0232 : Small, medium but not large arteries are involved in digital ulcers associated with systemic sclerosis

BackgroundDigital ulcers (DU) are a burden in systemic sclerosis (SSc). Microangiopathy is a cardinal feature of SSc that plays a critical role in the development of DU. However, whether injury of medium or large vessels also contributes to DU in SSc is unknown.MethodsTo measure concomitantly in SSc patients with and without active DU i) the Augmentation Index of the reflected wave (Aix_75) by radial applanation tonometry, an index of small and medium arterial function, II) the aortic pulse wave velocity (PWV), a marker of large vessel injury (aortic stiffness).Results63 consecutive SSc patients were included (49 females, aged 57±12 years, disease duration 9.7±7.1 years), including 10 (15.9%) with active DU.Patients with active DU versus those without had increased Aix_75 (35% [28-38] versus 28% [20-34], p=0.041) whereas no difference existed in PWV (7,0m/s [6.7-10.1] versus 7,6m/s [6.8-8.7], p=0.887), in systolic, diastolic, as well as aortic pulse pressure (p=0.126, 0.592, and 0.161 respectively).By multivariate analysis, DU remained independently associated with Aix_75 (p=0.020).Using Aix_75 as a longitudinal variable, and when compared to patients in the low tertile, patients having Aix_75 in the highest tertile had ten-fold more DU (OR=10.23; 95% CI 1.12 to 93.34, p=0.039).ConclusionThe presence of DU is independently associated with Aix_75 whereas there is no relation with PWV. These data suggest that small and medium arteries are involved in the occurrence of DU whether large vessel stiffness does not contribute. Whether Aix_75 is predictive of further DU remained to be studied

Usefulness of Mendelian Randomization in Observational Epidemiology

Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. In this review, we recall the principles of a “Mendelian randomization” approach in observational epidemiology, which is based on the technique of instrumental variables; we provide simulations and an example based on real data to demonstrate its implications; we present the results of a systematic search on original articles having used this approach; and we discuss some limitations of this approach in view of what has been found so far

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe