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Articles by S Su
Total Records ( 3 ) for S Su
  V Vaccarino , J Votaw , T Faber , E Veledar , N. V Murrah , L. R Jones , J Zhao , S Su , J Goldberg , J. P Raggi , A. A Quyyumi , D. S Sheps and J. D. Bremner

Background  Major depressive disorder (MDD) is associated with coronary heart disease (CHD), but the mechanisms are unclear. The presence of MDD may increase CHD risk by affecting microvascular circulation. It is also plausible that genetic factors influencing MDD may overlap with those for CHD. We sought to examine the relationship between MDD and coronary flow reserve (CFR), the ratio of maximum flow during stress to flow at rest measured in milliliters per minute per gram of tissue.

Methods  We examined 289 male middle-aged twins, including 106 twins (53 twin pairs) discordant for a lifetime history of MDD and 183 control twins (unrelated to any twins in the experimental group) without MDD. To calculate CFR, we used positron emission tomography with nitrogen 13 (13N) ammonia to evaluate myocardial blood flow at rest and after adenosine stress. A standard perfusion defect score was also used to assess myocardial ischemia.

Results  There was no difference in myocardial ischemia between twins with and without MDD. Among the dizygotic twin pairs discordant for MDD, the CFR was 14% lower in the twins with MDD than in their brothers without MDD (2.36 vs 2.74) (P = .03). This association was not present in the monozygotic discordant pairs who were genetically matched (2.86 vs 2.64) (P = .19). The zygosity-MDD interaction after adjustment was significant (P = .006). The CFR in the dizygotic twins with MDD was also lower than in the control twins.

Conclusions  Our results provide evidence for a shared genetic pathway between MDD and microvascular dysfunction. Common pathophysiologic processes may link MDD and early atherosclerosis.

  S Su , J Zhao , J. D Bremner , A. H Miller , W Tang , M Bouzyk , H Snieder , O Novik , N Afzal , J Goldberg and V. Vaccarino

Background— We explored the relationship of genetic variants of the serotonin transporter gene SLC6A4, a key regulator of the serotonergic neurotransmission, with both depressive symptoms and plasma interleukin-6 (IL-6) levels.

Methods and Results— We genotyped 20 polymorphisms in 360 male twins (mean age, 54 years) from the Vietnam Era Twin Registry. Current depressive symptoms were measured with the Beck Depression Inventory II. IL-6 was assessed using a commercially available ELISA kit. Genotype associations were analyzed using generalized estimating equations. To study how SLC6A4 genetic vulnerability influences the relationship between depressive symptoms and IL-6, bivariate models were constructed using structural equation modeling. Of the 20 polymorphisms examined, the effective number of independent tests was 6, and the threshold of significance after Bonferroni correction was 0.008. There were 6 single-nucleotide polymorphisms significantly associated with Beck Depression Inventory (P≤0.008), including rs8071667, rs2020936, rs25528, rs6354, rs11080122, and rs8076005, and 1 single-nucleotide polymorphism was borderline associated (rs12150214, P=0.017). Of these 7 single-nucleotide polymorphisms, 3 were also significantly associated with IL-6 (P<0.008), including rs25528, rs6354, and rs8076005, and the other 4 were borderline associated (P=0.009 to 0.025). The subjects with 1 copy of the minor allele of these 7 single-nucleotide polymorphisms had higher Beck Depression Inventory scores and IL-6 levels. Further bivariate modeling revealed that 10% of the correlation between Beck Depression Inventory and IL-6 could be explained by the SLC6A4 gene.

Conclusions— Genetic vulnerability involving the SLC6A4 gene is significantly associated with both increased depressive symptoms and elevated IL-6 plasma levels. Common pathophysiological processes may link depression and inflammation, and implicate the serotonin pathway in neural-immune interactions.

  A. H Harrill , P. B Watkins , S Su , P. K Ross , D. E Harbourt , I. M Stylianou , G. A Boorman , M. W Russo , R. S Sackler , S. C Harris , P. C Smith , R Tennant , M Bogue , K Paigen , C Harris , T Contractor , T Wiltshire , I Rusyn and D. W. Threadgill

Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.

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