Publications

In our previous study, we observed a severe reduction in the Src homology 2-containing-inositol-phosphatase-1 (SHIP1) protein in a subpopulation of subjects from a small adult Crohn's Disease (CD) cohort. This pilot study had been undertaken since we had previously demonstrated that engineered deficiency of SHIP1 in mice results in a spontaneous and severe CD-like ileitis. Here, we extend our analysis of SHIP1 expression in peripheral blood mononuclear cells in a second much larger adult Inflammatory Bowel Disease (IBD) cohort, comprised of both CD and Ulcerative Colitis patients, to assess contribution of SHIP1 to the pathogenesis of human IBD. SHIP1 protein and mRNA levels were evaluated from blood samples obtained from IBD subjects seen at UCSF/SFVA, and compared to healthy control samples. Western blot analyses revealed that ~15% of the IBD subjects are severely SHIP1-deficient, with less than 10% of normal SHIP1 protein present in PBMC. Further analyses by flow cytometry and sequencing were performed on secondary samples obtained from the same subjects. Pan-hematolymphoid SHIP1 deficiency was a stable phenotype and was not due to coding changes in the gene. A very strong association between SHIP1 deficiency and the presence of a novel SHIP1:ATG16L1 fusion transcript was seen. Similar to SHIP1-deficient mice, SHIP1-deficient subjects had reduced numbers of circulating CD4 T cell numbers. Finally, SHIP1-deficient subjects with CD had a history of severe disease requiring multiple surgeries. These studies reveal that the SHIP1 protein is crucial for normal T cell homeostasis in both humans and mice, and that it is also a potential therapeutic and/or diagnostic target in human IBD.

In academic medicine, under-represented minority women physician-scientists (URMWP)* are uncommon, particularly in leadership positions. Data from the American Association of Medical Colleges (AAMC) show that among internal medicine chairs, there are 12 Asian males, 10 African/American (blacks; 9 men), 7 Hispanics (2 females) and 137 whites (21 females). In the top 40 ranked cardiology programs, there are no female cardiology chiefs, whereas there are at least 10, 2, 1 and 24 Asian, black, Hispanic and white males respectively. There are more URMWP than URM males, yet URMWP are less likely to be professors and occupy leadership positions in academia. Specifically, among United States medical school faculty, relative proportions at assistant, associate and full professor levels according to race/ethnicity and gender have remained essentially unchanged over the past 20 years. AAMC information demonstrates that only 11%, 9%, 11% and 24% of Asian, black, Hispanic and white women are full professors compared with 21%, 18%, 19% and 36% of Asian, black, Hispanic and white men. Additionally, while there are representative proportions of women and Asians at the lowest faculty levels, they have not equitably progressed in academic medicine, likely reflecting discrimination and structural/organizational barriers that are also applicable to black and Hispanic females.

Our hypothesis was that children with mutations in genes coding for glutathione S-transferases (GST) have worse asthma outcomes compared with children with active type genotype. Data were collected in five populations. The rs1695 single nucleotide polymorphism (GSTP1) was determined in all cohorts (3692 children) and GSTM1 and GSTT1 null genotype were determined in three cohorts (2362 children). GSTT1 null (but not other genotypes) was associated with a minor increased risk for asthma attack and there were no significant associations between GST genotypes and asthma severity. Interactions between GST genotypes and SHS exposure or asthma severity with the study outcomes were nonsignificant. We find no convincing evidence that the GST genotypes studied are related to asthma outcomes.