A multivariate finite mixture latent trajectory model with application to dementia studies

Dementia patients exhibit considerable heterogeneity in individual trajectories of cognitive decline, with some patients showing rapid decline following diagnoses while others exhibiting slower decline or remaining stable for several years. Dementia studies often collect longitudinal measures of multiple neuropsychological tests aimed to measure patients’ decline across a number of cognitive domains. We propose a multivariate finite mixture latent trajectory model to identify distinct longitudinal patterns of cognitive decline simultaneously in multiple cognitive domains, each of which is measured by multiple neuropsychological tests. EM algorithm is used for parameter estimation and posterior probabilities are used to predict latent class membership. We present results of a simulation study demonstrating adequate performance of our proposed approach and apply our model to the Uniform Data Set from the National Alzheimer's Coordinating Center to identify cognitive decline patterns among dementia patients

Steroid Pathway Genes and Neonatal Respiratory Distress After Betamethasone Use in Anticipated Preterm Birth

Objective: To test several key glucocorticoid genes that are enhanced in lung development for associations with respiratory distress syndrome (RDS) after antenatal corticosteroid use. Methods: A prospective cohort of women received betamethasone to accelerate fetal lung maturity for threatened preterm delivery. DNA was obtained from mothers and newborns. Neonatal RDS was the primary outcome. Genotyping for single-nucleotide polymorphisms (SNPs) in 68 glucocorticoid genes found to be differentially expressed during lung development was performed. Multivariable analysis tested for associations of SNPs in the candidate genes with RDS. Results: Genotypic results for 867 SNPs in 96 mothers and 73 babies were included. Thirty-nine (53.4%) babies developed RDS. Maternal SNPs in the centromeric protein E (CENPE), GLRX, CD9, and AURKA genes provided evidence of association with RDS (P < .01). In newborns, SNPs in COL4A3, BHLHE40, and SRGN provided evidence of association with RDS (P < .01). Conclusion: Single-nucleotide polymorphisms in several glucocorticoid responsive genes suggest association with neonatal RDS after antenatal corticosteroid use

Multivariate finite mixture latent trajectory models with application to dementia studies

Indiana University-Purdue University Indianapolis (IUPUI)Dementia studies often collect multiple longitudinal neuropsychological measures in order to examine patients' decline across a number of cognitive domains. Dementia patients have shown considerable heterogeneities in individual trajectories of cognitive decline, with some patients showing rapid decline following diagnoses while others exhibiting slower decline or remain stable for several years. In the first part of this dissertation, a multivariate finite mixture latent trajectory model was proposed to identify longitudinal patterns of cognitive decline in multiple cognitive domains with multiple tests within each domain. The expectation-maximization (EM) algorithm was implemented for parameter estimation and posterior probabilities were estimated based on the model to predict latent class membership. Simulation studies demonstrated satisfactory performance of the proposed approach. In the second part, a simulation study was performed to compare the performance of information-based criteria on the selection of the number of latent classes. Commonly used model selection criteria including the Akaike information criterion (AIC), Bayesian information criterion (BIC), as well as consistent AIC (CAIC), sample adjusted BIC (SABIC) and the integrated classification likelihood criteria (ICLBIC) were included in the comparison. SABIC performed uniformly better in all simulation scenarios and hence was the preferred criterion for our proposed model. In the third part of the dissertation, the multivariate finite mixture latent trajectory model was extended to situations where the true latent class membership was known for a subset of patients. The proposed models were used to analyze data from the Uniform Data Set (UDS) collected from Alzheimer's Disease Centers across the country to identify various cognitive decline patterns among patients with dementia

Genome-wide association study of serum iron phenotypes in premenopausal women of European descent

A genome-wide association study was performed in 1,130 premenopausal women to detect common variants associated with three serum iron-related phenotypes. Total iron binding capacity was strongly associated (p=10−14) with variants in and near the TF gene (transferrin), the serum iron transporting protein, and with variants in HFE (p= 4×10−7), which encodes the human hemochromatosis gene. Association was also detected between percent iron saturation (p=10−8) and variants in the chromosome 6 region containing both HFE and SLC17A2, which encodes a phosphate transport protein. No significant associations were detected with serum iron, but variants in HFE were suggestive (p=10−6). Our results corroborate prior studies in older subjects and demonstrate that the association of these genetic variants with iron phenotypes can be detected in premenopausal women

Genome-wide association studies of the self-rating of effects of ethanol (SRE).

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders

Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats

BACKGROUND: Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats. METHODS: Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats. DNA sequence analysis was then performed to screen for polymorphism in Crhr2 in order to identify genetic variation, and luciferase reporter assays were then applied to test their functional significance. Next, binding assays were used to determine whether this polymorphism affected CRF2 receptor binding affinity as well as CRF2 receptor density in the CNS. Finally, social interaction and corticosterone levels were measured in the P and NP rats before and after 30-minute restraint stress. RESULTS: Crhr2 mRNA expression studies found lower levels of Crhr2 mRNA in iP rats compared to iNP rats. In addition, DNA sequencing identified polymorphisms in the promoter region, coding region, and 3'-untranslated region between the iP and iNP rats. A 7 bp insertion in the Crhr2 promoter of iP rats altered expression in vitro as measured by reporter assays, and we found that CRF2 receptor density was lower in the amygdala of iP as compared to iNP rats. Male P rats displayed decreased social interaction and significantly higher corticosterone levels directly following 30-minute restraint when compared to male NP rats. CONCLUSIONS: This study identified Crhr2 as a candidate gene of interest underlying the chromosome 4 QTL for alcohol consumption that was previously identified in the P and NP model. Crhr2 promoter polymorphism is associated with reduced mRNA expression in certain brain regions, particularly the amygdala, and lowered the density of CRF2 receptor in the amygdala of iP compared to iNP rats. Together, these differences between the animals may contribute to the drinking disparity as well as the anxiety differences of the P and NP rats

Charcot-Marie-Tooth gene, SBF2, associated with taxaneinduced peripheral neuropathy in African Americans

PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. EXPERIMENTAL DESIGN: Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. RESULTS: Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. CONCLUSION: Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel

SIBLING Family Genes and Bone Mineral Density: Association and Allele-specific Expression in Humans

Osteoporosis is a common complex disorder with reduced bone mineral density (BMD) and increased susceptibility to fracture. Peak BMD is one of the primary determinants of osteoporotic fracture risk, and is under substantial genetic control. Extracellular matrix, a major component of bone, influences BMD by regulating mineral deposition and maintaining cellular activity. It contains several SIBLING family proteins, null mutations of which cause mineralization defects in humans. In this study, we tested 59 single-nucleotide polymorphisms (SNPs) located in the 5 SIBLING family genes (DSPP, DMP1, IBSP, MEPE and SPP1) for association with normal variation in peak BMD in healthy men and women. We measured femoral neck (FN) and lumbar spine (LS) areal BMD by dual energy x-ray absorptiometry (DXA) in 1,692 premenopausal European-American women, 512 premenopausal African-American women and 715 European-American men. SNPs were tested for association with FN and LS BMD in the 3 subsamples. In the European-American women, we observed association (p≤0.005) with LS-BMD for SNPs in DSPP, IBSP and MEPE, and for FN-BMD with SNPs in DMP1 and IBSP. Allele specific regulation of gene expression (ASE) is an important mechanism in which an allele giving rise to modest influence in transcript abundance might result in a predisposition to disease. To identify whether there was ASE of SIBLING family genes at these SNPs, we examined 52 human bone samples obtained from the femoral neck during surgical hip replacement (27 female, 25 male; 44 European-American and 8 African-American). We observed unidirectional ASE for the IBSP gene, with lower expression of the G allele compared to the A allele for SNP rs17013181. Our data suggest that SNPs within the SIBLING genes may contribute to normal variation of peak BMD. Further studies are necessary to identify the functional variants and to determine the mechanisms underlying the differences in ASE and how these differences relate to the pathophysiology of osteoporosis

Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103

Purpose: Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. Patients and Methods: This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Results: Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). Conclusion: AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population

Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer’s disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration