The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States.

BACKGROUND: Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States. OBJECTIVE: We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations. METHODS: Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses. RESULTS: We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability. CONCLUSION: These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

Gender difference in interactions between MAOA promoter uVNTR polymorphism and negative familial stressors on body mass index among Chinese adolescents.

OBJECTIVES: Monoamine oxidase A (MAOA) modulates metabolism of serotonin and dopamine metabolism, neurotransmitters involved in regulation of appetite and food intake. The gene coding for MAOA contains a 30-bp tandem repeat (uVNTR) polymorphism in its promoter region that has been previously identified to be associated with obesity with mixed findings in the literature. Our goals were to replicate the population effects of this functional polymorphism on obesity risk, and to further explore gender differences and interaction effects with negative stressors. METHODS: Analyses were conducted with data on genotypes, measured weight and height, and self-reported behavioural characteristics among 1101 Chinese adolescents 11-15 years old living in Wuhan, China. RESULTS: Girls with the high-activity allele had significantly lower body mass index (BMI; ß = -0.25 ± 0.98, P = 0.011) compared to those with the low activity allele. Experience of negative familial stressors (e.g., death or illness of family members, hit or scolded by parents and increased quarrelling with parents, parents argued frequently) significantly weakened this protective genetic effect on BMI (P for interaction = 0.043). Stratified analyses showed a significant protective genetic effect on BMI only within the stratum of low stress level (ß = -0.44 ± 0.14, P = 0.002). No similar effect was observed among boys. CONCLUSIONS: Our findings confirm the genetic effects of MAOA uVNTR polymorphism on BMI in a Chinese adolescent population and suggest potential genetic interactions with negative familial stressors.

Integrative variable selection via Bayesian model uncertainty.

We are interested in developing integrative approaches for variable selection problems that incorporate external knowledge on a set of predictors of interest. In particular, we have developed an integrative Bayesian model uncertainty (iBMU) method, which formally incorporates multiple sources of data via a second-stage probit model on the probability that any predictor is associated with the outcome of interest. Using simulations, we demonstrate that iBMU leads to an increase in power to detect true marginal associations over more commonly used variable selection techniques, such as least absolute shrinkage and selection operator and elastic net. In addition, iBMU leads to a more efficient model search algorithm over the basic BMU method even when the predictor-level covariates are only modestly informative. The increase in power and efficiency of our method becomes more substantial as the predictor-level covariates become more informative. Finally, we demonstrate the power and flexibility of iBMU for integrating both gene structure and functional biomarker information into a candidate gene study investigating over 50 genes in the brain reward system and their role with smoking cessation from the Pharmacogenetics of Nicotine Addiction and Treatment Consortium.

Biomarkers for smoking cessation.

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.

Varenicline for smoking cessation: nausea severity and variation in nicotinic receptor genes.

This study evaluated association between common and rare sequence variants in 10 nicotinic acetylcholine receptor subunit genes and the severity of nausea 21 days after initiating the standard, Food and Drug Administration-approved varenicline regimen for smoking cessation. A total of 397 participants from a randomized clinical effectiveness trial with complete clinical and DNA resequencing data were included in the analysis (mean age=49.2 years; 68.0% female). Evidence for significant association between common sequence variants in CHRNB2 and nausea severity was obtained after adjusting for age, gender and correlated tests (all P(ACT)<0.05). Individuals with the minor allele of CHRNB2 variants experienced less nausea than did those without the minor allele, consistent with previously reported findings for CHRNB2 and the occurrence of nausea and dizziness as a consequence of first smoking attempt in adolescents, and with the known neurophysiology of nausea. As nausea is the most common reason for discontinuance of varenicline, further pharmacogenetic investigations are warranted.

Gender-stratified gene and gene-treatment interactions in smoking cessation.

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10(-4) to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r2 > 0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR) = 0.5; 95% confidence interval (CI): 0.3-0.6) at end of treatment (adjusted P < 6 × 10(-5)). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P = 3.9 × 10(-5)); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR = 0.04; 95% CI: 0.01-0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.

Urinary tract infections and reduced risk of bladder cancer in Los Angeles.

We investigated the association between urinary tract infections (UTIs) and transitional cell carcinoma of the bladder in a population-based case-control study in Los Angeles covering 1586 cases and age-, gender-, and race-matched neighbourhood controls. A history of bladder infection was associated with a reduced risk of bladder cancer among women (odds ratio (OR), 0.66; 95% confidence interval (CI), 0.46-0.96). No effect was found in men, perhaps due to power limitations. A greater reduction in bladder cancer risk was observed among women with multiple infections (OR, 0.37; 95% CI, 0.18-0.78). Exclusion of subjects with a history of diabetes, kidney or bladder stones did not change the inverse association. A history of kidney infections was not associated with bladder cancer risk, but there was a weak association between a history of other UTIs and slightly increased risk among men. Our results suggest that a history of bladder infection is associated with a reduced risk of bladder cancer among women. Cytotoxicity from antibiotics commonly used to treat bladder infections is proposed as one possible explanation.

Impact of preadjusting a quantitative phenotype prior to sib-pair linkage analysis when gene x environment interaction exists.

The investigation of potential gene x environment (G x E) interactions is an important facet in the study of complex diseases. When G x E interaction exists, linkage analyses of the interacting gene must treat the environmental factor appropriately. Specifically, the common approach of regressing out an environmental factor prior to linkage analysis may be inappropriate if that factor has an interaction with the gene. This is explored here in the Genetic Analysis Workshop 12 simulated data set using the G x E interaction between major gene four (MG4) and environmental factor two (E2). The analysis shows that preadjusting the quantitative trait three (Q3) phenotype for the main effects of several environmental variables, including one (E2) that interacts with MG4, affects the results of a Haseman-Elston linkage analysis. In particular, the agreement in detecting linkage between preadjusting versus not preadjusting was only 78% and 66% using alpha levels of 0.05 and 0.10, respectively. For both approaches, incorporating an interaction term in the regression models enabled linkage to be detected where the evidence was either minimal or not present in an identical-by-descent main effects-only model. Furthermore, preadjustment for E2 did not appear to account for the major discrepancies between the approaches.

Replication linkage study for prostate cancer susceptibility genes.

BACKGROUND: Since the publication of the first genome screen for prostate cancer (CaP) 5 years ago, over a dozen linkage studies have appeared. Most attention has been directed to chromosome 1, where two separate regions have been identified as harboring a prostate cancer susceptibility locus: HPC1 in the 1q24-25 interval and PCaP in the 1q42.2-43 interval. Linkage analysis of chromosome 16 has also provided evidence of harboring two loci predisposing to CaP. METHODS: We report on a replication linkage study of chromosomes 1 and 16 in 45 new and 4 expanded multiplex CaP families. Multipoint Z-scores were obtained for 30 highly polymorphic short-sequence tandem repeat markers spanning chromosome 1, and 22 markers spanning chromosome 16. RESULTS: The replication sample gave no evidence for a CaP susceptibility locus in the 1q24-25 interval and equivocal evidence for such a locus at 1q42.2-43. With respect to chromosome 16, positive Z-scores were obtained over a contiguous interval covering the entire p arm and the proximal half of the q arm. CONCLUSIONS: The linkage analysis of our replication sample does not support the existence of HPC1, and the evidence for the existence of PCaP remains equivocal. Evidence of a susceptibility locus on 16p remains strong, but the evidence for a susceptibility locus on 16q is weakened.

Genomewide scan for prostate cancer-aggressiveness loci.

The aggressiveness of prostate cancer (PCa) varies widely: some tumors progress to invasive, potentially life-threatening disease, whereas others stay latent for the remainder of an individual's lifetime. The mechanisms resulting in this variability are not yet understood, but they are likely to involve both genetic and environmental influences. To investigate genetic factors, we conducted a genomewide linkage analysis of 513 brothers with PCa, using the Gleason score, which reflects tumor histology, as a quantitative measure of PCa aggressiveness. To our knowledge, this is the first time that a measure of PCa aggressiveness has been directly investigated as a quantitative trait in a genomewide scan. We employed a generalized multipoint Haseman-Elston linkage-analysis approach that regresses the mean-corrected cross product between the brothers' Gleason scores on the estimated proportion of alleles shared by brothers identical by descent at each marker location. Our results suggest that candidate regions on chromosomes 5q, 7q, and 19q give evidence for linkage to PCa-aggressiveness genes. In particular, the strongest signals detected in these regions were at the following markers (with corresponding P values): for chromosome 5q31-33, between markers D5S1480 and D5S820 (P=.0002); for chromosome 7q32, between markers D7S3061 and D7S1804 (P=.0007); and, for chromosome 19q12, at D19S433 (P=.0004). This indicates that one or more of these candidate regions may contain genes that influence the progression of PCa from latent to invasive disease. Identification of such genes would be extremely valuable for elucidation of the mechanism underlying PCa progression and for determination of treatment in men in whom this disease has been diagnosed.