Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.

BACKGROUND: Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin-like low-density lipoprotein 1 receptor, encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems because the same protein domain binds oxidized low-density lipoprotein and bacterial cell wall proteins, the former contributing to atherosclerosis and the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and nonhuman primates, to determine whether variable selection can lead to conflicting results in cardiovascular disease association studies. METHODS AND RESULTS: We analyzed sequences from 11 nonhuman primate species, as well as single-nucleotide polymorphisms and sequence data from multiple human populations. Results indicate that the derived allele is favored across primate lineages (probably because of recent positive selection). However, both the derived and ancestral alleles were maintained in human populations, especially European ones (possibly because of balancing selection derived from dual roles of LOX-1). Balancing selection likely reflects response to diverse environmental pressures among humans. CONCLUSIONS: These data indicate that differential selection patterns, within and between species, in OLR1 render association studies difficult to replicate even if the gene is etiologically connected to cardiovascular disease. Selection analyses can identify genes exhibiting gene-environment interactions critical for unraveling disease association.

An intervention connecting low-acuity emergency department patients with primary care: effect on future primary care linkage.

STUDY OBJECTIVE: Our objective is to determine whether a point-of-care intervention that navigates willing, low-acuity patients from the emergency department (ED) to a Primary Care Clinic will increase future primary care follow-up. METHODS: We conducted a quasi-experimental trial at an urban safety net hospital. Adults presenting to the ED for select low-acuity problems were eligible. Patients were excluded if arriving by emergency medical services, if febrile, or if the triage nurse believed they required ED care. We enrolled 965 patients. Navigators escorted a subset of willing participants to the Primary Care Clinic (in the same hospital complex), where they were assigned a personal physician, were given an overview of clinic services, and received same-day clinic care. The primary outcome was Primary Care Clinic follow-up within 1 year of the index ED visit among patients having no previous primary care provider. RESULTS: In the bivariate intention-to-treat analysis, 50.3% of intervention group patients versus 36.9% of control group patients with no previous primary care provider had at least 1 Primary Care Clinic follow-up visit in the year after the intervention. In the multivariable analysis, the absolute difference in having at least 1 Primary Care Clinic follow-up for the intervention group compared with the control group was 9.3% (95% confidence interval 2.2% to 16.3%). There was no significant difference in the number of future ED visits. CONCLUSION: A point-of-care intervention offering low-acuity ED patients the opportunity to alternatively be treated at the hospital's Primary Care Clinic resulted in increased future primary care follow-up compared with standard ED referral practices.