Predicting the risk of recurrent adenoma and incident colorectal cancer based on findings of the baseline colonoscopy.

OBJECTIVES: The decision tree underlying current practice guidelines for post polypectomy surveillance relies on risk stratification based on predictive attributes gleaned from adenomas removed on screening colonoscopy examination. Our primary aim was to estimate the magnitude of association between baseline adenoma attributes and the risk of adenoma recurrence and invasive colorectal adenocarcinoma (CRC). Our secondary aims were to estimate the adenoma detection rate (ADR) of surveillance compared with screening colonoscopies and describe time trends in preventive colonoscopy utilization. METHODS: We used prospective analyses of retrospectively collected clinical data from electronic health records. A cohort of primary care patients eligible for colorectal cancer screening was assembled encompassing 110,452 subjects, of which 3,300 had adenomas removed on screening examination. Of those patients who had a follow-up surveillance colonoscopy (defined as a patient with a documented adenoma on prior colonoscopy) recorded during the study period, 537 had a recurrent adenoma. RESULTS: Of those recurrent adenomas, 354 had a high-risk attributes. High-risk attributes were described at >3 adenomas, at least one adenoma >10 mm in size, high-grade dysplasia, or villous features. The risk of developing invasive CRC among post polypectomy patients was significantly higher if the baseline adenomas displayed any of the following attributes: more numerous than 3 (4.3-fold higher risk, 95% confidence interval (CI) low, high 1.4, 12.9), larger than 10 mm in size (5.2-fold higher risk, 95% CI low, high 1.8, 15.1), high-grade dysplasia (13.2-fold risk, 95% CI low, high 2.8, 62.1), or villous features (7.4-fold higher risk, 95% CI low, high 2.5, 21.5). These attributes combined added a net value of 22.8% to the probability of correctly predicting CRC. There was a threefold increase in surveillance utilization relative to screening from 2005 to 2011. The ADR of surveillance (34.1%) was 1.5-fold higher than that of screening (23.1%). CONCLUSIONS: These results emphasize the need to mitigate excessive risk by performing timely surveillance colonoscopies in patients with baseline adenomas displaying high-risk attributes as recommended in practice guidelines.

Determination of accuracy of polycythemia vera diagnoses and use of the JAK2V617F test in the diagnostic scheme.

In 2005, three independent research groups described the presence of a specific mutation in the JAK2 gene, JAK2V617F, in patients with a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). The percentage of patients with the mutation varied according to specific disease with >98 % of polycythemia vera (PV) patients having the mutation. In 2008, the World Health Organization issued new diagnostic criteria for PV including use of the JAK2V617F test as a major diagnostic criterion. The goal of the present study is to determine the accuracy of diagnosing PV in a community practice and reporting of PV to cancer registries, as well as assessing the integration of molecular testing into diagnostic paradigms. Using Geisinger Medical Center's electronic medical records (EMR), patients with a PV diagnosis being seen by a hematologist/oncologist during 2004-2009 were identified. Records were reviewed by a single hematologist/oncologist to determine accuracy of the treating physician's diagnosis and use of the molecular test for the JAK2V617F mutation. There was a diagnosis of PV from the treating physicians in 121 of the 204 evaluable patients (59 %) and another MPN in 21 (10 %). However, we confirmed a PV diagnosis in only 90 patients (44 %). Of the 90 confirmed PV patients, 64 were JAK2V617F-mutation positive while 24 were not tested. While JAK2V617F testing has made a major impact in facilitating the successful delineation of the type of polycythemia (PV versus secondary polycythemia) in patients evaluated in a large, community-based Hematology/Oncology practice, physician usage of other critical tests is inconsistent leading to errors in diagnosis. JAK2V617F mutation testing in combination with other diagnostic criteria may help reduce diagnostic errors.

Predicting PTSD using the New York Risk Score with genotype data: potential clinical and research opportunities.

BACKGROUND: We previously developed a post-traumatic stress disorder (PTSD) screening instrument, ie, the New York PTSD Risk Score (NYPRS), that was effective in predicting PTSD. In the present study, we assessed a version of this risk score that also included genetic information. METHODS: Utilizing diagnostic testing methods, we hierarchically examined different prediction variables identified in previous NYPRS research, including genetic risk-allele information, to assess lifetime and current PTSD status among a population of trauma-exposed adults. RESULTS: We found that, in predicting lifetime PTSD, the area under the receiver operating characteristic curve (AUC) for the Primary Care PTSD Screen alone was 0.865. When we added psychosocial predictors from the original NYPRS to the model, including depression, sleep disturbance, and a measure of health care access, the AUC increased to 0.902, which was a significant improvement (P = 0.0021). When genetic information was added in the form of a count of PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (coded 0-6), the AUC increased to 0.920, which was also a significant improvement (P = 0.0178). The results for current PTSD were similar. In the final model for current PTSD with the psychosocial risk factors included, genotype resulted in a prediction weight of 17 for each risk allele present, indicating that a person with six risk alleles or more would receive a PTSD risk score of 17 × 6 = 102, the highest risk score for any of the predictors studied. CONCLUSION: Genetic information added to the NYPRS helped improve the accuracy of prediction results for a screening instrument that already had high AUC test results. This improvement was achieved by increasing PTSD prediction specificity. Further research validation is advised.

Development of a multi-institutional cohort to facilitate cardiovascular disease biomarker validation using existing biorepository samples linked to electronic health records.

BACKGROUND: Emerging biomarkers for acute myocardial infarction (AMI) may enhance conventional risk-prediction algorithms if they are informative and associated with risk independently of established predictors. In this study, we constructed a cohort for testing emerging biomarkers for AMI in managed-care populations using existing biospecimen repositories linked to electronic health records (EHR). HYPOTHESIS: Electronic health record-based biorepositories collected by healthcare systems can be federated to provide large, methodologically sound testing sets for biomarker validation. METHODS: Subjects ages 40 to 80 years were selected from 2 existing population-based biospecimen repositories. Incident AMI status and covariates were ascertained from the EHR. An ad hoc model for AMI risk was parameterized and validated. Simulation was used to test incremental gains in performance due to the inclusion of biomarkers in this model. Gains in performance were assessed in terms of area under the receiver operating characteristic curve (ROC-AUC) and case reclassification. RESULTS: A total of 18 329 individuals (57% female) contributed 108 400 person-years of EHR follow-up. The crude AMI incidence was 10.8 and 5.0 per 1000 person-years among males and females, respectively. Compared with the model with risk factors alone, inclusion of a simulated biomarker yielded substantial gains in sensitivity without loss of specificity. Furthermore, a net ROC-AUC gain of 13.3% was observed, as well as correct reclassification of 9.8% of incident cases (79 of 806) that were otherwise not considered statin-indicated at baseline under the National Cholesterol Education Program Adult Treatment Panel III criteria. CONCLUSIONS: More research is needed to assess incremental contribution of emerging biomarkers for AMI prediction in managed-care populations.

Mental health outcomes at the Jersey Shore after Hurricane Sandy.

On October 29, 2012, Hurricane Sandy made landfall in the most densely populated region in the US. In New Jersey, thousands of families were made homeless and entire communities were destroyed in the worst disaster in the history of the state. The economic impact of Sandy was huge, comparable to Hurricane Katrina. The areas that sustained the most damage were the small- to medium-sized beach communities along New Jersey's Atlantic coastline. Six months following the hurricane, we conducted a random telephone survey of 200 adults residing in 18 beach communities located in Monmouth County. We found that 14.5% (95% CI = 9.9-20.2) of these residents screened positive for PTSD and 6.0% (95% CI = 3.1-10.2) met criteria for major depression. Altogether 13.5% (95% CI = 9.1-19.0) received mental health counseling and 20.5% (95% CI = 15.1-26.8) sought some type of mental health support in person or online, rates similar to those reported in New York after the World Trade Center disaster In multivariate analyses, the best predictors of mental health status and service use were having high hurricane exposure levels, having physical health limitations, and having environmental health concerns. Research is needed to assess the mental health status and service use of Jersey Shore residents over time, to evaluate environmental health concerns, and to better understand the storm's impact among those with physical health limitations.

Grapheme-color synesthesia and posttraumatic stress disorder: preliminary results from the veterans health study.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with altered neuropsychological function, possibly including complex visual information processing. Grapheme-color synesthesia refers to the phenomenon that a particular letter or number elicits the visual perception of a specific color. The study objective was to assess if grapheme-color synesthesia was associated with PTSD among US veterans. METHOD: We surveyed 700 veterans who were outpatients in a multihospital system in Pennsylvania. All veterans had served at least one warzone deployment. PTSD and grapheme-color synesthesia were assessed using validated research instruments. RESULTS: The mean age of veterans was 59 years, and 96% were men. The prevalence of current PTSD was 7% (95% confidence interval [CI] = 5.1-8.8), and current partial PTSD was 11% (95% CI = 9.3-14.0). The prevalence of current depression was 6% (95% CI = 4.7-8.3). Altogether, 6% (95% CI = 4.8-8.5) of veterans screened positive for grapheme-color synesthesia. Bivariate analyses suggested that grapheme-color synesthesia was associated with current PTSD (odds ratio [OR] = 3.4, p = .004) and current partial PTSD (OR = 2.4, p = .013), but not current depression (OR = 1.1, p = .91). Multivariate logistic regression results, adjusting for age, sex, marital status, level of education, current psychotropic medication use, and concussion history, confirmed these results. CONCLUSIONS: Grapheme-color synesthesia seems to be associated with PTSD among veterans who had been deployed. This finding may have implications for PTSD diagnostic screening and treatment. Research is recommended to confirm this finding and to determine if synesthesia is a risk indicator for PTSD among nonveterans.

Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment.

OBJECTIVE: The study aim was to assess the cumulative burden of polymorphisms located within four genetic loci previously associated with posttraumatic stress disorder (PTSD) among outpatients at risk for PTSD. METHODS: Diagnostic interviews were completed and DNA samples collected among 412 pain patients to determine if FKBP5 (rs9470080), COMT (rs4680), CHRNA5 (rs16969968), and CRHR1 (rs110402) single nucleotide polymorphisms were cumulatively associated with increased risk for PTSD. RESULTS: In bivariate analyses, it was found that a count of specific PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (allele range = 0-6, mean count = 2.92, standard deviation = 1.36) was associated with lifetime (t [409] = 3.430, P = 0.001) and early onset PTSD (t [409] = 4.239, P = 0.000028). In logistic regression, controlling for demographic factors, personality traits, and trauma exposures, this risk allele count remained associated with both lifetime (odds ratio = 1.49, P = 0.00158) and early onset PTSD (odds ratio = 2.36, P = 0.000093). Interaction effects were also detected, whereby individuals with higher risk allele counts and higher trauma exposures had an increased risk of lifetime PTSD (allele count × high trauma, P = 0.026) and early onset PTSD (allele count × high trauma, P = 0.016) in these logistic regressions. Those with no or few risk alleles appeared resilient to PTSD, regardless of exposure history. CONCLUSION: A cumulative risk allele count involving four single nucleotide polymorphisms located within the FKBP5, COMT, CHRNA5, and CRHR1 genes are associated with PTSD. Level of trauma exposure interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment.

Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease.

Previous studies have shown association of single nucleotide polymorphisms (SNPs) in 3 contiguous genes (PON1, PON2, and PON3) encoding paraoxonase with risk of Alzheimer disease (AD). We evaluated the association of serum paraoxonase activity measured by phenyl acetate (PA) and thiobutyl butyrolactone (TBBL) with risk of AD and with 26 SNPs spanning the PON gene cluster in 266 AD cases and 306 sibling controls from the MIRAGE study. The odds of AD (adjusted for age, gender, and ethnicity) increased 20% for each standard deviation decrease in PA or TBBL activity. There were association signals with activity in all 3 genes. Haplotypes including SNPs spanning the PON genes were generally more significant than haplotypes comprising SNPs from 1 gene. Significant interactions were observed between SNP pairs located across the PON cluster with either serum activity measure as the outcome, and between several PON SNPs and PA activity with AD status as the outcome. Our results suggest that low serum paraoxonase activity is a risk factor for AD. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic.

Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria.

The authors estimated the prevalence of lifetime prescription opioid-use disorder among outpatients on opioid therapy using criteria from both versions 4 and 5 of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Using electronic records from a large health care system, a random sample of outpatients undergoing long-term opioid therapy for non-cancer pain was identified and 705 participants completed diagnostic interviews. The prevalence of lifetime DSM-5 opioid-use disorder among these patients was 34.9% (95% confidence interval [CI] = 30.5?39.5), similar to the prevalence of DSM-4 opioid dependence (35.5%, 95% CI = 31.1?40.2). The Kappa value between DSM-5 and DSM-4 criteria was high (Kappa = 0.873, p < 0.0001). Logistic regressions suggested DSM-5 opioid-use disorder was associated with age younger than 65 (odds ratio [OR] = 2.25, p = 0.009), history of opioid abuse (OR = 4.94, p < 0.001), higher opioid withdrawal symptoms (OR = 3.01, p = 0.008), and history of substance abuse treatment (OR = 1.62, p = 0.015), similar to DSM-4. Based on DSM-5, 21.7% of patients met criteria for moderate and 13.2% for severe opioid-use disorder, respectively. Given the changes proposed, the finding that the prevalence of and risk factors for DSM-5 opioid-use disorders were similar to DSM-4 were unexpected. Further research is advised.

Nicotinic acetylcholine receptor genes on chromosome 15q25.1 are associated with nicotine and opioid dependence severity.

A locus on chromosome 15q25.1 previously implicated in nicotine, alcohol, and cocaine dependence, smoking, and lung cancer encodes subunits of the nicotinic acetylcholine receptor (nAChR) expressed in the mesolimbic system and thought to mediate substance dependence. Opioid dependence severity (ODS), nicotine dependence severity (NDS), smoking status and quantity, and the number of attempts to quit were assessed using questionnaire instruments in 505 subjects who were prescribed opioid medications for chronic pain in outpatient practice sites. Multivariate regression was used to test for genetic association of these phenotypes with 5 SNPs in the nAChR gene cluster on chromosome 15q25.1, adjusting for background variables. A coding variant in CHRNA5 (rs16969968[A]) was significantly associated with 1.4-unit higher ODS (p < 0.00017). A variant in the 3' untranslated region of CHRNA3 (rs660652[G]) was significantly associated with 1.7-fold higher odds of lifetime smoking (p < 0.0092), 1.1-unit higher NDS (p < 0.0007), 0.7 more pack-years of cigarette smoking (p < 0.0038), and 0.8 more lifetime attempts to quit (p < 0.0084). Our data suggest an association of DNA variants in the nAChR gene cluster on chromosome 15q25.1 with ODS, as well as NDS and related smoking phenotypes. While the association of this locus with NDS and smoking phenotypes is well known, the association with ODS, a dimension of opioid substance dependence, is novel and requires verification in independent studies.

Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system.

AIMS: Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health-care system. METHODS: Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non-cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. RESULTS: Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0-29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). CONCLUSION: Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts.

A multidisciplinary investigation of a polycythemia vera cancer cluster of unknown origin.

Cancer cluster investigations rarely receive significant public health resource allocations due to numerous inherent challenges and the limited success of past efforts. In 2008, a cluster of polycythemia vera, a rare blood cancer with unknown etiology, was identified in northeast Pennsylvania. A multidisciplinary group of federal and state agencies, academic institutions, and local healthcare providers subsequently developed a multifaceted research portfolio designed to better understand the cause of the cluster. This research agenda represents a unique and important opportunity to demonstrate that cancer cluster investigations can produce desirable public health and scientific outcomes when necessary resources are available.

Low serum cholesterol and external-cause mortality: potential implications for research and surveillance.

OBJECTIVE: Previous studies suggested that low total cholesterol was associated with external mortality, including deaths from suicide, homicide, and accidents. However, this reported association was potentially confounded, since cholesterol was also reported to be associated with alcohol abuse, anti-social personality disorder, and other risk factors for external mortality. METHOD: We examined external-cause mortality among a national sample of 4462 male, US veterans at baseline in 1985. Using Cox regressions to estimate survival time, we assessed the impact of low baseline total cholesterol < or =165 mg/dl, age, race, intelligence, BMI, alcohol abuse, anti-social personality disorder, depression, and other factors at follow-up. Study follow-up continued until December 31, 2000. A total of 55 external mortalities occurred during this approximately 16-year period. RESULTS: Multivariate Cox regressions predicting external-cause mortality suggested that three predictor variables were significant: low total cholesterol, morbid depression, and anti-social personality disorder, with hazard ratios (HRs) of 1.97 (p=0.046), 1.76 (p=0.043), and 2.22 (p=0.006), respectively. In addition, a significant interaction was detected for low cholesterol x morbid depression (p<0.005), whereby those with both at baseline were approximately 7 times more likely to die from external mortality (HR=6.5, 95% CI=3.07-13.76). CONCLUSION: Among a national random sample of community-based men, lower baseline cholesterol predicted external mortality and revealed an interaction with morbid depression. Patients presenting with low cholesterol and morbid depression in clinical practice may warrant clinical attention and surveillance.

Magnetic resonance imaging traits in siblings discordant for Alzheimer disease.

BACKGROUND: Magnetic resonance imaging (MRI) can aid clinical assessment of brain changes potentially correlated with Alzheimer disease (AD). MRI traits may improve our ability to identify genes associated with AD-outcomes. We evaluated semi-quantitative MRI measures as endophenotypes for genetic studies by assessing their association with AD in families from the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) Study. METHODS: Discordant siblings from multiple ethnicities were ascertained through a single affected proband. Semi-quantitative MRI measures were obtained for each individual. The association between continuous/ordinal MRI traits and AD were analyzed using generalized estimating equations. Medical history and Apolipoprotein E (APOE)epsilon4 status were evaluated as potential confounders. RESULTS: Comparisons of 214 affected and 234 unaffected subjects from 229 sibships revealed that general cerebral atrophy, white matter hyperintensities (WMH), and mediotemporal atrophy differed significantly between groups (each at P < .0001) and varied by ethnicity. Age at MRI and duration of AD confounded all associations between AD and MRI traits. Among unaffected sibs, the presence of at least one APOEepsilon4 allele and MRI infarction was associated with more WMH after adjusting for age at MRI. CONCLUSION: The strong association between MRI traits and AD suggests that MRI traits may be informative endophenotypes for basic and clinical studies of AD. In particular, WMH may be a marker of vascular disease that contributes to AD pathogenesis.

Heritability of magnetic resonance imaging (MRI) traits in Alzheimer disease cases and their siblings in the MIRAGE study.

Magnetic resonance imaging (MRI) traits can serve as more specific measures of degenerative or cerebrovascular brain injury than can be ascertained through personal history, risk factors, clinical signs, or symptoms. They are potentially useful intermediate phenotypes for genetic studies of Alzheimer disease (AD). Recent studies have estimated heritability of white matter hyperintensity (WMH) among cognitively normal family members to be between 0.55 and 0.73. Persons discordant for AD are expected to have substantially different MRI phenotype distributions; our goal was to determine whether MRI traits in siblings discordant for AD are heritable. We measured cerebral atrophy, medial temporal atrophy (MTA), WMH, and a rating of cerebrovascular disease (CVR) via MRI in 815 participants from 424 families of the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. Residual heritability after adjustment for covariates ranged from 0.17 (P=0.009) for MTA to 0.57 (P=10(-7)) for CVR. The number of APOE-epsilon4 alleles was significantly associated with WMH (P=0.01) and CVR (P=0.005) but not cerebral atrophy (P=0.25) or MTA (P=0.83). Heritability remained significant and high after adjusting for APOE genotype, suggesting that a substantial proportion of the additive genetic variation in these MRI traits is explained by other genes. In the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study of AD-discordant siblings, MRI traits are heritable and are potential endophenotypes for genetic association studies.

Polymorphisms in the PON gene cluster are associated with Alzheimer disease.

Paraoxonase is an arylesterase enzyme that is expressed in the liver and found in the circulation in association with apoA1 and the high-density lipoprotein, and prevents the accumulation of oxidized lipids in low-density lipoproteins in vitro. Common polymorphisms in genes encoding paraoxonase are established risk factors in a variety of vascular disorders including coronary artery disease and carotid artery stenosis, but their association with Alzheimer disease (AD) is controversial. We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD. Eight SNPs were associated with AD in the African American families (0.0001< or =P< or =0.04) and two SNPs were associated with AD in Caucasian families (0.01< or =P< or =0.04). Of note, the pattern of association for the PON1 promoter SNP -161[C/T] was the same in both ethnic groups (P=0.006). Haplotype analysis using sliding windows revealed 11 contiguous SNP combinations spanning the three PON genes with significant global test scores (0.006< or =P< or =0.04) in the two ethnic groups combined. The most significantly associated haplotype comprised SNPs in the region spanning the -161[C/T] SNP (P=0.00009). Our results demonstrate association between AD and variants in the PON gene cluster in Caucasians and African Americans.

Genetic variants of WNK4 in whites and African Americans with hypertension.

Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single-nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P=0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P=0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P=0.027) or without (P=0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.

Genome-wide screen for heavy alcohol consumption.

BACKGROUND: To find specific genes predisposing to heavy alcohol consumption (self-reported consumption of 24 grams or more of alcohol per day among men and 12 grams or more among women), we studied 330 families collected by the Framingham Heart Study made available to participants in the Genetic Analysis Workshop 13 (GAW13). RESULTS: Parametric and nonparametric methods of linkage analysis were used. No significant evidence of linkage was found; however, weak signals were identified in several chromosomal regions, including 1p22, 4q12, 4q25, and 11q24, which are in the vicinity of those reported in other similar studies. CONCLUSION: Our study did not reveal significant evidence of linkage to heavy alcohol use; however, we found weak confirmation of studies carried out in other populations.