T cell receptor beta chain gene rearrangements and V beta gene usage in horse cytochrome c-specific T cell hybridomas.

Comparison of T cell receptor alpha and beta-chain genes in murine major histocompatibility complex (MHC) class I and class II-restricted T cell clones and hybridomas recognizing different antigens indicates that no simple correlation exists between the observed antigen/MHC specificity and the expression of certain alpha and beta-chain heterodimers. We have attempted to establish a possible correlation by analyzing T cell receptor beta chain gene rearrangements and V beta gene usage in five T cell hybridomas with identical antigen/MHC specificity and another hybridoma recognizing a different antigenic determinant in association with the same restriction molecule. We report here that in each of the five clones a uniquely rearranged beta chain gene is expressed in combination with at least two different V beta gene segments. The presence of the differently rearranged T cell receptor beta chain genes correlated with the finding of distinct fine specificity pattern of antigen recognition in each of the hybridomas. Interestingly, two hybridomas specific for different epitopes showed identical beta chain D-J rearrangements indicating that the differences might be encoded by the alpha chain gene or/and the V beta gene element.

Marked association between obesity and glomerular hyperfiltration: a cross-sectional study in an African population.

BACKGROUND: Obesity and African American ethnicity are established independent risk factors for the development of chronic kidney disease. No data exist about the association between obesity and renal hemodynamics in the African region. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 301 nondiabetic participants (97 lean, 108 overweight, and 96 obese) of African descent with a positive family history of hypertension from the Seychelles islands. PREDICTOR: Body mass index (BMI). OUTCOMES: Glomerular hyperfiltration, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction. MEASUREMENTS: GFR and ERPF were measured using inulin and para-aminohippurate clearances, respectively. Participants' baseline demographics, laboratory data, and blood pressure were measured using standard techniques. RESULTS: The prevalence of glomerular hyperfiltration (defined as GFR >or=140 mL/min) increased across BMI categories (7.2%, 14.8%, and 27.1% for lean, overweight, and obese participants, respectively; P < 0.001). Higher BMI was associated with higher median GFR (99, 110, and 117 mL/min for lean, overweight, and obese participants, respectively; P < 0.001), ERPF (424, 462, and 477 mL/min, respectively; P = 0.01), and filtration fraction (0.23, 0.24, and 0.25; P < 0.001). Multivariate analyses adjusting for age, sex, blood pressure, fasting glucose level, and urinary sodium excretion and accounting for familial correlations confirmed the associations between high BMI (>25 kg/m(2)) and increased GFR, ERPF, and filtration fraction. No association between BMI categories and GFR was found with adjustment for body surface area. LIMITATIONS: Participants had a positive family history of hypertension. CONCLUSION: Overweight and obesity are associated with increased GFR, ERPF, and filtration fraction and a high prevalence of glomerular hyperfiltration in nondiabetic individuals of African descent. The absence of associations between BMI categories and GFR indexed for body surface area raises questions regarding the appropriateness of indexing GFR for body surface area in overweight populations.

Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.

Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.

Association between white-coat effect and blunted dipping of nocturnal blood pressure.

In this study, we assessed whether the white-coat effect (difference between office and daytime blood pressure (BP)) is associated with nondipping (absence of BP decrease at night). Data were available in 371 individuals of African descent from 74 families selected from a population-based hypertension register in the Seychelles Islands and in 295 Caucasian individuals randomly selected from a population-based study in Switzerland. We used standard multiple linear regression in the Swiss data and generalized estimating equations to account for familial correlations in the Seychelles data. The prevalence of systolic and diastolic nondipping (<10% nocturnal BP decrease) and white-coat hypertension (WCH) was respectively 51, 46, and 4% in blacks and 33, 37, and 7% in whites. When white coat effect and nocturnal dipping were taken as continuous variables (mm Hg), systolic (SBP) and diastolic BP (DBP) dipping were associated inversely and independently with white-coat effect (P < 0.05) in both populations. Analogously, the difference between office and daytime heart rate was inversely associated with the difference between daytime and night-time heart rate in the two populations. These results did not change after adjustment for potential confounders. The white-coat effect is associated with BP nondipping. The similar associations between office-daytime values and daytime-night-time values for both BP and heart rate suggest that the sympathetic nervous system might play a role. Our findings also further stress the interest, for clinicians, of assessing the presence of a white-coat effect as a means to further identify patients at increased cardiovascular risk and guide treatment accordingly.

Common variants in mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Association between mannose-binding lectin deficiency and cytornegalovirus infection course after organ transplantation.

Background: Mannose binding lectin (MBL) is an innate humoral immune effector and MBL defi ciency has been suggested as a risk factor for the development of certain viral infections. However, there is no data about the possible association between MBL defi ciency and CMV, especially after organ transplantation. Methods: We measured MBL levels in 16 kidney transplant recipients with highrisk CMV serostatus (D+/R-) who received valganciclovir prophylaxis for 3 months (Study 1). In addition, MBL levels were retrospectively assayed in 55 recipients from a previous study of organ transplant recipients managed preemptively (Study 2). In Study 2, protracted CMV infection was associated with recipient CMV seronegativity, increasing age, and high viral load during the initial episode. In both studies, MBL defi ciency was diagnosed if MBL levels were <500 ng/ml. Results: In Study 1, after a follow-up of 12 months, 7 out of 16 patients developed CMV disease, 4 patients developed asymptomatic CMV infection, and 5 patients never developed any sign of CMV replication. Overall, 9/16 patients (56%) had MBL defi ciency: 5/7 (71%) of patients with CMV disease, 4/4 (100%) of patients with asymptomatic CMV infection, and 0/5 (0%) of patients without CMV infection (p=0.005, between CMV infection/disease versus no infection). Median MBL concentrations were higher in patients without CMV infection than in those with CMV infection (p<0.005). In Study 2, among 30 patients with CMV infection, 9/25 (36%) patients without MBL defi ciency had a protracted course, while 4/5 (80%) with MBL defi ciency did so (p=0.07). Conclusion: Data from two separate patient populations suggest that MBL defi ciency may be a signifi cant risk factor for late CMV disease/infection after prophylaxis, and protracted infection after preemptive treatment. This suggests a role for MBL in the control of CMV infection after organ transplantation.

Association of T-zone reticular networks and conduits with ectopic lymphoid tissues in mice and humans.

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node-like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin(+) T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell-rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter-CXCL13-transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell-rich zone.

A Multi-SNP Locus-Association Method Reveals a Substantial Fraction of the Missing Heritability.

There are many known examples of multiple semi-independent associations at individual loci; such associations might arise either because of true allelic heterogeneity or because of imperfect tagging of an unobserved causal variant. This phenomenon is of great importance in monogenic traits but has not yet been systematically investigated and quantified in complex-trait genome-wide association studies (GWASs). Here, we describe a multi-SNP association method that estimates the effect of loci harboring multiple association signals by using GWAS summary statistics. Applying the method to a large anthropometric GWAS meta-analysis (from the Genetic Investigation of Anthropometric Traits consortium study), we show that for height, body mass index (BMI), and waist-to-hip ratio (WHR), 3%, 2%, and 1%, respectively, of additional phenotypic variance can be explained on top of the previously reported 10% (height), 1.5% (BMI), and 1% (WHR). The method also permitted a substantial increase (by up to 50%) in the number of loci that replicate in a discovery-validation design. Specifically, we identified 74 loci at which the multi-SNP, a linear combination of SNPs, explains significantly more variance than does the best individual SNP. A detailed analysis of multi-SNPs shows that most of the additional variability explained is derived from SNPs that are not in linkage disequilibrium with the lead SNP, suggesting a major contribution of allelic heterogeneity to the missing heritability.

Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study

OBJECTIVE: Although genetic factors have been implicated in the etiology of bipolar disorder, no specific gene has been conclusively identified. Given the link between abnormalities in serotonergic neurotransmission and bipolar disorder, a candidate gene association approach was applied to study the involvement of the monoamine oxidase A (MAOA) gene, which codes for a catabolic enzyme of serotonin, in the susceptibility to bipolar disorder. METHOD: In France and Switzerland, 272 patients with bipolar disorder and 122 healthy subjects were typed for three polymorphic markers of the MAOA gene: the MAOA-CA repeat, the MAOA restriction fragment length polymorphism (RFLP), and a repeat directly adjacent to the variable number of tandem repeats (VNTR) locus. RESULTS: A significant difference in the distribution of the alleles for the MAOA-CA repeat was observed between the female bipolar patients and comparison group. CONCLUSIONS: The results obtained in the French and Swiss population confirm findings from two studies conducted in the United Kingdom.

Absence of association between specific common variants of the obesity-related FTO gene and psychological and behavioral eating disorder phenotypes.

Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single-nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1,085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls. © 2011 Wiley-Liss, Inc.

Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

Developing an Effective Construction Training Program for Hispanic and American Supervisors and Craft Workers, 2007

Hispanics are a large and growing part of the United States workforce. Projections of the U.S. Census Bureau (2001) state that, by the year 2050, Hispanics will account for 25% of the population. For the Midwest in particular, the Hispanic population is expected to increase 35% by the year 2025. The construction industry is expected to experience a greater percentage increase of its Hispanic population, due to the labor-intensive nature of the industry. This study addresses the expected increase of Hispanic workers in the construction industry by testing the best approaches for delivering training to construction crews with Hispanic workers as well as American supervisors and laborers in the state of Iowa. The research methodology consisted of assessing the effects on communication, safety, work environment, and productivity as a result of the integration training. Results show that integration on-site training decreases workers’ desire to move and increases quality of work and productivity. Most importantly, experimental design was used to show the increasing levels of direct construction communication due to the Toolbox Integration Course for Hispanic Workers and American Supervisors (TICHA) designed as part of this project. This study recommends the creation of a quasi-governmental or association program that can offer continuous research and training that can benefit the construction industry as well as society as a whole. The industry involvement in this process is crucial for contractors. Not only do contractors benefit from reduced insurance premiums when workers act safely, but workers with better communication skills are more productive.

Association between growth and blood pressure during the life course in children and adolescents

Background: Little is known on the relative importance of growth at different periods between birth and adolescence on blood pressure (BP). Objective: To assess the association between birth weight, change in body weight (growth) and BP across the entire span of childhood and adolescence. Methods: School-based surveys were conducted annually between 1998 and 2006 among all children in four school grades (kindergarten, 4th, 7th, and 10th year of compulsory school) in the Seychelles, Indian Ocean. Height and weight and BP were measured. Three cohorts of children examined twice were analyzed: 1606 children surveyed at age 5.5 and 9.1, 2557 at age 9.2 and 12.5, and 2065 at age 12.5 and 15.5, respectively. Weights at birth and at one year were extracted from medical files. Weights were expressed as Z-scores and growth was defined as a change in weight Z-scores (corresponding to weight centile crossing). The association between BP (at age 5.5, 9.2, 12.5, and 15.5) and weight at different times was assessed by linear regression. Using results of regression models of BP on all successive weights, life course plots were drawn by plotting regression coefficients against age at which weight was measured. The figure shows a life course plot of systolic BP in boys aged 15.5. Results: Without adjustment for current weight (at the time of BP measurement), birth weight was not associated with current BP, irrespective of age, excepted for girls at age 15.5 for whom a modest positive association was found. When adjusted for current weight, birth weight was negatively and modestly associated with current BP. BP was strongly associated with current weight, irrespective of age. Life course plots showed that BP was strongly associated with growth during the few preceding years but not with growth during earlier years, except for growth during the first year of life which tended to be associated with systolic BP. Conclusions: Our findings suggest that BP during childhood and adolescence is mainly determined by current body weight and recent growth.

Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection.

Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.