Survey of American College of Surgeons Committee on trauma members on firearm injury: Consensus and opportunities.

BACKGROUND: In the United States, there is a perceived divide regarding the benefits and risks of firearm ownership. The American College of Surgeons Committee on Trauma Injury Prevention and Control Committee designed a survey to evaluate Committee on Trauma (COT) member attitudes about firearm ownership, freedom, responsibility, physician-patient freedom and policy, with the objective of using survey results to inform firearm injury prevention policy development. METHODS: A 32-question survey was sent to 254 current U.S. COT members by email using Qualtrics. SPSS was used for χ exact tests and nonparametric tests, with statistical significance being less than 0.05. RESULTS: Our response rate was 93%, 43% of COT members have firearm(s) in their home, 88% believe that the American College of Surgeons should give the highest or a high priority to reducing firearm-related injuries, 86% believe health care professionals should be allowed to counsel patients on firearms safety, 94% support federal funding for firearms injury prevention research. The COT participants were asked to provide their opinion on the American College of Surgeons initiating advocacy efforts and there was 90% or greater agreement on 7 of 15 and 80% or greater on 10 of 15 initiatives. CONCLUSION: The COT surgeons agree on: (1) the importance of formally addressing firearm injury prevention, (2) allowing federal funds to support research on firearms injury prevention, (3) retaining the ability of health care professionals to counsel patients on firearms-related injury prevention, and (4) the majority of policy initiatives targeted to reduce interpersonal violence and firearm injury. It is incumbent on trauma and injury prevention organizations to leverage these consensus-based results to initiate prevention, advocacy, and other efforts to decrease firearms injury and death. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level I; therapeutic care, level II.

A Retrospective Cross-sectional Analysis of Health Education Disparities in Patients With Diabetes Using Data From the National Ambulatory Medical Care Survey.

Purpose The purpose of this study was to determine if there was an association between receipt of diet/nutrition, exercise, and weight loss education in adult patients with a primary diagnosis of diabetes with various demographic and socioeconomic variables using data from the National Ambulatory Medical Care Survey (NAMCS) for the years 2008 to 2011. Methods This retrospective, cross-sectional, observational study design included patients ≥ 18 years of age with diabetes in the NAMCS between 2008 and 2011, inclusive. A series of weighted multivariable logistic regression models was constructed to evaluate predictors of diet/nutrition, exercise, and weight loss education. Odds ratios and 95% confidence intervals were reported. Results Among patients included in this study (n = 3027), 35.6% received diet/nutrition education, 21.8% received exercise education, and 13.6% received weight loss education. From the multivariable analyses, visits using "other" payment type, visits with Medicaid, and visits occurring in non-Metropolitan Statistical Areas were significantly less likely to receive diet/nutrition education; visits using other payment type, visits in non-Metropolitan Statistical Areas, and visits by those ≥ 65 and 45-64 years of age were significantly less likely to receive exercise education. No significant disparities in the receipt of weight loss education were found. Conclusion These findings indicate that although only approximately one third or fewer patients diagnosed with diabetes were receiving diet/nutrition, exercise, or weight loss education, there appeared to be limited disparities among the groups studied. Education rates appear to be trending upward over time, to be slightly improved as compared with previous studies, and to include fewer disparities.

Utilization of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in patients diagnosed with diabetes: Analysis from the National Ambulatory Medical Care Survey.

OBJECTIVE: The objective of this study was to determine if a difference exists in the proportion of visits for the prescribing of angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARBs) in diabetic patients during 2007-2010. METHODS: This retrospective, cross-sectional, observational study included adults diagnosed with diabetes mellitus from the National Ambulatory Medical Care Survey (NAMCS) during 2007-2010. Weighted chi-square tests and a multivariable logistic regression model were used to analyze associations between ACEI/ARB prescriptions and predictors of interest. Odds ratios and 95% confidence intervals were reported. RESULTS: An unweighted total of 13,590 outpatient ambulatory care visits were identified for adult patients with diabetes without contraindications to ACEIs or ARBs in the NAMCS for the years studied. No statistically significant increase in the proportion of visits with an ACEI/ARB prescription was identified for years 2007-2010 (28.1% in 2007 to 32.2% in 2010). Females (OR 0.78, 95% CI 0.69- 0.89), patients 18-39 years old (OR 0.56, 95% CI 0.43- 0.75), and Medicare users (OR 0.81, 95% CI 0.70- 0.94) were significantly less likely to receive an ACEI/ARB prescription. Patients with hypertension (OR 2.80, 95% CI 2.39-3.29), hyperlipidemia (OR 1.42, 95% CI 1.22-1.65), and ischemic heart disease (OR 1.36, 95% CI 1.10-1.70) were significantly more likely to receive an ACEI/ARB prescription. CONCLUSIONS: Despite extensive evidence showing the benefits of ACEI/ARB medications in diabetic patients, disparities of treatment remain evident.

Setting a National Agenda for Surgical Disparities Research: Recommendations From the National Institutes of Health and American College of Surgeons Summit.

Health care disparities (differential access, care, and outcomes owing to factors such as race/ethnicity) are widely established. Compared with other groups, African American individuals have an increased mortality risk across multiple surgical procedures. Gender, sexual orientation, age, and geographic disparities are also well documented. Further research is needed to mitigate these inequities. To do so, the American College of Surgeons and the National Institutes of Health-National Institute of Minority Health and Disparities convened a research summit to develop a national surgical disparities research agenda and funding priorities. Sixty leading researchers and clinicians gathered in May 2015 for a 2-day summit. First, literature on surgical disparities was presented within 5 themes: (1) clinician, (2) patient, (3) systemic/access, (4) clinical quality, and (5) postoperative care and rehabilitation-related factors. These themes were identified via an exhaustive preconference literature review and guided the summit and its interactive consensus-building exercises. After individual thematic presentations, attendees contributed research priorities for each theme. Suggestions were collated, refined, and prioritized during the latter half of the summit. Breakout sessions yielded 3 to 5 top research priorities by theme. Overall priorities, regardless of theme, included improving patient-clinician communication, fostering engagement and community outreach by using technology, improving care at facilities with a higher proportion of minority patients, evaluating the longer-term effect of acute intervention and rehabilitation support, and improving patient centeredness by identifying expectations for recovery. The National Institutes of Health and American College of Surgeons Summit on Surgical Disparities Research succeeded in identifying a comprehensive research agenda. Future research and funding priorities should prioritize patients' care perspectives, workforce diversification and training, and systematic evaluation of health technologies to reduce surgical disparities.

Frequency of asthma education in primary care in the years 2007-2010.

OBJECTIVE: Recent research suggests that health disparities persist among asthmatic patients and receipt of asthma education, though recent guidelines have highlighted the importance of receiving asthma education. The purpose of this study was to identify trends in the receipt of asthma education as well as to identify disparities in asthma education using the most recently available data in National Ambulatory Medical Care Survey, 2007-2010. METHODS: Weighted chi-square tests were conducted to identify associations between asthma education and variables of interest. A weighted multivariate logistic regression model was subsequently constructed to jointly assess the association of factors of interest on receipt of asthma education. Submission to the Campbell University Institutional Review Board resulted in expedited approval. RESULTS: The percentage of patients who receive asthma education remains quite low. After adjusting for all variables of interest: no statistically significant difference in receipt of asthma education between year groups (2007-2008, 2009-2010) was found (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.52-1.34); patients seen by pediatricians (vs. internal medicine physicians) and Hispanic or Latino patients (vs. non-Hispanic or Latino patients) were more likely to receive asthma education (OR 2.72, 95% CI 1.11-6.66 and OR 2.33, 95% CI 1.18-4.60, respectively); and patients not prescribed a controller medication were less likely to receive asthma education than those who were (OR 0.56, 95% CI 0.37-0.82). CONCLUSIONS: Combined with previously published results, it appears the provision of asthma education continues to be low, despite proven benefits. Additionally, some patient and physician characteristics may be associated with the delivery of asthma education.

Statin Prescribing Patterns: An Analysis of Data From Patients With Diabetes in the National Hospital Ambulatory Medical Care Survey Outpatient Department and National Ambulatory Medical Care Survey Databases, 2005-2010.

PURPOSE: In 2008, the American Diabetes Association (ADA) recommended that patients aged >40 years with diabetes and cardiovascular disease or with ≥1 cardiovascular disease risk factor be prescribed a statin. This study assessed statin prescribing patterns in patients with diabetes, per the ADA guideline, using data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey-Outpatient Department for the years 2005 to 2010. This study also examined patients' demographic characteristics associated with statin prescribing, including sex, age, ethnicity, race, insurance type, body mass index, region, primary care provider, hypertension and hyperlipidemia. METHODS: This retrospective, cross-sectional, observational study included data dated between 2005 and 2010 from patients aged ≥18 years with diabetes and without contraindications to statin use. Associations between statin prescribing and variables of interest were analyzed using χ(2) tests. A multivariate logistic regression model included 2 groups stratified by 3-year observation period (2005-2007 and 2008-2010) plus all variables with an overall χ(2) test result of P < 0.2. P values, odds ratios (ORs) and 95% CIs are reported. FINDINGS: The majority of patients were aged ≥40 years (93.1%), had a body mass index of ≥30 (58.7%), had hypertension (65.6%), and did not have hyperlipidemia (54.0%). A low percentage of patients were prescribed a statin (35.1%), but it appears that this percentage is on the rise. During 2005-2007, 31.9% of patients received a statin, whereas 37.7% of patients received a statin during 2008-2010. After adjustment for covariates included in the multivariate logistic regression model, those with hypertension (vs none [reference]: OR = 1.31; 95% CI, 1.12-1.53) and/or hyperlipidemia (vs none [reference]: OR = 4.44; 95% CI, 3.70-5.33) were significantly more likely to have been prescribed a statin, whereas those in age group 18-<40 years (vs 40-<65 years [reference]: OR = 0.45; 95% CI, 0.31-0.65) and Hispanic/Latino patients (vs non-Hispanic/Latino patients [reference]: OR = 0.77; 95% CI, 0.61-0.97) were significantly less likely to have been prescribed a statin. IMPLICATIONS: Despite the call in the latest ADA recommendations for prescribing statins in many diabetic patients, an unexpectedly low percentage of patients were receiving them. Health disparities in age and ethnicity were also evident. The findings from this study highlight the need for further research into low statin prescribing rates.

Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5.

BACKGROUND: Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all samples using a custom Illumina array. Association analysis of each SNP with LDL-C was performed using multivariable linear regression (CATHGEN) and the quantitative trait transmission disequilibrium test (QTDT; GENECARD). SNPs associated with the intermediate quantitative trait, LDL-C, were then assessed for association with CAD (i.e., a qualitative phenotype) using linkage and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aortas). RESULTS: We identified four genes with SNPs that showed the strongest and most consistent associations with LDL-C and CAD: EBF1, PPP2R2B, SPOCK1, and PRELID2. The most significant results for association of SNPs with LDL-C were: EBF1, rs6865969, p = 0.01; PPP2R2B, rs2125443, p = 0.005; SPOCK1, rs17600115, p = 0.003; and PRELID2, rs10074645, p = 0.0002). The most significant results for CAD were EBF1, rs6865969, p = 0.007; PPP2R2B, rs7736604, p = 0.0003; SPOCK1, rs17170899, p = 0.004; and PRELID2, rs7713855, p = 0.003. CONCLUSION: Using an intermediate disease-related quantitative trait of LDL-C we have identified four novel CAD genes, EBF1, PRELID2, SPOCK1, and PPP2R2B. These four genes should be further examined in future functional studies as candidate susceptibility loci for cardiovascular disease mediated through LDL-cholesterol pathways.

Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease.

Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 × 10(-6) and 5 × 10(-6), respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.

Metrics for comparing three word-based software programs used for augmentative and alternative communication.

The purpose of this investigation was to conduct an analysis of a set of metrics developed for comparing features of software used in speech generating devices (SGD) for augmentative and alternative communication (AAC). These metrics - measures of speed, efficiency, and accuracy - were employed during a sentence reconstruction task. Twenty two participants without disabilities reconstructed nine sentences using each of three SGD software programs, counterbalanced to remove order effects. Results revealed differences in the metrics across the software programs that were supported by a social validation survey completed by the participants. These results provide benchmark data about relative speed, accuracy, and efficiency of these software programs in structured use, and can inform professionals in matching potential AAC users with specific features of word-based software.

Association of SSTR2 polymorphisms and glucose homeostasis phenotypes: the Insulin Resistance Atherosclerosis Family Study.

OBJECTIVE This study evaluated the influence of somatostatin receptor type 2 (SSTR2) polymorphisms on measures of glucose homeostasis in the Insulin Resistance Atherosclerosis Family Study (IRASFS). SSTR2 is a G-protein-coupled receptor that, in response to somatostatin, mediates inhibition of insulin, glucagon, and growth hormone release and thus may affect glucose homeostasis. RESEARCH DESIGN AND METHODS Ten single nucleotide polymorphisms (SNPs) spanning the gene were chosen using a SNP density selection algorithm and genotyped on 1,425 Hispanic-American individuals from 90 families in the IRASFS. These families comprised two samples (set 1 and set 2), which were analyzed individually and as a combined set. Single SNP tests of association were performed for four glucose homeostasis measures--insulin sensitivity (S(I)), acute insulin response (AIR), disposition index (DI), and fasting blood glucose (FBG)--using generalized estimating equations. RESULTS The SSTR2 locus was encompassed by a single linkage disequilibrium (LD) block (D' = 0.91-1.00; r(2) = 0.09-0.97) that contained four of the ten SNPs evaluated. Within the SSTR2-containing LD block, evidence of association was observed in each of the two sets and in a combined analysis with decreased S(I)(beta(homozygous) = -0.16; P(meta-analysis) = 0.0024-0.0030), decreased DI (beta(homozygous) = -0.35 to -5.16; P(meta-analysis) = 0.0075-0.027), and increased FBG (beta(homozygous) = 2.30; P(meta-analysis) = 0.045). SNPs outside the SSTR2-containing LD block were not associated with measures of glucose homeostasis. CONCLUSIONS We observed evidence for association of SSTR2 polymorphisms with measures of glucose homeostasis. Thus, variants in SSTR2 may influence pathways of S(I)to modulate glucose homeostasis.

Violations of behavioral practices revealed in closed claims reviews.

OBJECTIVE: Closed claims against general surgeons were reviewed, seeking insights into the effects of surgeons' deficient behavioral practices on outcomes. Research and educational strategies based on findings may reduce errors and improve care. SUMMARY BACKGROUND DATA: Adverse events occur in 2.9% to 3.7% of hospital admissions in the United States. Of these adverse events, 27.4% to 32.6% are the result of errors. Failures at the point-of-service can undermine the other elements of systems of care designed to reduce preventable adverse outcomes. In this regard, the relative importance of surgeons' behavior is poorly defined. METHODS: Fellows of the American College of Surgeons (ACS) reviewed 460 malpractice claims against general surgeons. The relationship between detrimental behavioral practice patterns--deficiencies in care that reflected a lack of diligence, vigilance, and/or commitment of time more than a lack of knowledge and/or skill--and the preventability of adverse events was assessed. RESULTS: Failures in practice patterns of behavior occurred in 78% of cases and were frequently associated with preventable injuries. When both behavioral practice violations and technical misadventures occurred, the complications were more likely to be preventable than if only a technical misadventure had occurred. Among several deficient behavioral practices, the failure to communicate was most pervasive, accounting for 22% of complications in the study. CONCLUSIONS: Stakeholders in health care policy should focus on the issue of physician behavior in crafting shifts in institutional cultures and in targeting new CME toward evidenced-based behavioral practices.

Tai Chi: moving for better balance -- development of a community-based falls prevention program.

BACKGROUND: This study was designed to develop an evidence- and community based falls prevention program -- Tai Chi: Moving for Better Balance. METHODS: A mixed qualitative and quantitative approach was used to develop a package of materials for program implementation and evaluation. The developmental work was conducted in 2 communities in the Pacific Northwest. Participants included a panel of experts, senior service program managers or activity coordinators, and older adults. Outcome measures involved program feasibility and satisfaction. RESULTS: Through an iterative process, a program package was developed. The package contained an implementation plan and class training materials (ie, instructor's manual, videotape, and user's guidebook). Pilot testing of program materials showed that the content was appropriate for the targeted users (community-living older adults) and providers (local senior service organizations). A feasibility survey indicated interest and support from users and providers for program implementation. A 2-week pilot evaluation showed that the program implementation was feasible and evidenced good class attendance, high participant satisfaction, and interest in continuing Tai Chi. CONCLUSIONS: The package of materials developed in this study provides a solid foundation for larger scale implementation and evaluation of the program in community settings.

Translation of an effective tai chi intervention into a community-based falls-prevention program.

Tai chi--moving for better balance, a falls-prevention program developed from a randomized controlled trial for community-based use, was evaluated with the re-aim framework in 6 community centers. The program had a 100% adoption rate and 87% reach into the target older adult population. All centers implemented the intervention with good fidelity, and participants showed significant improvements in health-related outcome measures. This evidence-based tai chi program is practical to disseminate and can be effectively implemented and maintained in community settings.

Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets.

Platelet-activating factor acetylhydrolase (PLA2G7) is a potent pro- and anti-inflammatory molecule that has been implicated in multiple inflammatory disease processes, including cardiovascular disease. The goal of this study was to investigate the genetic effects of PLA2G7 on coronary artery disease (CAD) risk in two large, independent datasets with CAD. Using a haplotype tagging (ht) approach, 19 ht single nucleotide polymorphisms (SNPs) were genotyped in CATHGEN case-control samples (cases = 806 and controls = 267) and in the GENECARD Family Study (n = 1101 families, 2954 individuals). Single SNP analysis using logistic regression revealed nine SNPs with significant association in all CATHGEN subjects (P = 0.0004-0.02). CATHGEN cases were further stratified into subgroups based on age of CAD onset (AOO) and severity of disease; 599 young affecteds (YA, AOO <56) and 207 old affected (OA, AOO >56). Significant genetic effects were observed in both OA and YA (P = 0.0001-0.02). The GENECARD probands demonstrated results similar to those seen in the YA CATHGEN cases (P = 0.002-0.05). Of the 19 SNPs genotyped, 3 SNPs result in nonsynonymous coding changes (I198T, A379V and R92H). Two of the coding SNPs, R92H and A379V, constitute two of the most significantly associated SNPs, even after Bonferroni correction and appear to represent independent associations (r(2) = 0.09). Multiple additional polymorphisms in low linkage disequilibrium with these coding SNPs were also strongly associated. In summary, PLA2G7 represents an important, potentially functional candidate in the pathophysiology of CAD based on replicated associations using two independent datasets and multiple statistical approaches. Further functional studies involving a combination of risk alleles are warranted.

The American College of Surgeons' closed claims study: new insights for improving care.

BACKGROUND: All physicians must be vigilant in the pursuit of safe care for patients. While problems in care are identified, education that provides an understanding of these problems and guidelines for improvement can enhance patient safety. Our objective was to determine problematic aspects of surgical care, including care provided by surgeons before, during, after, and instead of surgery, that negatively affect patient safety. STUDY DESIGN: Four hundred sixty malpractice claims against general surgeons were reviewed by surgeons (FACS). All claims were closed in 2003 or 2004. The data collection was completed at five medical liability companies representing a nationwide distribution of surgeons. Surgeons also dictated or wrote narratives for each case. The quantitative data and narratives were later analyzed to determine events responsible for unsafe care. RESULTS: Surgeon-reviewers identified deficiencies in care that fell below accepted standards more often before and after operations than during them. These deficiencies were often the result of a failure to recognize surgical injuries, and many of these deficiencies were preventable. The quality of surgical care was satisfactorily met in 36% of cases. The most common procedures involving patient safety concerns were those involving the biliary tract, intestines, hernias, vascular system, esophagus, and stomach. The most frequent events leading to claims included delayed diagnosis, failure to diagnose, failure to order diagnostic tests, technical misadventure, delayed treatment, and failure to treat. Complications occurring most frequently were organ injuries, adult respiratory distress syndrome, and infection. CONCLUSIONS: Closed claims reviews provide valuable data that may enhance provider performance through heightened awareness of common unsafe practices. Specifically, opportunities exist to improve surgical care provided during the preoperative and postoperative phases of treatment through continuing medical education to improve patient safety.

Genome-wide linkage of plasma adiponectin reveals a major locus on chromosome 3q distinct from the adiponectin structural gene: the IRAS family study.

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polymorphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.

Association of proopiomelanocortin gene polymorphisms with obesity in the IRAS family study.

Proopiomelanocortin (POMC) has been found to be associated with rare Mendelian forms of obesity in children, and, in linkage studies, genomic regions containing the POMC locus have been linked to leptin levels, a predictor of obesity, in white, Mexican-American, and African-American families. POMC polymorphisms have not been investigated in detail for association with obesity in the general population. Five single nucleotide polymorphisms (SNPs) (G-3460C, C17T, G3473A, C3755T, and A7069G) were genotyped on 811 Hispanic individuals in the Insulin Resistance Atherosclerosis Family Study and tested for association with multiple obesity quantitative traits. General and family-based association analyses for each individual SNP and for haplotypes were performed using the generalized estimating equation and quantitative pedigree disequilibrium test (QPDT), respectively. Modest but consistent associations were observed for SNP C3755T, with p values ranging from 0.011 to 0.045 for association with BMI, waist, visceral adipose tissue, and subcutaneous adipose tissue. G-3460C, G3473A, and A7069G were also found to be associated with additional obesity measurements (p value 0.025 to 0.04), with comparable levels of evidence observed for linkage disequilibrium between these traits and these SNPs. Results of the haplotype analyses were also consistent with the single SNP analysis, with haplotypes containing C3755T showing the greatest evidence of association (p values ranging 0.004 to 0.048). Monte Carlo simulations (gene dropping) that account for the number of comparisons and the correlation structure indicate that the multivariate significance for these obesity traits with these polymorphisms was p = 0.0091. Collectively, the POMC polymorphisms showed consistent evidence for association with obesity traits in Hispanic Americans across several analytical approaches using SNP and haplotype analysis. These results support the hypothesis that POMC contributes genetically to the development of obesity.

Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study.

Adiponectin, coded for by the APM1 gene, is a novel adipocyte-derived hormone implicated in energy homeostasis and obesity. Several genetic studies have observed evidence of association between APM1 gene polymorphisms and features of the metabolic syndrome, such as insulin resistance and obesity. As part of a comprehensive genetic analysis of the APM1 gene, we have screened 96 unrelated individuals for polymorphisms in the promoter, coding regions, and 3'untranslated region (UTR). Three promoter single-nucleotide polymorphisms (SNPs), two rare coding SNPs (G113A and T1233C), and 13 SNPs in the 3'UTR were identified. Eighteen SNPs were genotyped in 811 Hispanic individuals from 45 families in the IRAS Family Study (IRASFS). SNPs were tested for association with six obesity quantitative traits (body mass index, waist, waist:hip ratio, subcutaneous adipose tissue, visceral adipose tissue, and visceral:subcutaneous ratio). Significant evidence of association to at least one of the obesity traits was identified in seven of the 18 SNPs (<0.001-0.05). The promoter SNP INS CA-11156 was the most consistently associated SNP and was associated significantly with all measures of obesity, except the visceral:subcutaneous ratio (P-values 0.009-0.03). Haplotype analysis supported this evidence of association, with haplotypes containing an insertion of one CA repeat at position -11156 consistently being associated with lower obesity values (P-value <0.001-0.05). The adiponectin polymorphisms, in particular those in the promoter region, thus show significant association with obesity measures in the Hispanic population. Additional studies are needed to confirm our findings and determine which polymorphism causes the functional effect.

Association analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism in Hispanics and African Americans: the IRAS family study.

OBJECTIVE: Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-beta1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits. METHODS AND RESULTS: The Insulin Resistance and Atherosclerosis (IRAS) Family Study genotyped 287 African American (18 pedigrees) and 811 Hispanic American (45 pedigrees) individuals for the 4G/5G PAI-1 and two TGF-beta1 polymorphisms (R25P, C-509T). Individuals were recruited from three clinical centers located in San Antonio (urban Hispanic), San Luis Valley (rural Hispanic) and Los Angeles (African American). The presence of the 4G PAI-1 allele was positively associated with PAI-1 protein level (combined sample p < 0.0001). Hispanic Americans average 65% higher PAI-1 protein levels than African Americans (p < 0.0001). Consistently across ethnic groups, increased PAI-1 protein levels were associated with increased insulin resistance and overall and central obesity (p value < 0.0001, combined sample). Adjusting for PAI-1 protein levels, there was evidence of an association of PAI-1 genotype (4G) with insulin sensitivity (p < 0.002) and subcutaneous fat (p < 0.01). These associations were not influenced by TGF-beta1 genotypes. CONCLUSIONS: PAI-1 protein is a strong correlate of insulin resistance (IR) and obesity in Hispanics and African Americans. However, PAI-1 4G/5G polymorphism appears to influence insulin resistance and obesity beyond its direct influence on serum PAI-1 protein levels.