i>γ<i>RIIIA</i> are also found to be associated to SLE and lupus nephritis in a case-control cohort from Sweden. In the same cohort, the PD1.3A allele shows strong association to lupus nephritis. We suggest that there may be an additive effect between <i>Fc</i>γ<i>RIIA</i> and <i>PDCD1</i>, since having the disease-associated genotypes at both loci gives an increased risk for developing lupus nephritis.</p><p>Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder with a complex multifactorial aetiology. Genetic studies suggest that several genes are involved in disease pathogenesis and that extended genetic heterogeneity is present.</p>

<p>The aim with this thesis has been to identify genes involved in the pathogenesis of Systemic Lupus Erythematosus (SLE). SLE is a systemic autoimmune disorder, most likely caused by both several genetic and environmental factors. </p><p>In order to identify susceptibility loci for the disease we performed linkage analyses on data from 70 families of various ethnic origins. Significant linkage was found in two regions. One region (chromosome 17p12-q11) was linked to SLE in a set of Argentine families. Since the same region had been previously identified in several linkage studies on Multiple Sclerosis patients, we propose that this locus may contain a genetic variant that affects not only SLE, but also autoimmunity in general. The second locus is located on chromosome 4p14-13 and has only been identified in a set of Icelandic families. We suggest that this locus contains a mutation that has been enriched in the Icelandic population due to its population history.</p><p>The <i>BCL2 </i>gene has been suggested as a candidate gene for SLE. Three markers in this gene were investigated for association with the disease in two different populations. However, no association could be found with any of the markers or when these markers were analysed together as a haplotype. We conclude that the <i>BCL2</i> gene is not associated with SLE in our material. This result contradicts previously published results of an association between <i>BCL2</i> and SLE. </p><p>We suggest that the PD-1 pathway (involved in inhibition of T- and B-cell responses) is an important component in SLE pathogenesis. A regulatory variant in the <i>PD-1</i> gene had previously been associated with SLE and here we show strong association (p<0.0001) to a haplotype containing SNPs in both <i>PD-L1</i> and <i>PD-L2</i>. </p><p>Our results indicate that SLE is a disease caused by several genetic variations that differ between families and populations.</p>

Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disorder characterized by a failure in the mechanism of self-tolerance and production of autoantibodies, potentially affecting any organ in the body. The genetic factors behind the disease have been extensively studied in the past years and to date a list of more than 30 loci have been associated with SLE. However, very little is known about the functional significance of the risk variants. In this thesis, we focused on the analysis of SLE-associated variants in three genes: interferon regulatory factor 5 (IRF5), CD226 and the microRNA 146a. In paper I, we analyzed four polymorphisms in the IRF5 gene in a large set of individuals from different populations. We replicated a strong association of a promoter indel in our meta-analysis, but expression analysis indicated that it is rather another variant, SNP rs10954213 in the poly(A) signal of the gene that is in fact the major contributor to the altered gene expression in leukocytes. In manuscript II, we further characterized the regulation of IRF5 expression, showing that this gene can be up-regulated by estrogen in PBMCs and monocytes, regardless of the genotype, which could to some extent, explain the sex-bias of SLE. In paper III, we investigated the association of CD226 with SLE and the potential functional effect of the associated variants. The genetic analysis showed an association of a three-SNP-haplotype located at the 3’UTR region of the gene. The risk haplotype correlated with lower CD226 protein expression on the surface of cytotoxic and helper T cells, as well as in NK T cells. Reporter assays pointed to rs727088 in the 3’UTR as the main responsible variant for altered gene expression. In paper IV, we described the association of a variant in microRNA miR-146a, involved in the interferon pathway, with SLE in Europeans, which could in addition be correlated with decreased expression of both mature and primary miR-146a in leukocytes. In summary, we have investigated the genetic association of three genes with SLE in a large cohort of individuals and identified variants responsible for functional alterations of these genes, providing further insight into the pathogenesis of SLE.

Linkage in the 2q37 region was evaluated using microsatellite markers in multi-case families from Sweden, Iceland and Norway. Both the two-point and the multipoint linkage analysis show highly significant LOD scores (Z=4.51 and 6.03, respectively). Linkage disequilibrium mapping indicates that some association exists in this region. The PDCD1 gene was suggested as a candidate gene within the 2q37 locus due to its importance in immune regulation. Indeed, one haplotype, described by the presence of allele A of the PD1.3 SNP located within intron 4 of this gene, shows linkage to SLE in the Nordic families. The PD1.3A allele is also found to be strongly associated in familiar and sporadic cases of SLE in Europeans and Mexicans. Functional studies further support PD1.3A to be a susceptibility allele for SLE. The 1q23 region, containing the genes for the low affinity Fcγ receptors, was fine mapped using single- and multi- case families of various origins. Genetic variants of those genes were analysed and association is found to both the risk alleles of FcγRIIA and FcγRIIIA in all families. In these families, a single haplotype carrying both risk alleles is predominantly transmitted to patients with SLE, suggesting a presence of linkage disequilibrium between those two genes. FcγRIIA and FcγRIIIA are also found to be associated to SLE and lupus nephritis in a case-control cohort from Sweden. In the same cohort, the PD1.3A allele shows strong association to lupus nephritis. We suggest that there may be an additive effect between FcγRIIA and PDCD1, since having the disease-associated genotypes at both loci gives an increased risk for developing lupus nephritis. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder with a complex multifactorial aetiology. Genetic studies suggest that several genes are involved in disease pathogenesis and that extended genetic heterogeneity is present.

The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors. Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America. These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.

The aim with this thesis has been to identify genes involved in the pathogenesis of Systemic Lupus Erythematosus (SLE). SLE is a systemic autoimmune disorder, most likely caused by both several genetic and environmental factors. In order to identify susceptibility loci for the disease we performed linkage analyses on data from 70 families of various ethnic origins. Significant linkage was found in two regions. One region (chromosome 17p12-q11) was linked to SLE in a set of Argentine families. Since the same region had been previously identified in several linkage studies on Multiple Sclerosis patients, we propose that this locus may contain a genetic variant that affects not only SLE, but also autoimmunity in general. The second locus is located on chromosome 4p14-13 and has only been identified in a set of Icelandic families. We suggest that this locus contains a mutation that has been enriched in the Icelandic population due to its population history. The BCL2 gene has been suggested as a candidate gene for SLE. Three markers in this gene were investigated for association with the disease in two different populations. However, no association could be found with any of the markers or when these markers were analysed together as a haplotype. We conclude that the BCL2 gene is not associated with SLE in our material. This result contradicts previously published results of an association between BCL2 and SLE. We suggest that the PD-1 pathway (involved in inhibition of T- and B-cell responses) is an important component in SLE pathogenesis. A regulatory variant in the PD-1 gene had previously been associated with SLE and here we show strong association (p&lt;0.0001) to a haplotype containing SNPs in both PD-L1 and PD-L2. Our results indicate that SLE is a disease caused by several genetic variations that differ between families and populations.

Systemisk lupus erythematosus, (SLE) ingår i gruppen reumatiska sjukdomar och är en av ca 80 diagnoser inom området reumatologi. SLE är en kronisk , inflammatorisk, autoimmun sjukdom som orsakar inflammation i olika delar av kroppens organ. SLE förekommer i båda könen och alla åldrar,men sjukdomen är sju gånger vanligare bland kvinnor än hos män. Det oförutsägbara förloppet av denna kroniska sjukdom, dess symtom och eventuellt bieffekter av behandling kan betydande påverka patientens fysiska och psykiska välbefinnande. Tidigare studier har visade att patienter med diagnosen SLE hade ett behov av och efterfrågade kunskap om egenvård för att kunna nå en bättre livskvalitet. Förhoppningen var att om egenvård kommer i fokus i patientutbildningar för denna patientgrupp kan deras livskvalitet höjas. Föreliggande studie kartlägger vilken kunskap kvinnliga patienter i Uppsala län med SLE uppfattar att de hade om egenvård, samt hur mycket kunskap de uppfattade att de önskade inom egenvårdsområden. Studien omfattade följande områden; smärta, fysisk träning, kronisk trötthet och stress. Vidare berörde studien viket intresse det fanns att deltaga i patientutbildning som berör SLE och egenvård. Studien begränsade sig till kvinnliga patienter av den anledningen att det är flest kvinnor med den diagnosen. Det var 39 kvinnliga deltagare i denna studie. Deltagarna fick vis postenkäter besvara 12 frågor. Frågeformuläret var specifikt utformat för denna studie. Deltagarna ombads skatta i vilken grad de uppfattade att de hade kunskap och önskade kunskap inom olika egenvårdsområden. Resultatet av denna studie visade att patienter med SLE önskar mer kunskap än vad de redan har om områden som berör egenvård. Över hälften som deltog var intresserade av att vara med i patientutbildning.

Inflammation has been implicated in the development of cardiovascular disease and a potential underlying mechanism in the pathogenesis of impaired vascular function. Two different but complementary approaches were utilized to determine the role of inflammation on vascular function. First, to evaluate the effect of acute inflammation, we induced muscle damage to both small and large muscle mass and measured vascular function every 24 hours for up to 5 days of recovery. Eccentric exercise-induced muscle damage, in both small and large muscle mass, resulted in a transient increase in central arterial stiffness. Next, patients with systemic lupus erythematosus (SLE) were studied as a model of chronic inflammation. Measurements of vascular function were compared in habitually-exercising and sedentary SLE patients, and age-matched healthy controls. Individuals with SLE demonstrated lower vascular function than healthy controls. When SLE patients were grouped by exercise status, habitually-exercising SLE patients exhibited similar vascular function to healthy controls, and lower overall disease activity compared with sedentary SLE patients, supporting the beneficial effect of regular exercise in this population. Inflammatory biomarkers were associated with measures of macro- and microvascular function. In conclusion, acute muscle damage and chronic disease-related inflammation have a potent effect on measures of vascular function, suggesting that inflammation plays a role in the pathogenesis of vascular dysfunction and is an important biomarker for cardiovascular risk. / text