Biomedical subjects

Jennie Z Ma

Publications and source records attributed to Jennie Z Ma.

At least 19 recordsLinked to original sources

PubMed2005

Reductions in and relations between "craving" and drinking in a prospective, open-label trial of ondansetron in adolescents with alcohol dependence.

Recently, we reported that ondansetron (a 5-HT3 antagonist) as an adjunct to cognitive behavioral therapy (CBT) produced significant within-group decreases (improvement) in drinking in adolescents with alcohol dependence. We previously have hypothesized that the mechanism of ondansetron treatment response in adolescents with alcohol dependence should be similar to early onset adult alcoholics, wherein blockade of serotonin-3 receptors may decrease dopamine release and subsequent alcohol consumption and craving. We now suggest that one mechanism by which ondansetron diminishes drinking in adolescents with alcohol dependence is through a reduction in "craving" as measured by the Adolescent Obsessive-Compulsive Drinking Scale (A-OCDS). We conducted an 8-week, prospective, open-label study of ondansetron (4 microg/kg b.i.d.) in 12 adolescents (age 14-20 years) who had alcohol dependence. Results showed that "irresistibility" and total scores as measured by the A-OCDS were correlated significantly with drinking indices (drinks/day, percent days abstinent) at the end of treatment, and that "irresistibility" and total A-OCDS scores decreased significantly by the end of treatment. These preliminary results suggest that the A-OCDS can be useful as an outcome measure in clinical studies of adolescents with alcohol dependence.

Adolescent↗

PubMed2005

Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence.

DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.

Adult↗

PubMed2005

Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence.

We tested six single nucleotide polymorphisms (SNPs) in the alpha4 subunit gene (CHRNA4) and four SNPs in the beta2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505-rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR alpha4 subunit, but not of the nAChR beta2 subunit, in nicotine addiction.

Black People↗

PubMed2005

Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence.

Twelve single-nucleotide polymorphisms (SNPs) in the human gamma-aminobutyric acid type B (GABA(B)) receptor subunit 2 gene (GABAB2) were tested for association with nicotine dependence (ND) in an extensively phenotyped cohort of 1,276 smokers and nonsmokers, representing approximately 404 nuclear families of African American (AA) or European American (EA) origin. The GABAB2 gene encodes a subunit of the GABA(B) receptor for GABA, an inhibitory neurotransmitter involved in the regulation of many physiological and psychological processes in the brain. The gene is located within a region of chromosome 9q22 that showed a "suggestive" linkage to ND. Individual SNP analysis performed using the PBAT-GEE program indicated that two SNPs in the AAs and four SNPs in the EAs were significantly associated with ND. Haplotype analysis using the Family-Based Association Test revealed that, even after Bonferroni correction, the haplotype C-C-G of rs2491397-rs2184026-rs3750344 had a significant positive association with ND in both the pooled and the AA samples. In the EAs, we identified two haplotypes, C-A-C-A and T-A-T-A, formed by SNPs rs1435252-rs378042-rs2779562-rs3750344, that showed a highly significant negative and positive association with ND, respectively. In summary, our findings provide evidence of a significant association of GABAB2 variants with ND, implying that this gene plays an important role in the etiology of this drug addiction.

Adult↗

PubMed2005

Fine mapping functional sites or regions from case-control data using haplotypes of multiple linked SNPs.

Previously, we reported an algorithm for scanning a large number of tightly linked single nucleotide polymorphisms (SNPs) for LD mapping of functional sites or regions from a family-based association design. In the present study, we extend our method to a case-control design. We first use the expectation maximization (EM) algorithm to estimate haplotype frequencies of multiple linked SNPs, and follow this by constructing a contingency table statistic S for LD analysis, based on the estimated haplotype frequencies. An empirical p-value is obtained based on the null distribution of the maximum of S (S*) from a large number (e.g., 1,000 or more) of randomized permutations. The proposed algorithm has been implemented in a computer program in which window searching for functional SNP sites can cover any number of loci without limitation, except that of computer storage. Unlike other programs for a case-control design that always conduct tests at a fix window width, in our program after setting a maximum size of haplotype window width, for a given maximum window width all possible widths of haplotypes are utilized to find the maximum statistic S * for each locus under investigation. The sensitivity of the proposed algorithm has been examined with simulated and real genotyping datasets. Association analyses indicate that our program is powerful enough to detect most, if not all, functional SNPs simulated in the original model or identified in the original report. Moreover, the program is very flexible and can be used in either regional or genome-wide scanning for association analysis with SNP markers.

Algorithms↗

PubMed2004

Time-dependent changes in transcriptional profiles within five rat brain regions in response to nicotine treatment.

Many years of behavioral and neurobiology studies have demonstrated broad physiological and pharmacological effects of nicotine on the central nervous system (CNS). However, the gene expression profiles associated with these effects are largely unknown. In this study, we characterized gene expression profiles in the prefrontal cortex, striatum, hypothalamus, amygdala and ventral tegmental area of the rat brain in response to subacute and chronic systemic nicotine administration using a pathway-focused microarray developed in this laboratory that contains 638 sequence-verified genes representing broad, yet targeted, biological functions. By comparing the regional effects of nicotine treatment on gene expression levels, we derived the expression profiles of targeted genes and gene families responding to the new environment created by nicotine throughout the complex connections of the CNS. While the expression of many genes was modulated by nicotine in several regions, only a few were co-modulated in multiple brain regions, suggesting region-specific transcriptional responses. Cluster analysis of significantly altered genes within each brain region over the course of nicotine treatment indicated the genes could be grouped into clusters. Subsequent ANOVA analysis demonstrated these clusters within each brain region to be significantly different at most time points. The clusters were comprised of broad functional groups, such as signaling, neurotransmission and protein modifications, demonstrating unique expression patterns within each region. Using a systematic approach to compare the different regional responses to nicotine administration will eventually provide a better understanding of how the different brain regions responding to this drug.

Amygdala↗

PubMed2004

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain.

Previously, we used cDNA microarrays to demonstrate that the phosphatidylinositol and MAP kinase signaling pathways are regulated by nicotine in different rat brain regions. In the present report, we show that, after exposure to nicotine for 14 days, ubiquitin, ubiquitin-conjugating enzymes, 20S and 19S proteasomal subunits, and chaperonin-containing TCP-1 protein (CCT) complex members are upregulated in rat prefrontal cortex (PFC) while being downregulated in the medial basal hypothalamus (MBH). In particular, relative to saline controls, ubiquitins B and C were upregulated by 33% and 47% (P<0.01), respectively, in the PFC. The proteasome beta subunit 1 (PSMB1) and 26S ATPase 3 (PSMC3) genes were upregulated in the PFC by 95% and 119% (P<0.001), respectively. In addition to the protein degradation pathway of the ubiquitin-proteasome complexes, we observed in the PFC an increase in the expression of small, ubiquitin-related modifiers (SUMO) 1 and 2 by 80% and 33%, respectively (P<0.001), and in 3 of 6 CCT subunits by up to 150% (P<0.0001). To a lesser extent, a change in the opposite direction was obtained in the expression of the same gene families in the MBH. Quantitative real-time RT-PCR was used to validate the microarray results obtained with some representative genes involved in these pathways. Taken together, our results suggest that, in response to systemic nicotine administration, the ubiquitin-proteasome, SUMO, and chaperonin complexes provide an intricate control mechanism to maintain cellular homeostasis, possibly by regulating the composition and signaling of target neurons in a region-specific manner.

Animals↗

PubMed2004

A prospective, open-label trial of ondansetron in adolescents with alcohol dependence.

Ondansetron has been shown to be effective in the treatment of early-onset adult alcohol dependence. To date, no studies have been conducted in adolescents with alcohol dependence to assess the feasibility, safety, tolerability, and potential utility of ondansetron treatment. We conducted an 8-week, prospective, open-label study of ondansetron (4 microg/kg b.i.d.) in 12 adolescents who had alcohol dependence. Oral ondansetron was safe and well tolerated in our sample. Adverse events were mild and resolved quickly without intervention. No subjects discontinued due to adverse events. Intent-to-treat analyses showed a significant within-group decrease (improvement) for drinks/drinking day (t=-3.10, df=11, p=0.01), as well as decreases in drinks/day (t=-2.01, df=11, p=0.06) and percentage of days abstinent (t=1.45, df=11, p=0.18). These preliminary data suggest that ondansetron is safe and well tolerated in adolescents with alcohol dependence. Findings of decreased drinking underscore the need for future double-blind, placebo-controlled studies in this adolescent population.

Adolescent↗

PubMed2004

Long-term outcome of renal transplant recipients in the United States after coronary revascularization procedures.

BACKGROUND: Retrospective studies in dialysis patients have reported increased survival after coronary artery bypass (CAB) compared with coronary artery stenting and PTCA. The purpose of this study was to compare the long-term outcome of renal transplant recipients after stent, PTCA, or CAB with or without internal mammary grafting (CAB [IMG+] or CAB [IMG-]). METHODS AND RESULTS: Renal transplant recipients hospitalized from 1995 to 1999 for first coronary revascularization procedure were retrospectively identified from the United States Renal Data System database. Event-free survival for the end points of all-cause death, cardiac death, acute myocardial infarction (AMI), and the combined end point of cardiac death or AMI was estimated by the life-table method. The impact of independent predictors on survival was examined in a comorbidity-adjusted Cox model. In-hospital mortality rate was 2.3% for 909 stent patients, 4.3% for 652 PTCA patients, 9.4% for 288 CAB (IMG-) patients, and 5.0% for 812 CAB (IMG+) patients. Two-year all-cause survival (+/-SE) was: stent, 82.5+/-2.8%; PTCA, 81.6+/-3.1%; CAB (IMG-), 74.4+/-5.4%; and CAB (IMG+), 82.7+/-2.8%. The relative risks of all-cause and cardiac death were not significantly different among revascularization groups. The relative risk of cardiac death or AMI (versus PTCA) was 0.90 (95% CI, 0.69 to 1.17) for stent, 0.80 (95% CI, 0.55 to 1.17) for CAB (IMG-), and 0.57 (95% CI, 0.42 to 0.76) for CAB (IMG+). CONCLUSIONS: Renal transplant recipients in the United States have comparable long-term survival after percutaneous and surgical coronary revascularization procedures. The most favorable long-term outcome occurs after surgical coronary revascularization.

Adult↗

PubMed2004

Application of a customized pathway-focused microarray for gene expression profiling of cellular homeostasis upon exposure to nicotine in PC12 cells.

Maintenance of cellular homeostasis is integral to appropriate regulation of cellular signaling and cell growth and division. In this study, we report the development and quality assessment of a pathway-focused microarray comprising genes involved in cellular homeostasis. Since nicotine is known to have highly modulatory effects on the intracellular calcium homeostasis, we therefore tested the applicability of the homeostatic pathway-focused microarray on the gene expression in PC-12 cells treated with 1 mM nicotine for 48 h relative to the untreated control cells. We first provided a detailed description of the focused array with respect to its gene and pathway content and then assessed the array quality using a robust regression procedure that allows for the exclusion of unreliable measurements while decreasing the number of false positives. As a result, the mean correlation coefficient between duplicate measurements of the arrays used in this study (control vs. nicotine treatment, three samples each) has increased from 0.974+/-0.017 to 0.995+/-0.002. Furthermore, we found that nicotine affected various structural and signaling components of the AKT/PKB signaling pathway and protein synthesis and degradation processes in PC-12 cells. Since modulation of intracellular calcium concentrations ([Ca(2+)](i)) and phosphatidylinositol signaling are important in various biological processes such as neurotransmitter release and tissue pathogenesis including tumor formation, we expect that the homeostatic pathway-focused microarray potentially can be used for the identification of unique gene expression profiles in comparative studies of drugs of abuse and diverse environmental stimuli, such as starvation and oxidative stress.

Animals↗

PubMed2004

Oral topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial.

BACKGROUND: Topiramate, a fructopyranose derivative, was superior to placebo at improving the drinking outcomes of alcohol-dependent individuals. OBJECTIVES: To determine whether topiramate, compared with placebo, improves psychosocial functioning in alcohol-dependent individuals and to discover how this improvement is related to heavy drinking behavior. DESIGN: Double-blind, randomized, controlled, 12-week clinical trial comparing topiramate vs placebo for treating alcohol dependence (1998-2001). PARTICIPANTS: One hundred fifty alcohol-dependent individuals, diagnosed using the DSM-IV. INTERVENTIONS: Seventy-five participants received topiramate (escalating dose of 25 mg/d to 300 mg/d), and 75 had placebo and weekly standardized medication compliance management. MAIN OUTCOME MEASURES: Three elements of psychosocial functioning were measured: clinical ratings of overall well-being and alcohol-dependence severity, quality of life, and harmful drinking consequences. Overall well-being and dependence severity and quality of life were analyzed as binary responses with a generalized estimating equation approach; harmful drinking consequences were analyzed as a continuous response using a mixed-effects, repeated-measures model. RESULTS: Averaged over the course of double-blind treatment, topiramate, compared with placebo, improved the odds of overall well-being (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.16-2.60; P =.01); reported abstinence and not seeking alcohol (OR = 2.63; 95% CI, 1.52-4.53; P =.001); overall life satisfaction (OR = 2.28; 95% CI, 1.21-4.29; P =.01); and reduced harmful drinking consequences (OR = -0.07; 95% CI, -0.12 to -0.02, P =.01). There was a significant shift from higher to lower drinking quartiles on percentage of heavy drinking days, which was associated with improvements on all measures of psychosocial functioning. CONCLUSIONS: As an adjunct to medication compliance enhancement treatment, topiramate (up to 300 mg/d) was superior to placebo at not only improving drinking outcomes but increasing overall well-being and quality of life and lessening dependence severity and its harmful consequences.

Administration, Oral↗

PubMed2004

Long-term survival of dialysis patients with bacterial endocarditis in the United States.

BACKGROUND: The incidence of bacterial endocarditis is much greater in long-term dialysis patients compared with the general population, and chronic kidney disease has been postulated as an independent host-related risk factor. Limited data are available on the long-term survival of dialysis patients with endocarditis. METHODS: Dialysis patients hospitalized for bacterial endocarditis between 1977 and 2000 were studied retrospectively using data from the US Renal Data System database. Long-term survival was estimated by means of the life-table method. A Cox proportional hazards model was used to identify the impact of demographic characteristics and comorbidity on outcome. RESULTS: A total of 13,130 dialysis patients with bacterial endocarditis were identified. The in-hospital mortality rate for the entire cohort was 23.5%. Survival rates at 1, 2, 3, and 5 years were 45.9%, 33.3%, 24.3%, and 14.7% for patients hospitalized between 1977 and 1991 and 41.0%, 29.1%, 20.6%, and 10.9% for those hospitalized between 1992 and 1996, respectively. Survival rates at 1, 2, and 3 years were 38.4%, 25.3%, and 18.3% for patients hospitalized between 1997 and 2000, respectively. The most powerful independent predictors of all-cause death were age, diabetes as cause of end-stage renal disease, and cerebrovascular accident or transient ischemic attack as a comorbid condition. CONCLUSION: Dialysis patients with bacterial endocarditis have poor long-term survival, even in the current treatment era, with survival rates changing little in the past 2 decades. Additional studies are needed to identify risk-reduction measures and develop additional treatment strategies for dialysis patients with endocarditis.

Aged↗

PubMed2004

Normalization of cDNA microarray data using wavelet regressions.

Normalization is an essential step in microarray data mining and analysis. For cDNA microarray data, the primary purpose of normalization is removing the intensity-dependent bias across different slides within an experimental group or between multiple groups. The locally weighted regression (lowess) procedure has been widely used for this purpose but can be comparatively time consuming when the dataset becomes relatively large. In this study, we applied wavelet regressions, a new smoothing method for recovering a regression function from data that is supposed to outperform other methods in many cases, such as spline or local polynomial fitting, to normalize two cDNA microarray datasets. Relative to the lowess procedure, we found that wavelet regressions not only produced reliable normalization results but also ran much faster. The computing speed represents one of the most important advantages over other algorithms, especially when one is interested in analyzing a large microarray experiment involving hundreds of slides.

Algorithms↗

PubMed2003

A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population.

BACKGROUND: Although many years of genetic epidemiological studies have demonstrated that genetics plays a significant role in determining smoking behavior, little information is available on genomic loci or genes affecting nicotine dependence. Several susceptibility chromosomal regions for nicotine dependence have been reported, but few have received independent confirmation. To identify susceptibility loci for nicotine dependence, 313 extended pedigrees selected from the Framingham Heart Study population were analyzed by both the GENEHUNTER and S.A.G.E. programs. RESULTS: After performing linkage analyses on the 313 extended Framingham Heart Study families, the EM Haseman-Elston method implemented in GENEHUNTER provided evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 9, 14, and 17. Multipoint sib-pair regression analysis using the SIBPAL program of S.A.G.E. on 1389 sib pairs that were split from the 313 extended families identified suggestive linkage of smoking rate to chromosomes 4, 7, and 17. Of these identified positive regions for nicotine dependence, loci on chromosomes 7, 11, and 17 were identified by both GENEHUNTER and S.A.G.E. programs. CONCLUSION: Our genome-wide scan results on the Framingham Heart Study data provide evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 4, 7, 9, 14, and 17. These findings suggest that some of these regions may harbor susceptibility loci for nicotine dependence, and warrant further investigation in this and other populations.

Adult↗

PubMed2003

Mapping susceptibility loci for alcohol consumption using number of grams of alcohol consumed per day as a phenotype measure.

BACKGROUND: There is substantial evidence for a significant genetic component to the risk for alcoholism. However, susceptibility loci or genes for alcohol dependence remain largely unknown. To identify susceptibility loci for alcohol dependence, we selected 329 extended families from the Framingham Heart Study population in which at least one family member reported alcohol consumption during the interview in 1970-1971, and performed genome-wide linkage analyses using various analytical methods. RESULTS: Multi-point sib-pair regression analysis using the SIBPAL program of S.A.G.E. provided strong evidence for linkage of alcohol dependence to chromosomes 9 (p-value < 0.0001) and weak evidence to chromosomes 15 and 16 (p-value < 0.005). To confirm these findings, we re-analyzed the same data set by various methods implemented in GENEHUNTER and found that only one region was significant with a LOD score > 2.0 by the variance-component method. This region is located on chromosome 9 between markers GATA21F05 and GATA81C04. CONCLUSION: Analyses of the Framingham Heart Study population provided evidence of genetic susceptibility loci for alcohol dependence on chromosomes 9, 15, and 16. The genomic region identified on chromosome 9 was particularly interesting because the region has also been previously reported to be linked to alcohol dependence in the American Indian population by another group.

Adult↗

PubMed2003

Oral topiramate for treatment of alcohol dependence: a randomised controlled trial.

BACKGROUND: Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence. METHODS: We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving. FINDINGS: At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them. INTERPRETATION: Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.

Administration, Oral↗

PubMed2003

A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins.

BACKGROUND: Numerous twin studies on smoking behavior have shown that genetic and environmental factors play significant and approximately equal roles in the determination of smoking initiation (SI) and smoking persistence (SP). However, estimates of heritability (h2), shared (c2) and unique environmental effects (e2) from the literature display considerable variability for SI and SP, due most probably to differences in statistical analysis models, age, gender, sample size, origin of cohorts and measurement of smoking behavior. METHODS: A systematic literature search identified six studies for SI and 10 studies for SP. Data from these studies were obtained and re-analysed by meta-analytical techniques. RESULTS: For SI, our results indicate that the parameters h2, c2 and e2 are (mean +/- SEM): 0.37 +/- 0.04, 0.49 +/- 0.04 and 0.17 +/- 0.03 in male adults, and 0.55 +/- 0.04, 0.24 +/- 0.06 and 0.16 +/- 0.01 in female adults, respectively. These values were weighted by a combination of original estimates of variance from studies reporting variances plus estimated variances from studies where variances were not reported (called the combined variance method). Using the same approach for SP, we found that the parameters h2, c2 and e2 weighted by the combined variance method for the phenotype are (mean +/- SEM): 0.59 +/- 0.02, 0.08 +/- 0.04 and 0.37 +/- 0.03 in male adults, and 0.46 +/- 0.12, 0.28 +/- 0.08 and 0.24 +/- 0.07 in female adults, respectively. CONCLUSIONS: Our results indicate that genetic factors play a more significant role for SI but a less significant role for SP in female adults compared to male adults. Significant gender difference was also detected in shared environmental factors for SI and SP. However, no significant gender difference was detected for e2 for either phenotype. These findings suggest that genetic and environmental factors may contribute differently to the determination of smoking initiation and persistence in male and female smokers.

Adult↗

PubMed2003

Nonparametric disequilibrium mapping of functional sites using haplotypes of multiple tightly linked single-nucleotide polymorphism markers.

As the speed and efficiency of genotyping single-nucleotide polymorphisms (SNPs) increase, using the SNP map, it becomes possible to evaluate the extent to which a common haplotype contributes to the risk of disease. In this study we propose a new procedure for mapping functional sites or regions of a candidate gene of interest using multiple linked SNPs. Based on a case-parent trio family design, we use expectation-maximization (EM) algorithm-derived haplotype frequency estimates of multiple tightly linked SNPs from both unambiguous and ambiguous families to construct a contingency statistic S for linkage disequilibrium (LD) analysis. In the procedure, a moving-window scan for functional SNP sites or regions can cover an unlimited number of loci except for the limitation of computer storage. Within a window, all possible widths of haplotypes are utilized to find the maximum statistic S* for each site (or locus). Furthermore, this method can be applied to regional or genome-wide scanning for determining linkage disequilibrium using SNPs. The sensitivity of the proposed procedure was examined on the simulated data set from the Genetic Analysis Workshop (GAW) 12. Compared with the conventional and generalized TDT methods, our procedure is more flexible and powerful.

Algorithms↗