Electronic health record reveals community-level cardiometabolic health benefits associated with 10 years of community-based participatory research.

BACKGROUND: While a major goal of community-based participatory research (CBPR) is to improve community health; it is unclear how to measure longstanding success of CBPR. OBJECTIVE: We sought to determine the impact of ongoing CBPR on cardiometabolic health of participating communities, including in people not directly participating in research. METHODS: We used linear mixed-effects modelling with electronic medical records from 2002 to 2012 from the Yukon-Kuskokwim Health Corporation, which provides health care to all Alaska Native people in southwestern Alaska, to compare rates of change in cardiometabolic risk factors between communities that did and did not participate in ongoing CBPR beginning in 2003. RESULTS: We analysed 1,262,035 medical records from 12,402 individuals from 10 study and 38 control communities. Blood pressure declined faster in study than in control communities: systolic blood pressure (0.04 mmHg/year; 95% confidence interval [CI]: 0.01, 0.08); diastolic blood pressure (DBP) (0.07 mmHg/year; 95% CI: 0.04, 0.09). Body mass index increased 0.04 units/year faster in study communities than in control communities (95% CI: 0.03, 0.05). More study visits were associated with faster reduction of DBP and triglyceride levels in study communities. CONCLUSIONS: Ongoing CBPR may improve overall cardiometabolic health in communities, perhaps by increasing engagement in health and advocacy.

Prevalence of failure of passive transfer of immunity in dairy calves in a Mediterranean pasture-based production system of the south-west region of Western Australia.

The objective of this study was to estimate the prevalence of failure of passive transfer of immunity (FPTI) in dairy calves in the south-west region of Western Australia herds. A cross-sectional study was conducted in 26/140 dairy farms and serum samples were collected from 495 healthy 2-7 day-old calves. A radial immunodiffusion (RID) test was used to determine the concentration of serum IgG and calves were classified as having FPTI if the IgG concentration was less than 10 mg/mL. Estimation of FPTI was also assessed using two indirect methods using serum total protein (STP) and a brix refractometer. The estimated prevalence of FPTI was found to be 8.7% (43 calves out of 495) by RID with the concentration of IgG ranging between 0 and 6.2 mg/ml. The STP was found to vary from 46 to 96 mg/mL and using a cut-off point of 55 mg/mL the calf level prevalence was estimated as 7.1% (33 calves). Using the brix refractometer, the prevalence was found to be 13.1% (65 calves) with the refractometer reading ranging 6-14% of IgG. In the present study there was no association between calf-level factors (age, sex and breed) and FPTI. There was a higher correlation of the RID test results and the STP results compared to the RID and brix refractometer results. It is concluded that the prevalence of FPTI in dairy calves in the south-west region of Western Australia is low (8.7%) and the brix refractometer is not a reliable indirect method for determining passive transfer of immunity to calves.

APOL1, CDKN2A/CDKN2B, and HDAC9 polymorphisms and small vessel ischemic stroke.

OBJECTIVE: Worldwide, the highest frequencies of APOL1-associated kidney variants are found in indigenous West Africans among whom small vessel disease (SVD) ischemic stroke is the most common stroke phenotype. The objective of this study was to investigate the association and effect sizes of 23 selected SNPs in 14 genes of relevance, including the APOL1 G1 variants, with the occurrence of SVD ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study. MATERIALS AND METHODS: Cases were consecutively recruited consenting adults (aged 18 years or older) with neuroimaging-confirmed first clinical stroke. Stroke-free controls were ascertained using a locally validated version of the Questionnaire for Verifying Stroke-Free Status (QVSFS). Logistic regression models adjusting for known vascular risk factors were fitted to assess the associations of the 23 SNPs in rigorously phenotyped cases (N = 154) of SVD ischemic stroke and stroke-free (N = 483) controls. RESULTS: Apolipoprotein L1 (APOL1) rs73885319 (OR = 1.52; CI: 1.09-2.13, P-value = .013), rs2383207 in CDKN2A/CDKN2B (OR = 3.08; CI: 1.15-8.26, P -value = .026) and rs2107595 (OR = 1.70; CI: 1.12-2.60, P-value = .014) and rs28688791 (OR = 1.52; CI: 1.03-2.26, P-value = .036) in HDAC9 gene were associated with SVD stroke at 0.05 significance level. Polymorphisms in other genes did not show significant associations. CONCLUSION: This is the first report of a specific association of APOL1 with a stroke subtype. Further research is needed to confirm these initial findings and deepen understanding of the genetics of stroke in people of African ancestry with possible implications for other ancestries as all humans originated from Africa.

CPT1A methylation is associated with plasma adiponectin.

BACKGROUND AND AIMS: Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. METHODS AND RESULTS: We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE = 0.01 ± 0.001, P = 3.4 × 10-13) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n = 474, P = 0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n = 592, P = 0.0005) but not Black (n = 243, P = 0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. CONCLUSION: We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications.

Training in metabolomics research. I. Designing the experiment, collecting and extracting samples and generating metabolomics data.

Metabolomics is perhaps the most challenging of the -omics fields, given the complexity of an organism's metabolome and the rapid rate at which it changes. When one sets out to study metabolism there are numerous dynamic variables that can influence metabolism that must be considered. Recognizing the experimental challenges confronting researchers who undertake metabolism studies, workshops like the one at University of Alabama at Birmingham have been established to offer instructional guidance. A summary of the UAB course training materials is being published as a two-part Special Feature Tutorial. In this month's Part I the authors discuss details of good experimental design and sample collection and handling. In an upcoming Part II, the authors discuss in detail the various aspects of data analysis.

The effects of genes implicated in cardiovascular disease on blood pressure response to treatment among treatment-naive hypertensive African Americans in the GenHAT study.

African Americans have the highest prevalence of hypertension in the United States. Blood pressure (BP) control is important to reduce cardiovascular disease-related morbidity and mortality in this ethnic group. Genetic variants have been found to be associated with BP response to treatment. Previous pharmacogenetic studies of BP response to treatment in African Americans suffer limitations of small sample size as well as a limited number of candidate genes, and often focused on one antihypertensive treatment. Using 1131 African-American treatment-naive participants from the Genetics of Hypertension Associated Treatment Study, we examined whether variants in 35 candidate genes might modulate BP response to four different antihypertensive medications, including an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), and an a-adrenergic blocker (doxazosin) as compared with a thiazide diuretic (chlorthalidone) after 6 months of follow-up. Several suggestive gene by treatment interactions were identified. For example, among participants with two minor alleles of renin rs6681776, diastolic BP response was much improved on doxazosin compared with chlorthalidone (on average -9.49 mm Hg vs -1.70 mm Hg) (P=0.007). Although several suggestive loci were identified, none of the findings passed significance criteria after correction for multiple testing. Given the impact of hypertension and its sequelae in this population, this research highlights the potential for genetic factors to contribute to BP response to treatment. Continued concerted research efforts focused on genetics are needed to improve treatment response in this high-risk group.

Genetic association analysis of 30 genes related to obesity in a European American population.

OBJECTIVE: Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). METHODS: We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age(2), gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. RESULTS: With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. CONCLUSION: Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context.

Application of WHONET in the Antimicrobial Resistance Surveillance of Uropathogens: A First User Experience from Nepal.

INTRODUCTION: WHONET is a freely downloadable, Windows-based database software which is used for the management and analysis of microbiology data, with a special focus on the analysis of antimicrobial susceptibility test results. Urinary Tract Infections (UTI) are a common medical problem and they are responsible for notable morbidity among young and sexually active women. OBJECTIVES: The major objective of this study was the utilization and application of the WHONET program for the Antimicrobial Resistance (AMR) surveillance of uropathogens. METHODS: A total of 3209 urine samples were collected from patients who visited Manipal Teaching Hospital with a clinical suspicion of UTI, during December 2010 to July 2011. The isolation and characterization of the isolates were done by conventional methods. Antimicrobial Susceptibility Testing (AST) was performed by Kirby Bauer's disc diffusion method. The data entry and analysis were done by using the WHONET 5.6 software. RESULTS: Out of the 3209 specimens, 497 bacterial isolates were obtained and they were subjected to AST. Escherichia coli (66.2%) was the commonest bacterial isolate, followed by Enterococcus species (9.3%), Staphylococcus aureus (5.0%), and Klebsiella pneumoniae (4.2%). Among the gram-negative enteric bacilli, a high prevalence of resistance was observed against ampicillin and ciprofloxacin. The gram negative nonfermenters exhibited a high degree of resistance to ceftazidime. Staphylococcus species. showed a moderately high resistance to co-trimoxazole. One isolate was Vancomycin Resistant Enterococci (VRE). CONCLUSION: This study, a first of its kind which was done in Nepal, was carried out by using the WHONET software to monitor, analyze and share the antimicrobial susceptibility data at various levels. This study was also aimed at building a surveillance network in Nepal, with the National Public Health Laboratory, Nepal, acting as a nodal centre. This would help in the formulation of antibiotic policies and in identifying hospital and community outbreaks at the nodal centre, as well as in sharing information with the clinicians at the local level.

The association between LRP-1 variants and chylomicron uptake after a high fat meal.

BACKGROUND AND AIMS: In vitro studies suggest that low density lipoprotein receptor-related protein 1 (LRP1) plays a role in the secondary uptake of chylomicrons. In addition, in vivo studies using LRP-1 knockout mice show these animals exhibit delayed chylomicron clearance. Whether this is true in humans is unknown. We aimed to determine whether genetic variants in LRP-1 are associated with postprandial chylomicron uptake in humans given an oral fat challenge. METHODS AND RESULTS: As many as 817 men and women (mean age +/- standard deviation = 48.4 +/- 16.4 years) forming the study population for the Genetics of Lipid Lowering Drugs Network (GOLDN) study ingested an oral fat load of 700 kilocalories per m² of body surface area at 83% fat, after an 8-h fast. Chylomicrons were measured by nuclear resonance spectroscopy (NMR) at fasting, and 3.5 and 6 h after the meal. 26 Single nucleotide polymorphisms (SNPs) in the LRP-1 gene were genotyped on the Affymetrix 6.0 array. Chylomicrons were, as expected, zero at fasting. Mixed linear models adjusted for age, sex, study site and pedigree tested for associations between LRP-1 SNPs and changes in chylomicron concentrations 3.5-6 h. A gene-based test across all 26 SNPs was conducted which corrected for the linkage disequilibrium (LD) between SNPs. 11 LRP-1 SNPs were significantly associated with the change in chylomicron concentration correction for multiple testing (Q < 0.05). The subsequent gene-based test, was also significant (P = 0.01). CONCLUSION: These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.

The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study.

As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARα receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARα gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARα gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective.

Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network.

BACKGROUND AND AIMS: Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. METHODS AND RESULTS: Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10⁻8) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. CONCLUSIONS: We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.

Whole-exome sequencing and an iPSC-derived cardiomyocyte model provides a powerful platform for gene discovery in left ventricular hypertrophy.

RATIONALE: Left ventricular hypertrophy (LVH) is a heritable predictor of cardiovascular disease, particularly in blacks. OBJECTIVE: Determine the feasibility of combining evidence from two distinct but complementary experimental approaches to identify novel genetic predictors of increased LV mass. METHODS: Whole-exome sequencing (WES) was conducted in seven African-American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT) using Illumina HiSeq technology. Identified missense or nonsense (MS/NS) mutations were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and familial relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (induced pluripotent stem cell-CM) were stimulated to induce hypertrophy; mRNA sequencing (RNA-seq) was used to determine gene expression differences associated with hypertrophy onset. Statistically significant findings under both experimental approaches identified LVH candidate genes. Candidate genes were further prioritized by seven supportive criteria that included additional association tests (two criteria), regional linkage evidence in the larger HyperGEN cohort (one criterion), and publically available gene and variant based annotations (four criteria). RESULTS: WES reads covered 91% of the target capture region (of size 37.2 MB) with an average coverage of 65×. WES identified 31,426 MS/NS mutations among the 21 individuals. A total of 295 MS/NS variants in 265 genes were associated with LVMHT with q-value <0.25. Of the 265 WES genes, 44 were differentially expressed (P < 0.05) in hypertrophied cells. Among the 44 candidate genes identified, 5, including HLA-B, HTT, MTSS1, SLC5A12, and THBS1, met 3 of 7 supporting criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH. THBS1 gene expression was 34% higher in hypertrophied cells (P = 0.0003) and a predicted conserved and damaging NS variant in exon 13 (A2099G) was significantly associated with LVHMT (P = 4 × 10(-6)). CONCLUSION: Combining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci.

Dietary Carbohydrate Modifies the Inverse Association Between Saturated Fat Intake and Cholesterol on Very Low-Density Lipoproteins.

We aimed to investigate the relationship between dietary saturated fat on fasting triglyceride (TG) and cholesterol levels, and any mediation of this relationship by dietary carbohydrate intake. Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 1036, mean age ± SD = 49 ± 16 y) were included. Mixed linear models were run with saturated fat as a predictor variable and fasting TG, very low density lipoprotein cholesterol (VLDL-C), low density cholesterol (LDL-C) and high density cholesterol (HDL-C) as separate outcome variables. Subsequent models were run which included dietary carbohydrate as a predictor variable, and an interaction term between saturated fat and carbohydrate. All models controlled for age, sex, BMI, blood pressure and dietary covariates. In models that included only saturated fat as a predictor, saturated fat did not show significant associations with fasting lipids. When carbohydrate intake and an interaction term between carbohydrates and saturated fat intake was included, carbohydrate intake did not associate with lipids, but there was an inverse relationship between saturated fat intake and VLDL-C (P = 0.01) with a significant interaction (P = 0.01) between saturated fat and carbohydrate with regard to fasting VLDL-C concentrations. Similar results were observed for fasting TG levels. We conclude that, when controlling for carbohydrate intake, higher saturated fat was associated with lower VLDL-C and TGs. This was not the case at higher intakes of carbohydrate. This has important implications for dietary advice aimed at reducing TG and VLDL-C levels.

Evaluation of different tests for detection of Staphylococcus aureus using coagulase (coa) gene PCR as the gold standard.

A total of 288 staphylococcal specimens isolated from different clinical specimens were selected for the evaluation of tests used to detect Staphylococcus aureus. The coagulase (coa) gene PCR was preformed, which confirmed 288 specimens as S. aureus and 51 specimens as coagulase negative staphylococci (CONS). All the specimens were subjected to slide coagulase test, Slidex Staph plus test and tube coagulase test. Sensitivity, specificity, positive predictive value and negative predictive values of were calculated using coa gene PCR as gold standard for the detection ofS. aureus. The tube coagulase test showed very good sensitivity (98.7%), specificity (98.1%), PPV (99.5%) and NPV (94.4%) than other methods. Slidex Staph plus test showed fairly good sensitivity and specificity. Slide coagulase test has good specificity but poor sensitivity. Therefore we recommend that tube coagulase test be done routinely for the detection ofS. aureus in microbiology laboratory.

Studies on the residues of terramycin and furazolidone in broiler meat--a public health concern.

The concentration of Terramycin and Furazolidone residues in broiler meat following their subtherapeutic use in the ration of the birds were detected as 296 ng/g, 174 ng/g, 40 ng/g, 60 ng/g and 124 ng/ml in kidney, liver, thigh muscle, breast muscle and serum for Terramycin and 270 ng/g 160 ng/g and 88 ng/ml in kidney, liver and serum for Furazolidone. One week of withdrawal period from the antibiotic in feed/water was sufficient to render the meat free from residues.

Staphylococcal zoonosis on dairy farms in Assam and Meghalaya.

OBJECTIVE: To assess if Staphylococcus aureus is transmitted between man and animals & vice-versa. METHODS: Staphylococcus aureus belonging to biotype C (bovine origin) were isolated from nares and hands of workers on six dairy farms of Assam and Meghalaya. The cows on the farms had a high rate of prevalence of mastitis caused by the same biotype of S. aureus. Three strains of S. aureus biotype A (human origin) were isolated from mastitis milk samples from cows on one of these farms, in which one of the workers was having cuteneous lesions (crusty abscess) and one strain of S. aureus biotype A was isolated from a swab sample collected from an abscess on the skin of the worker. RESULTS: It has been revealed that all the members of the workers family were suffering from a similar type of cuteneous infection, indicating that it was a case of impetigo. The antibiotic susceptibility pattern of all the three biotype A strains from bovine origin was identical to that of the biotype A strains isolated from the worker. The percentage of resistance to 12 commonly used therapeutic antimicrobial agents was higher among the biotype C strains from human origin than the biotype C strains from bovine origin. Several strains from cattle and human origins showed identical antimicrobial susceptibility patterns against the tested agents.

Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis.

BACKGROUND: The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis. OBJECTIVE: To determine the allele frequencies of five common coding single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX. METHODS: Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African-Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African-American, as well as 103 normal controls (53 African-Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes. RESULTS: Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African-Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African-Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p<0.001 compared with African-Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p<0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28-joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African-Americans, but not in Caucasians. CONCLUSIONS: : These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African-Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African-Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.

Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults.

OBJECTIVE: To test for association of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q polymorphism with body mass index (BMI) and diabetes in a large sample of Caucasians and African-Americans by selectively genotyping individuals at the extremes of the phenotypic distribution. SUBJECTS: Subsets comprising the extremes of the BMI distribution (10th-20th and above the 90th BMI percentile for Caucasians and between the 10th-30th and above the 80th percentile for African-Americans) from a group of 10,260 Caucasian and 2268 African-American adults participating in New York Cancer Project were studied. METHODS: Subjects were genotyped for the ENPP1 K121Q polymorphism by pyrosequencing and tested for association with BMI and diabetes by regression analysis. RESULTS: Regression analysis with BMI as the dependent variable demonstrated a significant association (P = 0.02) of genotype at K121Q with BMI, with no significant race-by-genotype interaction (P = 0.30). Compared with Q/Q or Q/K individuals, the K/K individuals had a BMI approximately 1.3 kg/m2 higher, without effects of age, gender or race. By logistic regression analysis, the K121Q alleles had no significant effect on diabetes status (P = 0.37) in obese subjects. CONCLUSION: In both Caucasians and African-Americans, the K121 polymorphism in ENPP1 was associated with increased BMI, but not with diabetes.

Early rheumatoid arthritis in African-Americans: the CLEAR Registry.

African-Americans have been under-represented in genetic studies of rheumatoid arthritis (RA) susceptibility and severity. Genetic and non-genetic factors influencing the radiographic severity of RA and its response to treatment are poorly understood, particularly in African-Americans. The Consortium for the Longitudinal Evaluation of African-Americans with early RA (CLEAR) Registry, a collaborative effort among four institutions in the southeast USA, will hopefully provide a useful resource to study these issues.

Transmission/disequilibrium test analysis of total serum IgE levels in the Hutterite and Collaborative Study on the Genetics of Asthma data sets.

The Hutterite and Collaborative Study on the Genetics of Asthma data sets provided by Genetic Analysis Workshop 12 were analyzed using a regression-based transmission/disequilibrium test that assesses linkage between a marker locus and quantitative trait locus when allelic association is present, as proposed by George et al. [Am J Hum Genet 65:236-45, 1999]. Because the same marker set and analytical technique was used, the results from these data sets are amenable for comparison. Statistically significant results common to both data sets were found on chromosomes 1 and 3. A noteworthy result, significant at p < 10(-4), was detected on chromosome 18 in the Hutterites.