A graphical assessment of p-values from sliding window haplotype tests of association to identify asthma susceptibility loci on chromosome 11q.

Background: Past work on asthmatic African American families revealed a strong linkage peak with modest evidence of association on chromosome 11q. Here, we perform tests of association for asthma and a panel of 609 SNPs in African American subjects using a sliding window approach. While efficient in screening a region of dense genotyping, this approach does create some problems: high numbers of tests, assimilating thousands of results, and questions about setting priorities on regions with association signals.

Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury.

The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon-intron boundaries, and 2 kb of 5' UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs).

A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity.

Background: Asthma and atopy represent complex traits for which genetic predisposition has been demonstrated. Pollen sensitivity, whether seasonal or chronic, appears to be a major contributor to the asthmatic phenotype.

Objective: Regions of the genome contributing to skin test reactivity to 5 seasonal allergens are to be identified in a genome-wide scan.

Inheritance of total serum IgE in the isolated Tangier Island population from Virginia: complexities associated with genealogical depth of pedigrees in segregation analyses.

Objectives: This study was aimed at performing a segregation analysis of total serum immunoglobulin E (tIgE) in an isolated population using maximal genealogical information permitted by current software and computer capacities, while assessing the reliability of the best-fitting model of inheritance for tIgE through simulations.

Methods: All current Tangier Island, VA, residents (n = 664) belonged to one large extended pedigree (n = 3,501) spanning 13 generations, with an average inbreeding coefficient of 0.009.

Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study.

Background: Both a functional promoter polymorphism in the gene encoding CD14 (C-260T) and exposure to endotoxin are believed to play key roles in modulating the immune response and expression of atopic disease.

Objective: We aimed to evaluate the role of the CD14 C-260T polymorphism in a population of African descent and to test for interaction between this genotype and house dust endotoxin (HDE) exposure on atopic phenotypes.

Methods: Asthmatic probands and their families were recruited as part of the Barbados Asthma Genetics Study.

Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population.

Background: The T-cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases.

Objective: Genetic association of the sequence variants for TIM-1 and TIM-3 genes with asthma in an African American population was investigated.

Methods: Both case-control and family-based association analyses were performed for a total of 7 polymorphisms, including 3 single nucleotide polymorphism (SNPs) and 1 insertion/deletion polymorphism in the TIM-1 and 3 SNPs in the TIM-3 genes.

The effect of RANTES chemokine genetic variants on early HIV-1 plasma RNA among African American injection drug users.

HIV-1 plasma RNA is a prognostic indicator of HIV-1, and increased levels of HIV-1 plasma RNA are associated with rapid progression to AIDS. Because chemokines and chemokine receptors are involved in the binding and entry of HIV-1, possible effects of host genetics on viral RNA levels should be visible in early infection. HIV-1 plasma RNA was measured within 2 years of seroconversion in 198 seroincident injection drug users followed in the AIDS Link to Intravenous Experience cohort.

Homocysteine levels--before and after methionine loading--in 51 Dutch families.

Elevated levels of homocysteine are a risk factor for vascular disease, thrombosis, neural tube defects and dementia. The 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene appears to be the most important single determinant of plasma homocysteine concentration. In the current study, we estimated heritability and fit a series of models of inheritance for both fasting and postmethionine-load homocysteine levels in the HOFAM-study (HOmocysteine in FAMilies study), which included 306 participants from 51 pedigrees, ascertained through a hyperhomocysteinemic proband.

Oral clefts, maternal smoking, and TGFA: a meta-analysis of gene-environment interaction.

Objective: A meta-analysis was performed to examine the association among maternal cigarette smoking, infant genotype at the Taq1 site in the transforming growth factor alpha (TGFA) locus, and risk of nonsyndromic oral clefts, both cleft palate (CP) and cleft lip with or without cleft palate (CL/P).

Design: Five published case-control studies were included in the meta-analyis. Pooled Mantel-Haenszel odds ratios (OR) and 95% confidence intervals (CIs) were computed.

Clinical and molecular characterization of the bladder exstrophy-epispadias complex: analysis of 232 families.

Objective: To identify genetic and nongenetic factors contributing to the risk of bladder exstrophy-epispadias complex (BEEC).

Patients And Methods: In all, 285 families with BEEC were invited to participate in the study, and 232 of them were recruited. Epidemiological information was obtained from 151 of the consenting families, with a detailed clinical genetic examination of 94 probands.

Theory and methodology for utilizing genes as biomarkers to determine potential biological mixtures.

Purpose: Genetically determined mixture information can be used as a surrogate for physical or behavioral characteristics in epidemiological studies examining research questions related to socially stigmatized behaviors and horizontally transmitted infections. A new measure, the probability of mixture discrimination (PMD), was developed to aid mixture analysis that estimates the ability to differentiate single from multiple genomes in biological mixtures.

Methods: Four autosomal short tandem repeats (STRs) were identified, genotyped and evaluated in African American, European American, Hispanic, and Chinese individuals to estimate PMD.

Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability.

The gene, CRTH2, encoding a receptor for prostaglandin D(2) (PGD(2)), is located within the peak linkage region for asthma on chromosome (Chr.) 11q reported in African American families. Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3'-untranslated region of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P = 0.

Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35.

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6).

Associations between specific serum IgE response and 6 variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study.

Background: Among many published studies of specific IgE response or atopy, only a few showed positive marginal effects for 6 potentially functional single nucleotide polymorphisms (SNPs; C-590T in the IL4 gene, C-1055T and Arg130Gln in the IL13 gene, and Ile50Val, Ser478Pro, and Gln551Arg in the IL4RA gene). SNPs were commonly considered individually, and therefore the true effect could be masked by other genes or environmental factors.

Objective: We tested the relationship between these 6 SNPs and sensitization to food, mite, cat, and outdoor allergens in unrelated German children drawn from the Multicenter Atopy Study.

Influence of human leukocyte antigen class II alleles on susceptibility to Entamoeba histolytica infection in Bangladeshi children.

Background: The association of antibody responses with both innate and acquired immunity to amebiasis indicate that CD4+ T cells play a role in protection against Entamoeba histolytica infection. To test this hypothesis, we compared the genotype frequencies of human leukocyte antigen (HLA) class II alleles in a cohort of Bangladeshi children intensively monitored for E. histolytica infection for a 3-year period.

Multipoint linkage disequilibrium mapping for complex diseases.

Linkage disequilibrium (LD) or association studies using case-parent trios have become a common approach to locate unobserved susceptibility genes underlying complex diseases. With the availability of ever more dense marker maps, how to utilize the information carried by multiple markers simultaneously remains challenging. Recently, Liang et al.

A genome-wide scan for loci predisposing to non-syndromic cleft lip with or without cleft palate in two large Syrian families.

Non-syndromic cleft lip with/without cleft palate (CL/P) is a common, usually non-fatal birth defect of complex etiology. Several segregation analyses have demonstrated that genetic factors are important in the pathogenesis of CL/P, most likely through the interaction of several genes of modest effects. The aim of this study was to perform a genome-wide linkage analysis to identify/search for candidate gene loci for CL/P.

A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma.

Atopy is an IgE-mediated condition known to aggregate in families and is a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome-wide scan for atopy, defined by skin sensitivity to one or more common environmental allergens, was conducted in 287 CSGA families (115 African American, 138 Caucasian and 34 Hispanic). Using a nonparametric genetic analysis approach, two regions were observed in the sample of all families that yielded multipoint lod scores >1.

Segregation analysis of 231 Ashkenazi Jewish families for evidence of additional breast cancer susceptibility genes.

Between 5 and 10% of breast cancer is attributable to inherited cancer susceptibility genes. Mutations in the genes BRCA1 and BRCA2 account for two-thirds of hereditary breast cancer cases. Using segregation analysis, families of cases without BRCA1/2 mutations were studied for statistical evidence of another major breast cancer gene in a community-based sample of Jewish probands tested previously for the presence of three BRCA founder mutations.

Spouse controls in family case-control studies: a methodological consideration.

In case-control studies on familial aggregation of disease, spouses may be chosen as convenient controls. In this article the pros and cons of this control group are discussed. It is argued that the use of spouse controls can be time- and cost-efficient, because of easy accessibility and their ability to provide proxy data on the patients' relatives if necessary.

Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2.

Results from a genome-wide screen of 10 multiplex families ascertained through probands with nonsyndromic cleft lip with or without cleft palate (CL/P) in Mexico, Argentina, and the United States yielded suggestive evidence of linkage to chromosomes 2, 6, 17 and 18. Fine mapping excluded all regions except chromosome 2. Subsequent analysis was performed on the original 10 families plus an additional 16 families using 31 markers on chromosome 2.

Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn's disease phenotypes.

Background: Multiple factors, particularly IBD family history, tobacco use, age at diagnosis and recently, NOD2 mutant genotypes may influence Crohn's disease (CD) heterogeneity.

Methods: We performed a multicenter retrospective record analysis of 275 unrelated patients with CD. Age at diagnosis, IBD family history, Jewish ethnicity, tobacco use at diagnosis, surgical history, disease site and clinical behavior were correlated with genotypes for NOD2 mutations, and all risk factors were assessed for independent influence on outcomes of disease site, behavior and surgery free survival.

Multipoint linkage detection in the presence of heterogeneity.

Linkage heterogeneity is common for complex diseases. It is well known that loss of statistical power for detecting linkage will result if one assumes complete homogeneity in the presence of linkage heterogeneity. To this end, Smith (1963, Annals of Human Genetics 27, 175-182) proposed an admixture model to account for linkage heterogeneity.