Examining Health Outcomes in Juvenile Idiopathic Arthritis:A Genetic Epidemiology Study

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease; however, little is known about its wider health impacts. This study explores health outcomes associated with JIA genetic liability. METHODS: We used publicly available genetic data sets to interrogate the genetic correlation between JIA and 832 other health‐related traits using linkage disequilibrium score regression. Two‐sample Mendelian randomization (2SMR) was used to examine four genetic correlates for evidence of causality. RESULTS: We found robust evidence (adjusted P [P (adj)] < 0.05) of genetic correlation between JIA and rheumatoid arthritis (genetic correlation [r (g)] = 0.63, P (adj) = 0.029), hypothyroidism/myxedema (r (g) = 0.61, P (adj) = 0.041), celiac disease (CD) (r (g) = 0.58, P (adj) = 0.032), systemic lupus erythematosus (r (g) = 0.40, P (adj) = 0.032), coronary artery disease (CAD) (r (g) = 0.42, P (adj) = 0.006), number of noncancer illnesses (r (g) = 0.42, P (adj) = 0.016), paternal health (r (g) = 0.57, P (adj) = 0.032), and strenuous sports (r (g) = −0.52, P (adj) = 0.032). 2SMR analyses found robust evidence that genetic liability to JIA was causally associated with the number of noncancer illnesses reported by UK Biobank (UKBB) participants (increase of 0.03 noncancer illnesses per doubling odds of JIA, 95% confidence interval 0.01‐0.05). CONCLUSION: This study illustrates genetic sharing between JIA and a diversity of health outcomes. The causal association between genetic liability to JIA and noncancer illnesses suggests a need for broader health assessments of patients with JIA to reduce their potential comorbid burden. The strength of genetic correlation with hypothyroidism and CD implies that patients with JIA may benefit from CD and thyroid function screening. Strong positive genetic correlation between JIA and CAD supports the need for cardiovascular risk assessment and risk factor modification

Characterization of Shewanella oneidensis MtrC: a cell-surface decaheme cytochrome involved in respiratory electron transport to extracellular electron acceptors

MtrC is a decaheme c-type cytochrome associated with the outer cell membrane of Fe(III)-respiring species of the Shewanella genus. It is proposed to play a role in anaerobic respiration by mediating electron transfer to extracellular mineral oxides that can serve as terminal electron acceptors. The present work presents the first spectropotentiometric and voltammetric characterization of MtrC, using protein purified from Shewanella oneidensis MR-1. Potentiometric titrations, monitored by UV–vis absorption and electron paramagnetic resonance (EPR) spectroscopy, reveal that the hemes within MtrC titrate over a broad potential range spanning between approximately +100 and approximately -500 mV (vs. the standard hydrogen electrode). Across this potential window the UV–vis absorption spectra are characteristic of low-spin c-type hemes and the EPR spectra reveal broad, complex features that suggest the presence of magnetically spin-coupled low-spin c-hemes. Non-catalytic protein film voltammetry of MtrC demonstrates reversible electrochemistry over a potential window similar to that disclosed spectroscopically. The voltammetry also allows definition of kinetic properties of MtrC in direct electron exchange with a solid electrode surface and during reduction of a model Fe(III) substrate. Taken together, the data provide quantitative information on the potential domain in which MtrC can operate

Juvenile idiopathic arthritis polygenic risk scores are associated with cardiovascular phenotypes in early adulthood: a phenome-wide association study

Background: There is growing concern about the long-term cardiovascular health of patients with juvenile idiopathic arthritis (JIA). In this study we assessed the association between JIA polygenic risk and cardiovascular phenotypes (cardiovascular risk factors, early atherosclerosis/arteriosclerosis markers, and cardiac structure and function measures) early in life. Methods: JIA polygenic risk scores (PRSs) were constructed for 2,815 participants from the Avon Longitudinal Study of Parents and Children, using the single nucleotide polymorphism (SNP) weights from the most recent JIA genome wide association study. The association between JIA PRSs and cardiovascular phenotypes at age 24 years was assessed using linear and logistic regression. For outcomes with strong evidence of association, further analysis was undertaken to examine how early in life (from age seven onwards) these associations manifest. Results: The JIA PRS was associated with diastolic blood pressure (β 0.062, 95% CI 0.026 to 0.099, P = 0.001), insulin (β 0.050, 95% CI 0.011 to 0.090, P = 0.013), insulin resistance index (HOMA2_IR, β 0.054, 95% CI 0.014 to 0.095, P = 0.009), log hsCRP (β 0.053, 95% CI 0.011 to 0.095, P = 0.014), waist circumference (β 0.041, 95% CI 0.007 to 0.075, P = 0.017), fat mass index (β 0.049, 95% CI 0.016 to 0.083, P = 0.004) and body mass index (β 0.046, 95% CI 0.011 to 0.081, P = 0.010). For anthropometric measures and diastolic blood pressure, there was suggestive evidence of association with JIA PRS from age seven years. The findings were consistent across multiple sensitivity analyses. Conclusions: Genetic liability to JIA is associated with multiple cardiovascular risk factors, supporting the hypothesis of increased cardiovascular risk in JIA. Our findings suggest that cardiovascular risk is a core feature of JIA, rather than secondary to the disease activity/treatment, and that cardiovascular risk counselling should form part of patient care

Recent breast cancer incidence trends according to hormone therapy use: the California Teachers Study cohort

Abstract Introduction Recent, international declines in breast cancer incidence are unprecedented, and the causes remain controversial. Few data sources can address breast cancer incidence trends according to pertinent characteristics like hormone therapy use history. Methods We used the prospective California Teachers Study to evaluate changes in self-reported use of menopausal hormone therapy (HT) between 1995 to 1996 and 2005 to 2006 and age-adjusted breast cancer incidence among 74,647 participants aged 50 years or older. Breast cancer occurrence was determined by linkage with the California Cancer Registry. Results During 517,286 woman years of follow up, 565 in situ and 2,668 invasive breast cancers were diagnosed. In situ breast cancer incidence rates in this population did not change significantly from 2000 to 2002 to 2003 to 2005, whereas rates of invasive breast cancer declined significantly by 26.0% from 528.0 (95% confidence intervals (CI) = 491.1, 564.9) per 100,000 women in 2000 to 2002 to 390.6 (95% CI = 355.6, 425.7) in 2003 to 2005. The decline in invasive breast cancer incidence rates was restricted to estrogen receptor-positive tumors. In 1996 to 1999 and 2000 to 2002 invasive breast cancer incidence was higher for women who reported current HT use especially estrogen-progestin (EP) use at baseline than for never or past users; but by 2003 to 2005 rates were comparable between these groups. For women who were taking EP in 2001 to 2002,75% of whom had stopped use by 2005 to 2006, incidence had declined 30.6% by 2003 to 2005 (P = 0.001); whereas incidence did not change significantly for those who never took HT (P = 0.33). Conclusions Few data resources can examine prospectively individual HT use and breast cancer diagnosis. Stable in situ breast cancer rates imply consistent levels of screening and suggest recent declines in invasive breast cancer to be explained predominantly by changes in HT use

Mathematical Evaluation of Community Level Impact of Combining Bed Nets and Indoor Residual Spraying upon Malaria Transmission in Areas where the main Vectors are Anopheles Arabiensis Mosquitoes.

Indoor residual insecticide spraying (IRS) and long-lasting insecticide treated nets (LLINs) are commonly used together even though evidence that such combinations confer greater protection against malaria than either method alone is inconsistent. A deterministic model of mosquito life cycle processes was adapted to allow parameterization with results from experimental hut trials of various combinations of untreated nets or LLINs (Olyset, PermaNet 2.0, Icon Life nets) with IRS (pirimiphos methyl, lambda cyhalothrin, DDT), in a setting where vector populations are dominated by Anopheles arabiensis, so that community level impact upon malaria transmission at high coverage could be predicted. Intact untreated nets alone provide equivalent personal protection to all three LLINs. Relative to IRS plus untreated nets, community level protection is slightly higher when Olyset or PermaNet 2.0 nets are added onto IRS with pirimiphos methyl or lambda cyhalothrin but not DDT, and when Icon Life nets supplement any of the IRS insecticides. Adding IRS onto any net modestly enhances communal protection when pirimiphos methyl is sprayed, while spraying lambda cyhalothrin enhances protection for untreated nets but not LLINs. Addition of DDT reduces communal protection when added to LLINs. Where transmission is mediated primarily by An. arabiensis, adding IRS to high LLIN coverage provides only modest incremental benefit (e.g. when an organophosphate like pirimiphos methyl is used), but can be redundant (e.g. when a pyrethroid like lambda cyhalothin is used) or even regressive (e.g. when DDT is used for the IRS). Relative to IRS plus untreated nets, supplementing IRS with LLINs will only modestly improve community protection. Beyond the physical protection that intact nets provide, additional protection against transmission by An. arabiensis conferred by insecticides will be remarkably small, regardless of whether they are delivered as LLINs or IRS. The insecticidal action of LLINs and IRS probably already approaches their absolute limit of potential impact upon this persistent vector so personal protection of nets should be enhanced by improving the physical integrity and durability. Combining LLINs and non-pyrethroid IRS in residual transmission systems may nevertheless be justified as a means to manage insecticide resistance and prevent potential rebound of not only An. arabiensis, but also more potent, vulnerable and historically important species such as Anopheles gambiae and Anopheles funestus

Socioeconomic status and prostate cancer incidence and mortality rates among the diverse population of California

The racial/ethnic disparities in prostate cancer rates are well documented, with the highest incidence and mortality rates observed among African-Americans followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders. Whether socioeconomic status (SES) can account for these differences in risk has been investigated in previous studies, but with conflicting results. Furthermore, previous studies have focused primarily on the differences between African-Americans and non-Hispanic Whites, and little is known for Hispanics and Asian/Pacific Islanders. To further investigate the relationship between SES and prostate cancer among African-Americans, non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders, we conducted a large population-based cross-sectional study of 98,484 incident prostate cancer cases and 8,997 prostate cancer deaths from California. Data were abstracted from the California Cancer Registry, a population-based surveillance, epidemiology, and end results (SEER) registry. Each prostate cancer case and death was assigned a multidimensional neighborhood-SES index using the 2000 US Census data. SES quintile-specific prostate cancer incidence and mortality rates and rate ratios were estimated using SEER*Stat for each race/ethnicity categorized into 10-year age groups. For prostate cancer incidence, we observed higher levels of SES to be significantly associated with increased risk of disease [SES Q1 vs. Q5: relative risk (RR) = 1.28; 95% confidence interval (CI): 1.25–1.30]. Among younger men (45–64 years), African-Americans had the highest incidence rates followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders for all SES levels. Yet, among older men (75–84 years) Hispanics, following African-Americans, displayed the second highest incidence rates of prostate cancer. For prostate cancer deaths, higher levels of SES were associated with lower mortality rates of prostate cancer deaths (SES Q1 vs. Q5: RR = 0.88; 95% CI: 0.92–0.94). African-Americans had a twofold to fivefold increased risk of prostate cancer deaths in comparison to non-Hispanic Whites across all levels of SES. Our findings suggest that SES alone cannot account for the greater burden of prostate cancer among African-American men. In addition, incidence and mortality rates of prostate cancer display different age and racial/ethnic patterns across gradients of SES

Type 2 diabetes, socioeconomic status and life expectancy in Scotland (2012-2014):a population-based observational study

Aims/hypothesis: The aim of this study was to assess the role of socioeconomic status (SES) in the associations between type 2 diabetes and life expectancy in a complete national population. Methods: An observational population-based cohort study was performed using the Scottish Care Information – Diabetes database. Age-specific life expectancy (stratified by SES) was calculated for all individuals with type 2 diabetes in the age range 40–89 during the period 2012–2014, and for the remaining population of Scotland aged 40–89 without type 2 diabetes. Differences in life expectancy between the two groups were calculated. Results: Results were based on 272,597 individuals with type 2 diabetes and 2.75 million people without type 2 diabetes (total for 2013, the middle calendar year of the study period). With the exception of deprived men aged 80–89, life expectancy in people with type 2 diabetes was significantly reduced (relative to the type 2 diabetes-free population) at all ages and levels of SES. Differences in life expectancy ranged from −5.5 years (95% CI −6.2, −4.8) for women aged 40–44 in the second most-deprived quintile of SES, to 0.1 years (95% CI −0.2, 0.4) for men aged 85–89 in the most-deprived quintile of SES. Observed life-expectancy deficits in those with type 2 diabetes were generally greater in women than in men. Conclusions/interpretation: Type 2 diabetes is associated with reduced life expectancy at almost all ages and levels of SES. Elimination of life-expectancy deficits in individuals with type 2 diabetes will require prevention and management strategies targeted at all social strata (not just deprived groups)