Brenda Elias

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

OBJECTIVE Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives. METHODS The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease. RESULTS ACPA positivity was observed in 19% of the healthy relatives and approximately 91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs. CONCLUSION The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.

Antibodies to Porphyromonas gingivalis Are Associated with Anticitrullinated Protein Antibodies in Patients with Rheumatoid Arthritis and Their Relatives

Objective. Anticitrullinated protein antibodies (ACPA) are relatively specific for rheumatoid arthritis (RA), and predate disease. The oral pathogen Porphyromonas gingivalis may play a role in breaking immune tolerance to citrullinated antigens. We studied a cohort of patients with RA and their relatives looking for associations between anti-P. gingivalis antibodies and ACPA. Methods. Patients with RA (n = 82) and their relatives (n = 205) from a North American Native (NAN) population were studied, along with 47 NAN and 60 non-NAN controls. IgM and IgA rheumatoid factor (RF) were tested by nephelometry and ELISA. Second-generation anticyclic citrullinated peptide (anti-CCP2) isotypes and IgG anti-P. gingivalis lipopolysaccharides were tested by ELISA. HLA-DRB1 typing was performed by sequencing. Oral hygiene and smoking habits were assessed by questionnaires. Results. Autoantibody frequency in patients with RA and relatives: ACPA 91% vs 19%, respectively; IgM RF 82% vs 17%; IgA RF 48% vs 22%. Anti-P. gingivalis levels were higher in patients with RA compared to relatives and controls (p = 0.005) and higher in ACPA-positive patients with RA than in ACPA-negative patients with RA (p = 0.04) and relatives (p < 0.001), but comparable in RF-positive and RF-negative patients and relatives. Poor oral hygiene and smoking were prevalent, but with no clear association with autoantibodies. Relatives with 2 shared-epitope alleles were more likely to be ACPA-positive (OR 2.5, p = 0.02). Conclusion. In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalis antibodies were associated with ACPA. These findings suggest that immune responses to P. gingivalis may be involved in breaking immune tolerance to citrullinated antigens.

Spirituality, religion and suicidal behavior in a nationally representative sample.

BACKGROUND Studies show that religion and spirituality are associated with decreased rates of mental illness. Some studies show decreased rates of suicide in religious populations, but the association between religion, spirituality and suicidal behaviors in people with mental illness are understudied. Few studies have examined the influence of social supports in these relationships. METHODS Data were drawn from the Canadian Community Health Survey 1.2. Logistic regression was used to examine the relationship between spiritual values and religious worship attendance with twelve-month suicidal ideation and attempts. Regressions were adjusted for sociodemographic factors and social supports. Interaction variables were then tested to examine possible effect modification by presence of a mental disorder. RESULTS Identifying oneself as spiritual was associated with decreased odds of suicide attempt (adjusted odds ratio-1 [AOR-1]=0.65, CI: 0.44-0.96) but was not significant after adjusting for social supports. Religious attendance was associated with decreased odds of suicidal ideation (AOR-1=0.64, 95% CI: 0.53-0.77) but not after adjusting for social supports. Religious attendance was associated with decreased odds of suicide attempt and remained significant after adjusting for social supports (AOR-2=0.38, 95% CI: 0.17-0.89). No significant interaction effects were observed between any of the tested mental disorders and religion, spirituality and suicidal behavior. LIMITATIONS This was a cross-sectional survey and causality of relationships cannot be inferred. CONCLUSIONS Results suggest that religious attendance is associated with decreased suicide attempts in the general population and in those with a mental illness independent of the effects of social supports.

Trauma and suicide behaviour histories among a Canadian indigenous population: An empirical exploration of the potential role of Canada's residential school system

It has been theorized that suicide behaviours amongst indigenous peoples may be an outcome of mass trauma experienced as a result of colonization. In Canada, qualitative evidence has suggested that the Indian Residential School System set in motion a cycle of trauma, with some survivors reporting subsequent abuse, suicide, and other related behaviours. It has been further postulated that the effects of trauma can also be passed inter-generationally. Today, there are four generations of Canadian First Nations residential school survivors who may have transmitted the trauma they experienced to their own children and grandchildren. No empirical study has ever been undertaken to demonstrate this dynamic. This study is therefore the first to investigate whether a direct or indirect exposure to Canadas residential school system is associated with trauma and suicide behaviour histories. Data were collected in 2002/2003 from a representative sample of Manitoba, Canada, First Nations adults (N = 2953), including residential (N = 611) and non-residential school attendees (N = 2342). Regression analyses showed that for residential school attendees negative experiences in residential school were associated with a history of abuse, and that this history and being of younger age was associated with a history of suicide thoughts, whereas abuse history only was associated with a history of suicide attempts. For First Nations adults who did not attend a residential school, we found that age 28-44, female sex, not having a partner, and having a parent or grandparent who attended a residential school was associated with a history of abuse. This history, along with age and having had a parent or grandparent who attended residential school was associated with a history of suicide thoughts and attempts. In conclusion, this is the first study to empirically demonstrate, at the population level, the mental health impact of the residential school system on survivors and their children.

Immunogenetic Risks of Anti-Cyclical Citrullinated Peptide Antibodies in a North American Native Population with Rheumatoid Arthritis and Their First-degree Relatives

Objective. To determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in unaffected relatives of North American Native probands with rheumatoid arthritis (RA); and the associations of the shared epitope (SE) and HLA-DRB1*0901 with RA and anti-CCP antibodies. Methods. The subjects were RA probands, affected relatives, unaffected first-degree (FDR) and more distant relatives, and unaffected controls from the same population. HLA-DRB1 typing was determined by DNA sequencing and anti-CCP antibodies were determined by ELISA. Results. DRB1*0901, SE, and SE/DRB1*0901 genotypes were all associated with RA. SE/DRB1*0901, but not other SE genotypes, was associated with disease onset at age < 16 years. The frequency of anti-CCP antibodies was 82% in RA probands, 17% in FDR, 11% in more distant relatives, and 3% in controls. Among unaffected relatives, a significant increased risk of anti-CCP was associated with SE/DRB1*0901 genotype, but not with SE. Conclusion. An independent association of the non-SE allele DRB1*0901 with RA was confirmed in this population, and this allele in combination with a SE allele was associated with younger age at disease onset. FDR of RA probands have a higher prevalence of anti-CCP antibodies than more distant relatives and unrelated controls, suggesting a gradient of risk for disease development. Immunogenetic risks may act early in disease pathogenesis at the level of initiation of RA autoantibody formation; however, it is not clear what additional genetic and environmental risks are involved in progression to clinical disease.

Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients

OBJECTIVE Rheumatoid arthritis (RA) is prevalent in North American Native populations, with a high frequency of multicase families and seropositivity in first-degree relatives. This study was undertaken to determine whether the serum cytokine profile of first-degree relatives of North American Native patients with RA differed from that of individuals with no family history of autoimmunity and whether there was an association with RA autoantibodies. METHODS North American Native patients with RA (n = 105), their first-degree relatives (n = 273), healthy North American Native controls (n = 200), and Caucasian controls (n = 150) were studied. Serum levels of 42 cytokines were tested using a multiplex laser bead assay. Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (anti-CCP-2), monocyte chemotactic protein 1 (MCP-l), and high-sensitivity C-reactive protein (hsCRP) were tested by enzyme-linked immunosorbent assay, and HLA-DRB1 alleles by specific primers. Discriminant analysis and logistic regression classified individuals based on their cytokine profile. RESULTS The prevalence of RF (cutoff level predetermined to include 5% of Caucasian controls) and anti-CCP (cutoff level of ≥40 units) was, respectively, 88% and 81% in the RA patients, 34% and 9% in first-degree relatives, and 9% and 4% in North American Native controls; the prevalence of anti-CCP was 0% in Caucasian controls. Levels of most cytokines were highest in RA patients; 17 of 40 cytokines (43%) were significantly higher in first-degree relatives than in controls, including multiple proinflammatory cytokines. Discriminant analysis showed a notable distinction between the groups, with 85% classification accuracy. First-degree relatives had markedly higher MCP-1 and hsCRP levels than North American Native controls, but there was no consistent association with RA autoantibodies. CONCLUSION Our findings indicate that levels of multiple cytokines and hsCRP are higher in first-degree relatives of North American Native patients with RA compared to individuals from a nonautoimmune background. These data suggest that elevated baseline cytokine levels may be part of the risk profile for developing RA.

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by ‘shared epitope’ (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2–5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6–3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

GATEKEEPER TRAINING FOR SUICIDE PREVENTION IN FIRST NATIONS COMMUNITY MEMBERS: A RANDOMIZED CONTROLLED TRIAL

Gatekeeper training aims to train people to recognize and identify those who are at risk for suicide and assist them in getting care. Applied Suicide Intervention Skills Training (ASIST), a form of gatekeeper training, has been implemented around the world without a controlled evaluation. We hypothesized that participants in 2 days of ASIST gatekeeper training would have increased knowledge and preparedness to help people with suicidal ideation in comparison to participants who received a 2‐day Resilience Retreat that did not focus on suicide awareness and intervention skills (control condition).

The burden of cancer risk in Canada&#39;s indigenous population: a comparative study of known risks in a Canadian region

Background Canadian First Nations, the largest of the Aboriginal groups in Canada, have had lower cancer incidence and mortality rates than non-Aboriginal populations in the past. This pattern is changing with increased life expectancy, a growing population, and a poor social environment that influences risk behaviors, metabolic conditions, and disparities in screening uptake. These factors alone do not fully explain differences in cancer risk between populations, as genetic susceptibility and environmental factors also have significant influence. However, genetics and environment are difficult to modify. This study compared modifiable behavioral risk factors and metabolic-associated conditions for men and women, and cancer screening practices of women, between First Nations living on-reserve and a non-First Nations Manitoba rural population (Canada). Methods The study used data from the Canadian Community Health Survey and the Manitoba First Nations Regional Longitudinal Health Survey to examine smoking, binge drinking, metabolic conditions, physical activity, fruit/vegetable consumption, and cancer-screening practices. Results First Nations on-reserve had significantly higher rates of smoking (P < 0.001), binge drinking (P < 0.001), obesity (P < 0.001) and diabetes (P < 0.001), and less leisure-time physical activity (P = 0.029), and consumption of fruits and vegetables (P < 0.001). Sex differences were also apparent. In addition, First Nations women reported significantly less uptake of mammography screening (P < 0.001) but similar rates for cervical cancer screening. Conclusions Based on the findings of this retrospective study, the future cancer burden is expected to be high in the First Nations on-reserve population. Interventions, utilizing existing and new health and social authorities, and long-term institutional partnerships, are required to combat cancer risk disparities, while governments address economic disparities.

Correlates of suicidality: investigation of a representative sample of Manitoba First Nations adolescents.

OBJECTIVES We examined individual, friend or family, and community or tribe correlates of suicidality in a representative on-reserve sample of First Nations adolescents. METHODS Data came from the 2002-2003 Manitoba First Nations Regional Longitudinal Health Survey of Youth. Interviews were conducted with adolescents aged 12 to 17 years (n=1125) from 23 First Nations communities in Manitoba. We used bivariate logistic regression analyses to examine the relationships between a range of factors and lifetime suicidality. We conducted sex-by-correlate interactions for each significant correlate at the bivariate level. A multivariate logistic regression analysis identified those correlates most strongly related to suicidality. RESULTS We found several variables to be associated with an increased likelihood of suicidality in the multivariate model, including being female, depressed mood, abuse or fear of abuse, a hospital stay, and substance use (adjusted odds ratio range=2.43-11.73). Perceived community caring was protective against suicidality (adjusted odds ratio=0.93; 95% confidence interval=0.88, 0.97) in the same model. CONCLUSIONS Results of this study may be important in informing First Nations and government policy related to the implementation of suicide prevention strategies in First Nations communities.