Genes Associated with SLE Are Targets of Recent Positive Selection

The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles

Premature atherosclerosis is associated with hypovitaminosis d and angiotensin-converting enzyme inhibitor non-use in lupus patients

The ultimate goal is to identify and target modifiable risk factors that will reduce major cardiovascular events in African American lupus patients. As a first step toward achieving this goal, this study was designed to explore risk factor models of preclinical atherosclerosis in a predominantly African American group of patients with systemic lupus erythematosus (SLE) using variables historically associated with endothelial function in nonlupus populations. Fifty-one subjects with SLE but without a history of clinical cardiovascular events were enrolled. At entry, a Framingham risk factor history and medication list were recorded. Sera and plasma samples were analyzed for lipids, lupus activity markers and total 25-hydroxyvitamin D (25 OH)D) levels. Carotid ultrasound measurements were performed to determine total plaque area (TPA) in both carotids. Cases had TPA values above age-matched controls from a vascular prevention clinic population. Logistic regression and machine learning analyses were performed to create predictive models. 25(OH)D levels were significantly lower, and SLE disease duration was significantly higher in cases. 25(OH)D levels inversely correlated with age-adjusted TPA. Angiotensin-converting enzyme (ACE) inhibitor nonuse associated with case status. Logistic regression models containing ACE inhibitor use, 25(OH)D levels and low-density lipoprotein levels had a diagnostic accuracy of 84% for predicting accelerated atherosclerosis. Similar results were obtained with machine learning models, but hydroxychlo-roquine use associated with controls in these models. This is the first study to demonstrate an association between atherosclerotic burden and 25(OH)D insufficiency or ACE inhibitor nonuse in lupus patients. These findings provide strong rationale for the study of ACE inhibitors and vitamin D replenishment as preventive therapies in this high-risk population. © Copyright 2012 Southern Society for Clinical Investigation

Movement Disorder Society-sponsored revision of the Unified Parkinson\u27s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results

We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson\u27s Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson\u27s disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach\u27s alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index \u3e 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD

Premature Atherosclerosis Is Associated With Hypovitaminosis D and Angiotensin-Converting Enzyme Inhibitor Non-use in Lupus Patients

Our ultimate goal is to identify and target modifiable risk factors that will reduce major cardiovascular events in African-American lupus patients. As a first step toward achieving this goal, this study was designed to explore risk factor models of preclinical atherosclerosis in a predominantly African-American group of SLE patients using variables historically associated with endothelial function in non-lupus populations. 51 subjects with SLE but without a history of clinical cardiovascular events were enrolled. At entry, a Framingham risk factor history and medication list were recorded. Sera and plasma samples were analyzed for lipids, lupus activity markers, and total 25-hydroxyvitamin D (25(OH)D) levels. Carotid ultrasound measurements were performed to determine total plaque area (TPA) in both carotids. Cases had TPA values above age-matched controls from a vascular prevention clinic population. Logistic regression and machine learning analyses were performed to create predictive models. 25(OH)D levels were significantly lower and SLE disease duration was significantly higher in cases. 25(OH)D levels inversely correlated with age-adjusted TPA. ACE-inhibitor non-use associated with case status. Logistic regression models containing ACE-inhibitor use, 25(OH)D levels, and LDL levels had a diagnostic accuracy of 84% for predicting accelerated atherosclerosis. Similar results were obtained with machine learning models, but hydroxychloroquine use associated with controls in these models. This is the first study to demonstrate an association between atherosclerotic burden and 25(OH)D insufficiency or ACE-inhibitor non-use in lupus patients. These findings provide strong rationale for the study of ACE-inhibitors and vitamin D replenishment as preventive therapies in this high-risk population