Melville's "Bartleby, the Scrivener: A Story of Wall-Street": The Vicissitudes of Treating a Difficult Patient.

Taking the liberty of imagining the lawyer in Melville's "Bartleby, the Scrivener" as narrator/therapist and Bartleby as patient, this article, written with the therapist/reader in mind, traces the vicissitudes of countertransference and speculates on what constitutes a "good enough" therapeutic effort.

Circulating Interleukin-6 concentration covaries inversely with self-reported sleep duration as a function of polymorphic variation in the glucocorticoid receptor.

Growing evidence links extremes of self-reported sleep duration with higher circulating markers of inflammatory disease risk, although not all findings are consistent. Extremes of sleep duration also associate with activation of the hypothalamic-pituitary-adrenocortical (HPA) system and the peripheral release of cortisol, a glucocorticoid (GC) important in downregulating transcription of pro-inflammatory molecules. Polymorphic variation in the gene encoding the GC receptor (GR; NR3C1) modulates cellular sensitivity to GC-mediated anti-inflammatory signaling, thereby affecting levels of pro-inflammatory molecules. Thus, we hypothesized that extremes of self-reported sleep duration may covary with circulating levels of inflammatory markers as a function of allelic variation in NR3C1. Specifically, we examine the possibility that a single nucleotide polymorphism of the GR gene-(rs6198), the minor (G) allele of which confers reduced GR sensitivity-moderates an association of sleep duration with interleukin (IL)-6 and C-reactive protein (CRP) among a large sample (IL-6: N = 857; CRP: N = 929) of midlife community volunteers of European ancestry. Findings showed that sleep duration varied inversely with IL-6 (ß = -0.087, p = .012), and this association was stronger among individuals homozygous for the rs6198 G-allele compared to alternate genotypes (ß = -0.071, p = .039). We also found that sleep duration showed a U-shaped association with CRP (polynomial term: ß = 0.093, p = .006), which was not moderated by rs6198 genotype. In conclusion, we show that a common genetic variant in the GR moderates an inverse association of self-reported sleep duration with circulating IL-6, possibly contributing to the increased disease risk observed among some short sleepers.

Genetic association and differential expression of PITX2 with acute appendicitis.

Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value = 8.82 × 10-14) and was replicated in an independent sample of Caucasians (59 affected, 607 unaffected; p value = 0.005). Meta-analysis of the associated variant across our two cohorts and cohorts from Iceland and the Netherlands (in which this association had previously been reported) showed strong cumulative evidence of association (OR = 1.12; 95% CI 1.09-1.14; p value = 1.81 × 10-23) and some evidence for effect heterogeneity (p value = 0.03). Eight other loci were identified at suggestive significance in the discovery GWAS. Associations were followed up by measuring gene expression across resected appendices with varying levels of inflammation (N = 75). We measured expression of 27 genes based on physical proximity to the GWAS signals, evidence of being targeted by eQTLs near the signals according to RegulomeDB (score = 1), or both. Four of the 27 genes (including PITX2) showed significant evidence (p values < 0.0033) of differential expression across categories of appendix inflammation. An additional ten genes showed nominal evidence (p value < 0.05) of differential expression, which, together with the significant genes, is more than expected by chance (p value = 6.6 × 10-12). PITX2 impacts morphological development of intestinal tissue, promotes an anti-oxidant response, and its expression correlates with levels of intestinal bacteria and colonic inflammation. Further studies of the role of PITX2 in appendicitis are warranted.

Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.

OBJECTIVES: Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred. METHODS: We carried out genetic analyses of 439 individuals from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of SAs and first-degree relatives of individuals who have attempted or died by suicide. RESULTS: We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these individuals, two-fold higher than ROH rates for individuals from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications more than 500 kb was associated with an increased risk for attempt (odds ratio: 2.9; P=0.01; 95% confidence interval: 1.3-6.6). Although not significant after correction for multiple testing, the risk for SA appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate glutamate receptors, and is involved in glutamatergic neurotransmission. CONCLUSION: Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase the risk for several neuropsychiatric disorders, including depression and SA, irrespective of ancestry.

5-HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD, depressive and anxiety symptoms in soldiers deployed to iraq.

Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype in predicting the emergence of post-traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5-HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5-HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or LG ) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (LA ). These data suggest that 5-HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress.

Blood pressure interacts with APOE ε4 to predict memory performance in a midlife sample.

OBJECTIVE: Elevated blood pressure and the Apolipoprotein ε4 allele (APOE ε4) are independent risk factors for Alzheimer's disease. We sought to determine whether the combined presence of the APOE ε4 allele and elevated blood pressure is associated with lower cognitive performance in cognitively healthy middle-aged adults. METHODS: A total of 975 participants aged 30-54 (mean age = 44.47) were genotyped for APOE. Cardiometabolic risk factors including blood pressure, lipids, and glucose were assessed and cognitive function was measured using the Trail Making Test and the Visual Reproduction and Logical Memory subtests from the Wechsler Memory Scale. RESULTS: Multivariable regression analysis showed that the association between APOE ε4 and episodic memory performance varied as a function of systolic blood pressure (SBP), such that elevated SBP was predictive of poorer episodic memory performance only in APOE ε4 carriers (ß = -.092; t = -2.614; p = .009). Notably, this association was apparent at prehypertensive levels (≥130 mmHg), even after adjusting for physical activity, depression, smoking, and other cardiometabolic risk factors. CONCLUSIONS: The joint presence of APOE ε4 and elevated SBP, even at prehypertensive levels, is associated with lower cognitive performance in healthy, middle-aged adults. Results of this study suggest that the combination of APOE ε4 and elevated SBP may synergistically compromise memory function well before the appearance of clinically significant impairments. Interventions targeting blood pressure control in APOE ε4 carriers during midlife should be studied as a possible means to reduce the risk of cognitive decline in genetically susceptible samples.

Indirect association of DAT1 genotype with executive function through white matter volume in orbitofrontal cortex.

The dopamine transporter (DAT1) gene has been associated with impulsivity and executive functioning. Further, DAT1 has been associated with brain structural characteristics and resting state connectivity. This study tested an indirect effect model in which DAT1 genotype (9-repeat (9R) carriers vs 10-repeat (10R) homozygotes) is linked to phenotypes representing impulsivity and executive function (planning behavior) through effects on white matter (WM) volumes in prefrontal cortex (PFC), particularly orbitofrontal cortex (OFC). Adolescents (ages 14-18, n=38) were recruited from substance use treatment (n=22) and the community (n=16) to increase phenotype variation. Results indicated that DAT1 10/10 genotype was associated with lower WM volume in the PFC, specifically the left OFC. Further, lower WM volume in the left OFC predicted more difficulties in self-reported planning behavior, but not impulsivity. Indirect effect analysis indicated that lower WM volume in the left OFC mediated the association between DAT1 10/10 genotype and difficulties in planning behavior. Results suggest a brain structural mechanism, involving lower WM volume in the left OFC, as a link in the association between DAT1 genotype and a specific aspect of executive function. Genetic effects on regional WM volume that are linked to behavioral outcomes could ultimately inform the development of tailored interventions that address an individual׳s unique risk factors.

The -93T/G LPL Promoter Polymorphism Is Associated With Lower Third-Trimester Triglycerides in Pregnant African American Women.

BACKGROUND: Hypertriglyceridemia is a risk factor for cardiovascular disease and several pregnancy complications. Lipoprotein lipase (LPL) genetic variation modulates nonpregnancy plasma triglycerides, but its effects during pregnancy are unknown. The G allele of the LPL -93T/G promoter polymorphism is 16-23 times more prevalent in Blacks than in Whites, contributing to lower triglycerides in nonpregnant African Americans by increasing LPL expression. PURPOSE: This study investigated whether the triglyceride-lowering effect of -93G is observed in African Americans during pregnancy. METHODS: Genotyping was performed on 124 African American women with uncomplicated pregnancies for common functional LPL polymorphisms/mutations (-93T/G, D9N, N291S, and S447X). Third-trimester plasma triglyceride, high- and low-density lipoprotein cholesterol, apolipoprotein B, and free fatty acid concentrations were measured with colorimetric assays. Clinical characteristics and lipid values were compared across the -93T/G genotypes. RESULTS: Triglycerides were significantly lower in women with the -93GG compared to the -93TT genotype, both with (n = 124, p = .02) and without (n = 108, p = .03) inclusion of participants with other LPL variant alleles. Triglyceride differences persisted after adjustment for prepregnancy body mass index, gestational age at delivery, and smoking. There were no significant differences in the other lipids or apolipoprotein B by -93T/G genotype. CONCLUSIONS: Despite the considerable metabolic changes accompanying pregnancy, the triglyceride-lowering effect associated with the -93GG LPL genotype in African Americans persists during late pregnancy. The -93GG genotype might protect against pregnancy complications stemming from hypertriglyceridemia, but the overall increased risk of pregnancy complications in African American women points to complex, multifactorial relationships among risk factors, race, and adverse pregnancy outcomes.

Variation in the BDNF gene interacts with age to predict mortality in a prospective, longitudinal cohort with severe TBI.

BACKGROUND: Mortality predictions following traumatic brain injury (TBI), and our understanding of TBI pathology, may be improved by including genetic risk in addition to traditional prognostic variables. One promising target is the gene coding for brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin important for neuronal survival and neurogenesis. OBJECTIVE: We hypothesized the addition of BDNF genetic variation would improve mortality prediction models and that BDNF Met-carriers (rs6265) and C-carriers (rs7124442) would have the highest mortality rates post-TBI. METHODS: This study examined BDNF functional single nucleotide polymorphisms rs6265 (val66met) and rs7124442 (T>C) in relation to mortality in a prospective, longitudinal cohort with severe TBI. We examined 315 individuals receiving care for a closed head injury within the University of Pittsburgh Medical Center, aged 16 to 74 years. Mortality was examined acutely (0-7 days postinjury) and postacutely (8-365 days postinjury). A gene risk score (GRS) was developed to examine both BDNF loci. Cox proportional hazards models were used to calculate hazard ratios for survivability post-TBI while controlling for covariates. RESULTS: BDNF GRS was significantly associated with acute mortality, regardless of age. Interestingly, subjects in the hypothesized no-risk allele group had the lowest survival probability. Postacutely, BDNF-GRS interacted with age such that younger participants in the no-risk group had the highest survival probability, while older participants in the hypothesized no-risk group had the lowest probability of survival. CONCLUSIONS: These data suggest complex relationships between BDNF and TBI mortality that interact with age to influence survival predictions beyond clinical variables alone. Evidence supporting dynamic, temporal balances of pro-survival/pro-apoptotic target receptors may explain injury and age-related gene associations.

Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice.

BACKGROUND & AIMS: Augmenter of liver regeneration (ALR, encoded by GFER) is a widely distributed pleiotropic protein originally identified as a hepatic growth factor. However, little is known about its roles in hepatic physiology and pathology. We created mice with liver-specific deletion of ALR to study its function. METHODS: We developed mice with liver-specific deletion of ALR (ALR-L-KO) using the albumin-Cre/LoxP system. Liver tissues were collected from ALR-L-KO mice and ALR(floxed/floxed) mice (controls) and analyzed by histology, reverse-transcription polymerase chain reaction, immunohistochemistry, electron microscopy, and techniques to measure fibrosis and lipids. Liver tissues from patients with and without advanced liver disease were determined by immunoblot analysis. RESULTS: Two weeks after birth, livers of ALR-L-KO mice contained low levels of ALR and adenosine triphosphate (ATP); they had reduced mitochondrial respiratory function and increased oxidative stress, compared with livers from control mice, and had excessive steatosis, and hepatocyte apoptosis. Levels of carbamyl-palmitoyl transferase 1a and ATP synthase subunit ATP5G1 were reduced in livers of ALR-L-KO mice, indicating defects in mitochondrial fatty acid transport and ATP synthesis. Electron microscopy showed mitochondrial swelling with abnormalities in shapes and numbers of cristae. From weeks 2-4 after birth, levels of steatosis and apoptosis decreased in ALR-L-KO mice, and numbers of ALR-expressing cells increased, along with ATP levels. However, at weeks 4-8 after birth, livers became inflamed, with hepatocellular necrosis, ductular proliferation, and fibrosis; hepatocellular carcinoma developed by 1 year after birth in nearly 60% of the mice. Hepatic levels of ALR were also low in ob/ob mice and alcohol-fed mice with liver steatosis, compared with controls. Levels of ALR were lower in liver tissues from patients with advanced alcoholic liver disease and nonalcoholic steatohepatitis than in control liver tissues. CONCLUSIONS: We developed mice with liver-specific deletion of ALR, and showed that it is required for mitochondrial function and lipid homeostasis in the liver. ALR-L-KO mice provide a useful model for investigating the pathogenesis of steatohepatitis and its complications.

OXTR polymorphism predicts social relationships through its effects on social temperament.

Humans have a fundamental need for strong interpersonal bonds, yet individuals differ appreciably in their degree of social integration. That these differences are also substantially heritable has spurred interest in biological mechanisms underlying the quality and quantity of individuals' social relationships. We propose that polymorphic variation in the oxytocin receptor gene (OXTR) associates with complex social behaviors and social network composition through intermediate effects on negative affectivity and the psychological processing of socially relevant information. We tested a hypothesized social cascade from the molecular level (OXTR variation) to the social environment, through negative affectivity and inhibited sociality, in a sample of 1295 men and women of European American (N = 1081) and African American (N = 214) ancestry. Compared to European Americans having any T allele of rs1042778, individuals homozygous for the alternate G allele reported significantly lower levels of negative affectivity and inhibited sociality, which in turn predicted significantly higher levels of social support and a larger/more diverse social network. Moreover, the effect of rs1042778 variation on social support was fully accounted for by associated differences in negative affectivity and inhibited sociality. Results replicated in the African American sample. Findings suggest that OXTR variation modulates levels of social support via proximal impacts on individual temperament.

A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay.

Executive functions (EF) are a complex set of neurodevelopmental, higher-ordered processes that are especially salient during adolescence. Disruptions to these processes are predictive of psychiatric problems in later adolescence and adulthood. The objectives of the current study were to characterize the latent structure of EF using bifactor analysis and to investigate the independent and interactive effects of genes and environments on EF during adolescence. Using a representative young adolescent sample, we tested the interaction of a polymorphism in the serotonin transporter gene (5-HTTLPR) and parental supervision for EF through hierarchical linear regression. To account for the possibility of a hierarchical factor structure for EF, a bifactor analysis was conducted on the eight subtests of the Delis-Kaplan Executive Functions System (D-KEFS). The bifactor analysis revealed the presence of a general EF construct and three EF subdomains (i.e., conceptual flexibility, inhibition, and fluency). A significant 5-HTTLPR by parental supervision interaction was found for conceptual flexibility, but not for general EF, fluency or inhibition. Specifically, youth with the L/L genotype had significantly lower conceptual flexibility scores compared to youth with S/S or S/L genotypes given low levels of parental supervision. Our findings indicate that adolescents with the L/L genotype were especially vulnerable to poor parental supervision on EF. This vulnerability may be amenable to preventive interventions.

The haptoglobin 1 allele correlates with white matter hyperintensities in middle-aged adults with type 1 diabetes.

Although the haptoglobin (Hp) 1-1 genotype is associated with a lower coronary artery disease (CAD) risk in diabetes, we recently reported an increased stroke incidence in type 1 diabetes with Hp 1-1. We, thus, evaluated differences in earlier brain vascular abnormality markers by Hp using neuroimaging. Neuroimaging was completed in 94 participants of the Pittsburgh Epidemiology of Diabetes Complications study with Hp genotyping available (mean age, 49; duration, 41 years). White matter hyperintensities (WMH) volume, lacunar infarcts, and gray matter atrophy were quantified. Sixteen percent were homozygous for Hp 1 and 43% for Hp 2. A significant trend toward increased WMH was observed with greater duration and the number of Hp 1 alleles. Associations were strongest for the interhemispheric connecting fibers of the corpus callosum. Allowing for duration, sex, waist-to-hip ratio, HbA1c, systolic blood pressure, and lipids in models with backward elimination, results were similar. No significant differences by Hp were noted for atrophy or lacunar infarcts. Consistent with its direct association with stroke, the Hp 1-1 genotype is associated with higher WMH in this population. Further, including mechanistic, studies on the role of the Hp genotype in cerebrovascular disease and the implications for worsening cognitive function are needed.

X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury.

OBJECTIVE(S): Clinical research characterizing the mechanisms responsible for sex-based outcome differences postinjury remain conflicting. We sought to characterize an X chromosome-linked IRAK-1 (IL-1 receptor-associated kinase) polymorphism as an alternative mechanism responsible for sex differences postinjury. IRAK-1 is key intermediate in the toll-like receptor (TLR) pathway thought to drive inflammation postinjury. METHODS: A prospective cohort study was performed over a 24-month period. Bluntly injured patients requiring intensive care unit admission were enrolled, whereas patients with isolated brain and spinal cord injuries were excluded. Outcomes of interest included multiple organ failure (MOF, Marshall MOD score > 5) and mortality. Logistic regression was utilized to determine the independent risk of poor outcome associated with the IRAK-1 variant after controlling for important differences. RESULTS: In an enrolled cohort of 321 patients, the IRAK-1 variant was common (12.5%). Patients with and without the variant were similar in age, injury severity, and 24hr blood transfusion. After controlling for important confounders, the IRAK1 variant was independently associated with more than eightfold (OR = 8.4, P = 0.005, 95% CI: 1.9-37.1) and 11-fold (OR = 11.8, P = 0.037, 95% CI: 1.1-121) greater risk of MOF and mortality, respectively. These differences were most prominent in men, whereas women heterozygous for the variant demonstrated worse outcome in a dose-dependent fashion. CONCLUSIONS: The IRAK1 polymorphism is a strong independent predictor of MOF and mortality postinjury and represents a common variant with prognostic potential. These data demonstrate the importance of TLR signaling postinjury and supports that a genetic mechanism may drive sex outcome differences postinjury.

Haptoglobin genotype and cerebrovascular disease incidence in type 1 diabetes.

OBJECTIVE: We prospectively evaluated the haptoglobin (Hp)-stroke association in type 1 diabetes and hypothesized that despite increasing the risk of coronary artery disease, the presence of the Hp 2 allele would be associated with a lower incidence of stroke. METHODS: Participants from the Epidemiology of Diabetes Complications study without prevalent stroke and Hp available were evaluated (n = 607; mean age 27.6 years and duration 19.3 years). RESULTS: During 22 years of follow-up, stroke incidence did not differ by Hp genotype (p = 0.49). Restricting analyses to those diagnosed with diabetes ≥1965 (13% mortality vs 40% in the <1965 cohort) to diminish potential survival bias, the adjusted hazard ratio (HR) for Hp 1-1 was 3.08 (95% confidence interval (CI) = 0.81-11.77, p = 0.10). Further stratifying by hypertension prevalence, an increased stroke incidence was observed with Hp 1-1 only in those with hypertension (HR = 7.03, 95% CI = 1.42-34.89, p = 0.02). CONCLUSION: Despite the protective effect against vascular diabetes complications, a borderline increased risk of stroke was observed with Hp 1-1 in type 1 diabetes. This mixed Hp effect on cardiovascular risk by outcome studied merits further investigation and cautions against the universal application of preventive therapies across all Hp genotypes.

Serotonin Transporter Genotype Linked to Adolescent Substance Use Treatment Outcome through Externalizing Behavior.

Meta-analyses suggest that the serotonin transporter linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for alcohol dependence, particularly among individuals with early onset antisocial alcoholism. Youth in substance use treatment tend to show antisocial or externalizing behaviors, such as conduct problems, which predict worse treatment outcome. This study examined a pathway in which 5-HTTLPR genotype is associated with externalizing behavior, and the intermediate phenotype of externalizing behavior serves as a link between 5-HTTLPR genotype and substance use treatment outcome in youth. Adolescents (n = 142) who were recruited from addictions treatment were genotyped for 5-HTTLPR polymorphisms (S and LG carriers vs. LALA), assessed for externalizing and internalizing behaviors shortly after starting treatment, and followed over 6-months. 5-HTTLPR genotype was not associated with internalizing behaviors, and was not directly associated with 6-month substance use outcomes. However, 5-HTTLPR genotype was associated with externalizing behaviors (S and LG > LALA), and externalizing behaviors predicted alcohol and marijuana problem severity at 6-month follow-up. Results indicated an indirect (p < 0.05) and non-specific (i.e., both alcohol and marijuana severity) effect of 5-HTTLPR genotype on youth substance use treatment outcomes, with externalizing behaviors as an important linking factor. Adolescents in substance use treatment with low expressing (S and LG) 5-HTTLPR alleles and externalizing behavior might benefit from intervention that addresses serotonergic functioning, externalizing behaviors, and substance use to improve outcomes.

Cross-sectional analysis of Toll-like receptor variants and bacterial vaginosis in African-American women with pelvic inflammatory disease.

OBJECTIVE: Bacterial vaginosis (BV) is a common condition associated with serious complications including pelvic inflammatory disease (PID). However, the pathogenesis of BV is poorly understood. Toll-like receptors (TLR) are responsible for microbial recognition and elimination through inflammatory responses. TLR variants have been implicated in infectious and inflammatory diseases and may be involved in BV pathogenesis. We conducted a cross-sectional study to determine if TLR variants are associated with BV. METHODS: Logistic regression was used to test associations between 14 variants assayed in 6 genes (TLR1, TLR2, TLR4, TLR6, TIRAP and MyD88) and BV/intermediate flora among 192 African-American women with clinical PID from the PID Evaluation and Clinical Health (PEACH) Study. Additionally, we examined associations between variants and endometrial BV-associated anaerobes. To account for multiple comparisons a permutated p<0.003 was used to determine statistical significance. RESULTS: African-American women with PID carrying the AA genotype for TLR2 SNP rs1898830 had a threefold increased rate of BV/intermediate flora (OR 2.9, 95% CI 1.2 to 7.3). This was not significant after accounting for multiple comparisons (p=0.0201). TLR2 variants rs1898830, rs11938228 and rs3804099 were associated with increased endometrial anaerobic gram-negative rods (p=0.0107, p=0.0076 p=0.0121), anaerobic non-pigmented Gram-negative rods (p=0.0231, p=0.0083, p=0.0044), and anaerobic Gram-positive cocci (p=0.0596, p=0.0640, p=0.1459). CONCLUSIONS: Among African-American women with PID, we observed trends between TLR2 variants, BV/intermediate flora, and BV-associated microbes. This provides some insight into BV pathogenesis. As not all BV-associated microbes may lead to pathology, future studies should focus on associations between TLR variants and individual BV-associated microbes.

Multi-institutional Study of Outcomes After Pediatric Heart Transplantation: Candidate Gene Polymorphism Analysis of ABCC2.

OBJECTIVES: Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA. METHODS: PHTx recipients from 6 institutions in the Pediatric Heart Transplantation Study (PHTS) from the period of 1993-2009, receiving MPA therapy, were genotyped for ABCC2 rs717620. Genotyping was accomplished by direct sequencing. Demographic and outcome data were limited to the data routinely collected as part of the PHTS and included RHC and mortality. RESULTS: Two hundred ninety patients were identified who received MPA at some point post transplantation, of which 200 carried the GG genotype, 81 carried the AG genotype, and 9 carried the AA genotype. Follow-up time after transplantation was 6 years. RHC occurred in 76 patients and 18 patients died. In the 281 patients followed up more than 1 year, late RHC (>1 year post transplantation) occurred in 42 patients. While both RHC and late RHC were associated with the ABCC2 rs717620 GG genotype (hazard ratios: 1.80 and 4.57, respectively, p<0.05) in all patients, this association was not significant in PHTx patients receiving only MPA as the antiproliferative agent from the time of transplant (n=142). CONCLUSIONS: ABCC2 rs717620 polymorphisms varied within racial groups. As a candidate gene assessment, the ABCC2 rs717620 AG and AA genotypes may be associated with improved, rather than poorer, RHC in PHTx patients receiving MPA therapy. ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation.

The BDNF Val66Met polymorphism does not moderate the effect of self-reported physical activity on depressive symptoms in midlife.

The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism may be associated with clinical and subsyndromal depression, but physical activity improves mood and increases BDNF expression. The aim of the study was to examine whether the BDNF polymorphism moderates an effect of physical activity on depressive symptoms. BDNF genotype, physical activity measured by the Paffenbarger Questionnaire, and depressive symptoms using the Center for Epidemiology Depression Scale (CES-D) were collected on 1072 participants (mean age=44). Multiple linear regression was used to examine the association between BDNF genotype, physical activity, and depressive symptoms. After adjusting for family income, age, and education, depressive symptoms were higher in Met carriers compared to Val homozygotes (p=0.03), but this was only significant in men. Physical activity was associated with fewer depressive symptoms, but only in women (p=0.01). BDNF genotype did not moderate the effect of physical activity on depressive symptoms (p=0.94). In midlife, the BDNF Val66Met polymorphism neither attenuates nor magnifies the effect of physical activity on depressive symptoms.

Haptoglobin genotype and functional outcome after aneurysmal subarachnoid hemorrhage.

OBJECT: Haptoglobin allele heterogeneity has been implicated in differential reactive oxidant inhibition and inflammation. Haptoglobin α2-α2 has a lower affinity for binding hemoglobin, and when bound to hemoglobin, is cleared less easily by the body. The authors hypothesized that haptoglobin α2-α2 genotype should be less protective for downstream injury after aneurysmal subarachnoid hemorrhage (aSAH) and should portend a worse outcome. METHODS: Patients with Fisher Grade 2 or higher aSAH were enrolled in the study. Genotyping for haptoglobin genotype was performed from blood and/or CSF. Demographic information, medical condition variables, and hospital course were abstracted from the medical record upon enrollment into the study. Outcome data (modified Rankin Scale score, Glasgow Outcome Scale score, and mortality) were collected at 3 months posthemorrhage. RESULTS: The authors enrolled 193 patients who ranged in age from 18 to 75 years. Only Caucasians were used in this analysis to minimize bias from variable haptoglobin allele frequencies in populations of different ancestral backgrounds. The sample had more women than men (overall mean age 54.45 years). Haptoglobin α2 homozygotes were older than the other individuals in the study sample (57.27 vs 53.2 years, respectively; p = 0.02) and were more likely to have Fisher Grade 3 SAH (p = 0.02). Haptoglobin α2-α2 genotype, along with Fisher grade and Hunt and Hess grade, was associated with a worse 3-month outcome compared to those with the haptoglobin α1-α1 genotype according to modified Rankin Scale score after controlling for covariates (OR 4.138, p = 0.0463). CONCLUSIONS: Patients with aSAH who carry the haptoglobin α2-α2 genotype had a worse outcome. Interestingly, the presence of a single α-2 allele was associated with worse outcome, suggesting that the haptoglobin α-2 protein may play a role in the pathology of brain injury following aSAH, although the mechanism for this finding requires further research. The haptoglobin genotype may provide additional information on individual risk of secondary injury and recovery to guide care focused on improving outcomes.