European genetic ancestry is associated with a decreased risk of lupus nephritis

Objective

African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than are SLE patients of European descent. This study was undertaken to investigate whether European genetic ancestry protects against the development of lupus nephritis, with the aim of exploring the genetic and socioeconomic factors that might explain this effect.

Methods

This was a cross‐sectional study of SLE patients from a multiethnic case collection. Participants were genotyped for 126 single‐nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. Logistic regression was used to test the association between European ancestry and renal disease. Analyses were adjusted for continental ancestries, socioeconomic status (SES), and candidate genes.

Results

Participants (n = 1,906) had, on average, 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among the participants, 656 (34%) had renal disease. A 10% increase in the proportion of European ancestry estimated in each participant was associated with a 15% reduction in the odds of having renal disease, after adjustment for disease duration and sex (odds ratio 0.85, 95% confidence interval 0.82–0.87; P = 1.9 × 10⁻³⁰). Adjustment for other genetic ancestries, measures of SES, or SNPs in the genes most associated with renal disease (IRF5 [rs4728142], BLK [rs2736340], STAT4 [rs3024912], and HLA–DRB1*0301 and DRB1*1501) did not substantively alter this relationship.

Conclusion

European ancestry is protective against the development of renal disease in SLE, an effect that is independent of other genetic ancestries, candidate risk alleles, and socioeconomic factors.

     

Linkage analysis of rheumatoid arthritis in US and UK families reveals interactions between HLA–DRB1 and loci on chromosomes 6q and 16p

Objective

HLA is the most strongly associated locus in rheumatoid arthritis (RA), accounting for up to one‐third of the genetic contribution. Conditioning on the effect of true disease loci such as HLA can lead to increased power to detect effects at other loci and, in addition, allows investigation of the underlying disease models, including interactions. The aim of this study was to detect susceptibility loci for RA by conditioning on HLA in a large sample of affected sibling pairs (ASPs) and to test for evidence of interaction between novel loci and HLA.

Methods

Genotype data from 3 whole‐genome linkage scans for RA in a US population and a UK population were pooled, resulting in a combined data set of 886 ASPs. This pooling of data increased the power to detect loci showing low levels of heterogeneity. Nonparametric linkage analysis was performed to identify regions of interest. Joint 2‐locus analysis was then performed for HLA and each of the loci that demonstrated evidence of linkage in the 886 ASPs.

Results

Evidence for linkage was most significant at HLA (P = 4 × 10⁻¹⁶), with 7 non‐HLA loci showing some evidence for linkage (P = 0.05–0.003). Joint modeling of these loci with HLA provided evidence for linkage at a genome‐wide significance level for loci on 6q (P = 2.7 × 10⁻⁶) and 16p (P = 2 × 10⁻⁴).

Conclusion

These data provide the most convincing evidence to date that 6q and 16p harbor susceptibility genes. In addition, these loci may interact with HLA, facilitating the search for candidate genes within this region.

     

Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor–negative juvenile idiopathic arthritis in Finnish patients: Haplotype analysis in Finnish families

Objective

The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)–negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2.

Methods

A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single‐nucleotide polymorphisms: an intragenic insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471).

Results

Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6‐marker, 4‐marker, and 2‐marker haplotypes. Most impressively, 1 of the 6‐marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6–6.2) in all JIA patients, 3.5 (95% CI 1.9–6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5–6.7) in those with polyarticular RF‐negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well‐characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9–9.2] versus P = 0.5, OR 1.6 [95% CI 0.4–6.0]).

Conclusion

Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.

     

Correlations between Oxidative DNA Damage, Oxidative Stress and Coenzyme Q10 in Patients with Coronary Artery Disease

The correlation of coronary artery disease (CAD) with pro-oxidant/antioxidant balance and oxidative DNA damage was investigated.Seventy-seven patients with CAD and 44 healthy individuals as control were included in this study. The comparative ratios of ubiquinol-10/ubiquinone-10, 8-hydroxy-2^''-deoxyguanosine/deoxyguanosine and the level of MDA measured by HPLC and the activities of GPX and SOD by colorimetric approach in blood samples obtained from patients with CAD were unraveled.8-OHdG/dG ratios, serum MDA level and GPX activity were found significantly elevated level in serum of CAD patients compared to control group. The SOD activity was observed in stable levels in CAD patients. Ubiquinol-10/ubiquinone-10 ratio was significantly lower in patients with CAD than the controls.The positive correlation was observed between 8-OHdG/dG ratios in both MDA levels and GPX activity, while the significant negative correlation was seemed between the ratio of 8-OHdG/dG and ubiquinol-10/ ubiquinone-10 as well as MDA levels and ubiquinol-10/ ubiquinone-10 ratio.We conclude that, both the disruption of pro-oxidant/antioxidant balance and oxidative stress in DNA may play an important role in the pathogenesis of coronary artery disease.     

Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort

We evaluated the roles of five single-nucleotide polymorphisms (SNPs) within PDCD1, and haplotypes defined by these SNPs, for the development of systemic lupus erythematosus (SLE) and specific sub-phenotypes (nephritis, antiphospholipid antibody positive, arthritis and double-stranded DNA positive) within a multiethnic US cohort of 1036 patients. Family based analyses were performed using 844 simplex families from four ethnic groups (Caucasian, Asian, Hispanic and African American). Subjects were genotyped for five 'tag' SNPs (selected from 15) to provide complete genetic information in all main ethnic groups. We employed transmission disequilibrium testing to assess risk for SLE by allele or haplotype, and multiple logistic regression analysis of SLE cases to examine associations with specific sub-phenotypes. In family based analyses, a haplotype containing the PD1.3A allele was significantly associated with SLE susceptibility among Caucasian families (P=0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P=0.005 and 0.01). In multivariate logistic regression analyses, five haplotypes were associated with specific sub-phenotypes among the different ethnic groups. These results suggest that PDCD1 genetic variation influences the risk and expression of SLE and that these associations vary according to ethnic background.     

Sensitive skin evaluation in the Japanese population

Sensitive skin syndrome was first described in 1977; however, no robust study has been carried out to evaluate its prevalence in Japan. A national representative sample of the Japanese population over the age of 18 years was taken. Individuals were questioned by telephone and selected according to the quota method. When asked “Do you have a sensitive skin?”, 52.84% of men and 55.98% of women answered “rather sensitive” or “very sensitive”. There was no significant difference (P = 0.22) between the two sexes. The non‐response rate among respondents was zero, suggesting that the term “sensitive skin” held a meaning for the majority of the population. Concerning questions about the onset of a rash, tingling or irritation in the presence of various factors, such as emotional issues, cold, heat, sun, dry air, air‐conditioning, water, air pollution and temperature variations, respondents with rather sensitive or very sensitive skin responded “yes” more often than others: approximately three‐times more often for water (18.97%/6.15%), air pollution (39.29%/12.45%) and warm climatic conditions (29.74%/9.8%). To our knowledge, this epidemiological study is the first to focus on sensitive skin among Japanese people of this century. It is of particular interest for two reasons: (i) it was conducted on a representative sample of the Japanese population; and (ii) the methodology used was identical to that used for sensitive skin assessment studies conducted in Europe and the USA, making it possible to draw certain comparisons.     

Self-Coding of Fidelity as a Potential Active Ingredient of Consultation to Improve Clinicians’ Fidelity

A key goal for implementation science is the identification of evidence-based consultation protocols and the active ingredients within these protocols that drive clinician behavior change. The current study examined clinicians’ self-coding of fidelity as a potential active ingredient of consultation for the Attachment and Biobehavioral Catch-up (ABC) intervention. It also examined two other potential predictors of clinician fidelity in response to consultation: dosage of consultation and working alliance. Twenty-nine clinicians (97% female, 62% White, M age?=?34 years) participated in a year of weekly fidelity-focused ABC consultation sessions, for which clinicians self-coded fidelity and received consultant feedback on both their coding and their fidelity. Data from the ABC fidelity measure were available for 1067 sessions coded by consultants, and clinicians’ self-coding accuracy was calculated from 1044 sessions coded by both clinicians and consultants. Alliance was measured with the Working Alliance Inventory—Trainee and Supervisor Versions. The study was observational, and fidelity and self-coding accuracy were modeled across time using hierarchical linear modeling. Clinicians’ ABC fidelity, as well as their self-coding accuracy, increased over the course of consultation. Clinicians’ self-coding accuracy predicted their initial fidelity and growth in fidelity. Working alliance was also linked to fidelity and self-coding accuracy. These results suggest that clinician self-coding should be further examined as an active ingredient of consultation. The study has important implications for the design of consultation procedures and fidelity assessments.

     

Gianotti-Crosti syndrome: a study of 26 cases

We have studied 26 patients presenting with a symmetrical papular or papulovesicular acrolocated eruption of more than 10 days duration. Mean age at onset was 2 years (range 10 months to 5.75 years). Lymphadenopathy was noted in eight cases, and hepatomegaly in one case. In 12 cases, histopathology and direct immunofluorescence were non-contributory. Cytolytic hepatitis occurred in one case and was associated with HBs antigenemia. A history of recent immunization was given in two cases. There was serological evidence of recent Epstein-Barr virus infection in seven out of 13 cases tested. Coxsackie B viruses were isolated from three patients, and cytomegalovirus was probably associated with the syndrome in one case. We conclude that the Gianotti-Crosti syndrome is not rare in France, and that non-hepatitis B virus (HBV)-associated cases are more frequent than the classical HBV-associated papular acrodermatitis of childhood.     

Nuclear cardiology: myocardial perfusion and function

Myocardial perfusion studies continue to be a major focus of research, with new investigations of the relationship of exercise-redistribution thallium imaging to diagnosis, prognosis, and case management. The redistribution phenomenon, which seemed to be fairly well understood a few years ago, is now recognized to be much more complex than originally thought, and various strategies have been proposed to clarify the meaning of persistent defects. Pharmacologic intervention with dipyridamole and adenosine has become available as an alternative to exercise, and comparisons with exercise imaging and catheterization results have been described. Thallium itself is no longer the sole single-photon perfusion radiopharmaceutical; two new technetium agents are now widely available. In addition to perfusion studies, advances in the study of ventricular function have been made, including reports of studies performed in conjunction with technetium perfusion studies, new insights into cardiac physiology, and the prognostic and case-management information that function studies provide. Finally, work has continued with monoclonal antibodies for the identification of areas of myocyte necrosis.