No abstract

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

The presence of moderate or severe obstructive lung disease is a significant predictor of incident lung cancer in long-term follow-up. This finding may be useful clinically and in studies evaluating the utility of new tools for the early detection of lung cancer.

In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

Some suggest that sickle cell disease (SCD) is associated with a "proinflammatory state" that predisposes patients to acute chest syndrome in the setting of triggering factors. Conflicting data emerged when inflammation markers in SCD were compared with healthy individuals. Therefore, we examined transgenic sickle and control mice at baseline and with endotoxin (LPS) intraperitoneal injection to determine whether a proinflammatory state truly exists. At baseline, sickle mice had elevated levels of circulating leukocytes and soluble vascular cell adhesion molecule 1 (sVCAM-1). No other differences were observed at baseline or in response to saline. However, LPS challenge was associated with significant increases in mortality (p<0.05), airway tone (p<0.03), serum and bronchoalveolar lavage levels of cytokines tumor necrosis factor-alpha (p<0.03), interleukin-1beta (p<0.02), and sVCAM-1 (p<0.01) in sickle mice compared with control subjects. Furthermore, 4 hours after LPS, microarray analysis identified 413 genes differentially expressed in the sickle mice (n=5) compared with only 7 in the control subjects (n=5). No difference in lung parenchyma was observed by light microscopy. This enhanced response to LPS suggests that the sickle red blood cell confers a subclinical "proinflammatory state." This enhanced response to inflammatory insult, particularly by adhesion molecules such as sVCAM-1, could play a role in the increased susceptibility to pulmonary dysfunction that has been observed clinically in SCD.