Faculty Bibliography

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition most often caused by smoking. Genetic association studies have identified multiple genetic loci associated with COPD phenotypes. Similarly, protein biomarker studies have identified blood biomarkers associated with COPD. However, the relationship between genetic markers and protein levels, protein quantitative trait loci (pQTL), has not been extensively explored. Using SPIROMICS and COPDGene, two large genotyped cohorts of older nonsmokers and smokers with COPD, we performed a pQTL analysis to identify genetic associations with protein biomarker levels. Methods: We tested the relationship between genome wide genetic markers and 96 candidate COPD blood biomarkers in 750 (SPIROMICS) and 590 (COPDGene) non-Hispanic White subjects. Genotyping was performed on Illumina platforms. Candidate biomarkers were assessed in fresh frozen serum and plasma using 13 Myriad-RBM single and multiplex panels. Local and distant pQTL were identified using an additive regression model adjusted for covariates and genetic principal components, in addition to correction for multiple comparisons. A meta-analysis was used to combine the p-values from the two studies. Results: In preliminary results from currently available data, we identified 539 significant pQTL SNPs (69% local; 31% distant) for 36 proteins (p < 10^-8). Several top pQTL SNPs have been reported in previous studies to be associated with lung disease. For a third of the proteins, the top pQTL SNP and covariates explained more than 20% of variance in biomarker levels, with some reaching 50-75%. For most of these cases, the genetic variant was the major contributor to the percent variance explained. The top local pQTL association was for GC (Vitamin D binding protein) and rs7041, a SNP associated with more severe COPD. The top distant association was for SELE (chromosome 1; E-selectin) and rs507666, an intron variant in ABO (alpha 1-3-N-acetylgalactosaminyltransferase) previously associated with blood group and altered glycosyltransferase activities. The ABO locus is also a genetic hot-spot as it was found to be associated with several of the protein measurements. The relationship between the pQTLs and known expression QTLs (eQTLs) also suggest both overlapping and independent mechanisms. Conclusions: This is the largest integration of genetics and protein biomarkers with replication in two highly phenotyped COPD cohorts. We find a strong association between genotype and blood protein measurements for many biomarkers, which suggests that genotype should be included in biomarker disease association studies. These associations will also help to unravel the mechanisms through which genotype influences COPD risk

Renal mucinous tubular and spindle cell carcinoma (MTSCC) was recently described as a distinct subtype of renal cell carcinoma (RCC) in the 2004 World Health Organization classification of kidney tumors. MTSCC is a rare low grade malignancy with < 100 cases reported in the literature. To the best of our knowledge, there are 5 case reports with a total of 6 patients describing its diagnosis by fine needle aspiration (FNA). All of these cases were diagnosed as conventional RCC on FNA. Subsequent excisions proved them to be MTSCC. We herein report a case in a 67-year-old male. He presented with abdominal pain and was found to have a new colon adenocarcinoma with metastasis to the liver and lungs. The extent of disease made the patient ineligible for surgical excision, and he received chemotherapy. Work-up also revealed a kidney mass which was later biopsied by FNA and core biopsy. The tumor was composed of epithelial and spindled cell components embedded in a myxoid background. It was positive for CK7, AMCAR, vimentin, and epithelial membrane antigen. The tumor was diagnosed as MTSCC. One year later the kidney mass remained stable. However, the patient developed new metastasis to the liver from colonic primary. The kidney mass was not resected. Although rarely encountered in FNA cytology of the kidney, we believe the cytologic features of this tumor are distinctive and are different from conventional and other subtypes of RCC. Therefore, its accurate diagnosis on FNA is possible once pathologists are aware that MTSCC should be considered in the differential diagnosis of kidney tumors.

BACKGROUND: The electrocardiogram (ECG) is the most important diagnostic tool for acute myocardial infarction (AMI). T wave inversion (TWI) in lead aVL has not been emphasized or well recognized. OBJECTIVE: This study examined the relationship between the presence of TWI before the event and mid-segment left anterior descending (MLAD) artery lesion in patients with AMI. METHODS: Retrospective charts of patients with acute coronary syndrome between the months of January 2009 and December 2011 were reviewed. All patients with MLAD lesion were identified and their ECG reviewed for TWI in lead aVL. RESULTS: Coronary angiography was done on 431 patients. Of these, 125 (29%) had an MLAD lesion. One hundred and six patients (84.8%) had a lesion > 50% and 19 patients (15.2%) had a lesion < 50%. Of the 106 patients who had a MLAD lesion > 50%, 90 patients (84.9%) had TWI in lead aVL and one additional lead. Of the 19 patients who had an MLAD lesion < 50%, 8 patients (42.1%) had TWI in lead aVL and one additional lead. Isolated TWI in lead aVL had an overall sensitivity of 76.7% (95% confidence interval [CI] 0.65-0.86), a specificity of 71.4% (95% CI 0.45-0.88), a positive predictive value of 92%, a negative predictive value of 41.7%, a positive likelihood ratio of 2.7 (95% CI 1.16-6.22), and negative likelihood ratio of 0.32 (95% CI 0.19-0.58) for predicting a MLAD lesion of > 50% (p = 0.0011). CONCLUSIONS: TWI in lead aVL might signify a mid-segment LAD lesion. Recognition of this finding and early appropriate referral to a cardiologist might be beneficial. Additional studies are needed to validate this finding.

Subthreshold-activating A-type K(+) currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K(+) current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.