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PubMed2003

Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case-control association studies.

Single nucleotide polymorphisms (SNP) may be used in case-control designs to test for association between a SNP marker and a disease. Such designs may assume that the genotype data are reported without error. Our goal is quantifying the effects that errors have on sample size for case-control studies with haplotypes formed by a disease locus and a SNP marker locus in the presence of linkage disequilibrium (LD). We consider the effects of a recently published error model on 2x3 chi-square analysis. We study the joint relation of LD and errors with sample size for three specific genetic disease models and two settings each of marker allele frequencies (total of 6 studies). Minimal sample size necessary for fixed asymptotic power is estimated as a 4th degree polynomial in the variables S (error) and D' (LD measure) via a backward step-wise regression. We find that increased error rates lower power. In all studies, we observe that LD and errors interact in a non-linear fashion. In particular, regression analyses shows that several higher order interaction terms have coefficients significantly different from 0 in each study, with fraction of variance explained greater than 0.9999. Finally, the increase in sample size necessary to maintain constant asymptotic power and level of significance as a function of S is smallest when D' = 1 (perfect LD). The increase grows monotonically as D' decreases to 0.5 for all studies.

Case-Control Studies↗

PubMed2004

Reconstruction of ancestral haplotypes in a 12-generation schizophrenia pedigree.

We searched for candidate chromosomal regions inherited identical by descent in 19 patients suffering from schizophrenia or schizoaffective disorder that are related 12 generations back, to an ancestral couple born in the middle of the seventeenth century. To accomplish this goal, we constructed complete chromosomal haplotypes for each patient using genotype data from 450 markers. In total, 12 haplotype regions (with sizes ranging from 0.6 to 10.9 cM) constituted by three markers each were identical in three or more of the affected individuals. The largest genomic segment was located on 6q25, a region previously shown to be significantly more frequent in patients than controls, and proposed to contain a schizophrenia susceptibility locus. For the remaining 11 candidate haplotypes, we estimated haplotype frequencies from all the 43 affected members collected from the same family and 46 unrelated control individuals. This analysis indicated that at least four of the 11 candidate haplotypes are ancestral, since the frequencies were significantly higher in patients than in controls. Five additional haplotypes showed higher estimated frequencies in the patients but the differences were not significant. Interestingly, five of these 11 genomic regions are located in, or close to, candidate regions previously suggested to contain susceptibility genes for schizophrenia. The regions are 5q21-23, 8p21-22, 10p13-15, 13q12-13 and 22q12-13. Several of these haplotypes are probably ancestral linkage disequilibrium blocks inherited from the original couple. There exists, however, the possibility that one or more of these regions harbour schizophrenia susceptibility loci that may have epistatic interactions among them.

Chromosomes, Human↗

PubMed2005

Comparison of HIV type 1 protease inhibitor susceptibility results in viral samples analyzed by phenotypic drug resistance assays and by six resistance algorithms: an analysis of a subpopulation of the CHORUS cohort.

Drug resistance testing is increasingly used to guide treatment decisions in patients infected with HIV-1. A number of rules-based algorithms have been designed to predict drug resistance profiles based on the HIV-1 genotypic data. Drug-resistance mutations in 206 viral samples from protease inhibitor (PI)-experienced subjects with HIV-1 infection were assessed, and the level of susceptibility of the samples predicted using seven unique algorithms. kappa scores were used to compare agreement of results obtained using each of the predictive algorithms with the phenotypic assay results. Good overall agreement between the different algorithms and the phenotypic results was observed. Good or excellent agreement was observed between the results obtained by the predictive algorithms and the phenotypic assay results for ritonavir, indinavir, saquinavir, and nelfinavir. For amprenavir and lopinavir, there were marked differences between the different algorithms, with poor agreement (kappa < 0.40) obtained with four of the seven algorithms for amprenavir. For lopinavir, poor agreement was obtained with three of seven algorithms using the 2.5-fold biological cut-off and four of seven with the clinical cut-off of 10. Atazanavir susceptibility was evaluated for concordance among six algorithms, with a range of 23-50% of the samples maintaining susceptibility. Although this cohort of patients included many who were highly antiretroviral experienced, predictive algorithms demonstrated good agreement with phenotype for several Pls. For those where discordance among algorithms existed, further improvement will likely occur as drug resistance pathways for the more recently approved PIs are elucidated.

Adult↗

PubMed2000

Linkage analysis of candidate regions in Swedish nonsyndromic cleft lip with or without cleft palate families.

OBJECTIVE: To analyze linkage of five candidate regions for nonsyndromic cleft lip with or without palate (CLP) on chromosome 2p13, 4q, 6p23, and 19q13; in addition chromosome 1q32, the locus for van der Woude syndrome, on Swedish CLP families. DESIGN: Three to five linked microsatellite markers were selected from each candidate region. Polymerase chain reaction (PCR) with fluorescent-labeled microsatellite markers was performed on DNA samples from the participating families. Electrophoresis of the PCR products was performed on a laser-fluorescent DNA sequencer. The genotype data were analyzed with multipoint linkage analysis. Modes of inheritance tested included two autosomal dominant, an autosomal recessive, and a nonparametric model. Multipoint logarithm of odds (LOD) scores were also calculated by assuming genetic heterogeneity. PARTICIPANTS: Nineteen Swedish multigenerational families with at least two first-degree relatives affected with CLP. Greater than 50% of the families studied show vertical transmission of the clefting phenotype and both inter- and intrafamilial variability were noted. RESULTS: Cumulative multipoint LOD scores for the whole group of families calculated under autosomal dominant modes of inheritance were negative in all regions and less than -2 except chromosome 6p23. LOD scores calculated under recessive inheritance and the nonparametric model were inconclusive. There was no significant evidence of genetic heterogeneity among the sample group. CONCLUSIONS: The group of Swedish CLP families did not demonstrate significant linkage to any of the five candidate regions examined. This might suggest a new but yet unknown CLP locus or loci in this family group. However, because linkage could not be excluded in some individual families, they should still be tested with candidate genes from these regions.

Chromosome Mapping↗

PubMed1997

Clinical and genetic analysis of a family affected with dominant optic atrophy (OPA1)

OBJECTIVES: To refine the dominant optic atrophy locus, OPA1, on chromosome 3q and to characterize the phenotype of a 6-generation family pedigree affected with this disease. METHODS: Fifty-six family members had a complete eye examination. Clinical records of an additional 3 patients were reviewed. Goldmann perimetry and a 21-chip subtest of the Farnsworth-Munsell 100-Hue test were performed on selected patients. Affected patients, unaffected siblings, and potentially informative spouses were genotyped with short tandem repeat polymorphisms located on chromosome 3. The genotypic data were subjected to linkage analysis. RESULTS: Thirty-four family members were found to be clinically affected. Most experienced vision loss (20/40 or poorer) in the first decade of life. Most (9 of the 16 eyes) progressed to 20/800 or poorer visual acuity by age 60 years, while 2 patients maintained visual acuities of 20/40 at that age. Affected patients had a 2- to 10-fold increase in the error score of a 21-chip subtest of the Farnsworth-Munsell 100-Hue test compared with age-matched unaffected family members. The optic nerve examination revealed temporal pallor and excavation in all affected individuals. Linkage analysis revealed significant lod scores with 9 markers. The highest lod score, 10.1 (theta = 0) [corrected], was obtained with marker D3S2305. Analysis of recombinants narrowed the disease interval to approximately 3.8 centimorgans, flanked by D3S3669 (centromeric) and D3S1305 (telomeric). CONCLUSIONS: Most patients affected with dominant optic atrophy in this family progressed to legal blindness by middle age. Color vision testing is a sensitive method for detection of affected patients. The dominant optic atrophy locus, OPA1, has been refined by the identification of new flanking markers: D3S3669 (centromeric) and D3S1305 (telomeric).

Adolescent↗

PubMed2007

A procedure for the detection of linkage with high density SNP arrays in a large pedigree with colorectal cancer.

BACKGROUND: The apparent dominant model of colorectal cancer (CRC) inheritance in several large families, without mutations in known CRC susceptibility genes, suggests the presence of so far unidentified genes with strong or moderate effect on the development of CRC. Linkage analysis could lead to identification of susceptibility genes in such families. In comparison to classical linkage analysis with multi-allelic markers, single nucleotide polymorphism (SNP) arrays have increased information content and can be processed with higher throughput. Therefore, SNP arrays can be excellent tools for linkage analysis. However, the vast number of SNPs on the SNP arrays, combined with large informative pedigrees (e.g. >35-40 bits), presents us with a computational complexity that is challenging for existing statistical packages or even exceeds their capacity. We therefore setup a procedure for linkage analysis in large pedigrees and validated the method by genotyping using SNP arrays of a colorectal cancer family with a known MLH1 germ line mutation. METHODS: Quality control of the genotype data was performed in Alohomora, Mega2 and SimWalk2, with removal of uninformative SNPs, Mendelian inconsistencies and Mendelian consistent errors, respectively. Linkage disequilibrium was measured by SNPLINK and Merlin. Parametric linkage analysis using two flanking markers was performed using MENDEL. For multipoint parametric linkage analysis and haplotype analysis, SimWalk2 was used. RESULTS: On chromosome 3, in the MLH1-region, a LOD score of 1.9 was found by parametric linkage analysis using two flanking markers. On chromosome 11 a small region with LOD 1.1 was also detected. Upon linkage disequilibrium removal, multipoint linkage analysis yielded a LOD score of 2.1 in the MLH1 region, whereas the LOD score dropped to negative values in the region on chromosome 11. Subsequent haplotype analysis in the MLH1 region perfectly matched the mutation status of the family members. CONCLUSION: We developed a workflow for linkage analysis in large families using high-density SNP arrays and validated this workflow in a family with colorectal cancer. Linkage disequilibrium has to be removed when using SNP arrays, because it can falsely inflate the LOD score. Haplotype analysis is adequate and can predict the carrier status of the family members.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Risk of celiac disease in children with type 1 diabetes is modified by positivity for HLA-DQB102-DQA105 and TNF -308A.

OBJECTIVE: The overlap between genetic susceptibility to celiac disease (CD) and to type 1 diabetes is incomplete; therefore, some genetic polymorphisms may significantly modify the risk of CD in subjects with type 1 diabetes. This study aimed to investigate whether the susceptibility to CD in diabetic children is modified by positivity for HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03 and by alleles of single nucleotide polymorphisms within the genes encoding CTLA4, transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1, IL-2, IL-6, and IL-10. RESEARCH DESIGN AND METHODS: Genotypic data were compared between 130 case subjects (children with type 1 diabetes and CD diagnosed using endomysium antibodies) and 245 control subjects (children with type 1 diabetes only, optimally two per case, matched for center, age at type 1 diabetes onset, and type 1 diabetes duration). The subjects were recruited from 10 major European pediatric diabetes centers performing regular screening for CD. The polymorphisms were determined using PCR with sequence-specific primers, and the risk was assessed by building a step-up conditional logistic regression model using variables that were significantly associated with CD in the univariate analysis. RESULTS: The best-fitted model showed that risk of CD is increased by presence of HLA-DQB1*02-DQA1*05 (odds ratio 4.5 [95% CI 1.8-11], for homozygosity, and 2.0 [1.1-3.7], for a single dose) and also independently by TNF -308A (1.9 [1.1-3.2], for phenotypic positivity), whereas IL1-alpha -889T showed a weak negative association (0.6 [0.4-0.9]). CONCLUSIONS: The results indicate that the risk of CD in children with type 1 diabetes is significantly modified both by the presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene within the major histocompatibility complex, the TNF -308A.

Adolescent↗

PubMed2002

A genome-wide scan for loci linked to plasma levels of glucose and HbA(1c) in a community-based sample of Caucasian pedigrees: The Framingham Offspring Study.

Elevated blood glucose levels are the hallmark of type 2 diabetes as well as a powerful risk factor for development of the disease. We conducted a genome-wide search for diabetes-related genes, using measures of glycemia as quantitative traits in 330 pedigrees from the Framingham Heart Study. Of 3,799 attendees at the 5th Offspring Study exam cycle (1991--1995), 1,461, 1,251, and 771 men (49%) and women provided information on levels of 20-year mean fasting glucose, current fasting glucose, and HbA(1c), respectively, and 1,308 contributed genotype data (using 401 microsatellite markers with an average spacing of 10 cM). Levels of glycemic traits were adjusted for age, cigarette smoking, alcohol and estrogen use, physical activity, and BMI. We ranked standardized residuals from these models, created normalized deviates from the ranks, and used the variance component model implemented in SOLAR (Sequential Oligogenic Linkage Analysis Routines) to evaluate linkage to normalized deviates as quantitative traits. We found peak evidence for linkage to 20-year mean fasting glucose levels on chromosome 1 at approximately 247 cM from p-telomere (pter) (multipoint logarithm of odds [LOD] 2.33) and on chromosome 10 at approximately 86 cM from pter (multipoint LOD 2.07); to current fasting glucose levels on chromosome 1 at approximately 218 cM from pter (multipoint LOD 1.80) and on chromosome 10 at approximately 96 cM from pter (multipoint LOD 2.15); and to HbA(1c) levels on chromosome 1 at approximately 187 cM (multipoint LOD 2.81). This analysis of unselected European Caucasian pedigrees suggests localization of quantitative trait loci influencing glucose homeostasis on chromosomes 1q and 10q. Findings at approximately 187--218 cM on chromosome 1 appear to replicate linkage reported in previous studies of other populations, pointing to this large chromosomal region as worthy of more detailed scrutiny in the search for type 2 diabetes susceptibility genes.

Adult↗

PubMed1997

Phenotypic and genotypic characterization of Vagococcus fluvialis, including strains isolated from human sources.

This study presents phenotypic and genotypic data for seven isolates of Vagococcus fluvialis, including four strains recovered from human clinical sources, one strain isolated from an environmental source, and two strains isolated from pigs. On the basis of phenotypic characteristics, most isolates were initially classified as "unidentified enterococci," because they resembled atypical arginine-negative enterococcal species. All seven strains as well as the type strain of V. fluvialis reacted with the AccuProbe Enterococcus genetic probe. The seven isolates had virtually indistinguishable whole-cell protein profiles that were similar to that of the V. fluvialis type strain and distinct from those of Enterococcus and Lactococcus species. DNA-DNA reassociation experiments confirmed that the strains were V. fluvialis. They were 71% or more related to the V. fluvialis type strain under optimum and stringent conditions, with 2.5% or less divergence within related sequences. All strains were susceptible to ampicillin, cefotaxime, trimethoprim-sulfamethoxazole, and vancomycin and were resistant to clindamycin, lomefloxacin, and ofloxacin. Strain-to-strain variation was observed in relation to susceptibilities to 18 other antimicrobial agents. Chromosomal DNA was analyzed by pulsed-field gel electrophoresis (PFGE) after digestion with SmaI. Distinctive PFGE patterns were generated, suggesting the nonclonal nature of V. fluvialis strains. Although the number of strains was small, this report provides molecular characterization of V. fluvialis and the first evidence of a possible connection of this species with human infections.

Animals↗

PubMed2000

A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans.

Although several genetic forms of rare or syndromic hypertriglyceridemia have been reported, little is known about the specific chromosomal regions across the genome harboring susceptibility genes for common forms of hypertriglyceridemia. Therefore, we conducted a genomewide scan for susceptibility genes influencing plasma triglyceride (TG) levels in a Mexican American population. We used both phenotypic and genotypic data from 418 individuals distributed across 27 low-income, extended Mexican American families. For the analyses, TG values were log transformed (ln TG). We used a variance-components technique to conduct multipoint linkage analyses for localizing susceptibility genes that determine variation in TG levels. We used an approximately 10-15-cM map, which was made on the basis of information from 295 microsatellite markers. After accounting for the effects of sex and sex-specific age terms, we found significant evidence for linkage (LOD = 3.88) of ln TG levels to a genetic location between the markers GABRB3 and D15S165 on chromosome 15q. This putative locus explains 39.7+/-7% (P=.000012) of total phenotypic variation in ln TG levels. Suggestive evidence was found for linkage of ln TG levels to two different locations on chromosome 7, which are approximately 85 cM apart from each other. Also, there is some evidence for linkage of high-density lipoprotein cholesterol concentrations to a genetic location near one of the regions on chromosome 7. In conclusion, we found strong evidence for linkage of ln TG levels to a genetic location on chromosome 15q in a Mexican American population, which is prone to disease conditions such as type 2 diabetes and the insulin-resistance syndrome that are associated with hypertriglyceridemia. This putative locus appears to have a major influence on ln TG variation.

Adult↗

PubMed2026

Genetics of major depressive disorder in a homogeneous population with uniform phenotyping.

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. Liability-scale SNP-based heritability was 12.0% (SE = 1.4%) as estimated by LDSC (assuming a lifetime prevalence of 15%) and 26.6% (SE = 1.1%) when estimated by LDAK-REML on individual-level genotype data, indicating substantial common-variant signal in this clinically harmonized sample. The genetic correlation with the latest major depression GWAS from the Psychiatric Genomics Consortium (PGC-MD) was high (rG = 0.89, SE = 0.048). Polygenic scores (PGSs) based on BIONIC predicted depression in UK Biobank, and PGSs derived from PGC-MD predicted MDD in BIONIC, supporting transferability of depression polygenic signal across cohorts and phenotype definitions. Within-family PGS analyses in twins suggested that the observed prediction was not primarily driven by detectable family-level confounding, and twin concordance for MDD increased with polygenic burden. We identified one genome-wide significant locus, indexed by rs3818852 in PALMD, but this finding currently lacks independent replication and should be interpreted cautiously. Finally, genetic correlation and latent causal variable analyses identified multiple traits showing shared or directionally consistent genetic associations with MDD. Together, these findings underscore the value of clinically harmonized phenotyping in regional biobank collaborations for studying the genetic architecture of MDD.

Humans↗

PubMed2003

Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis.

OBJECTIVE: Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis. METHODS: Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated. RESULTS: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed. CONCLUSION: The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.

Alleles↗

PubMed1998

Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations.

Waardenburg syndrome (WS) type 1 is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary abnormalities of the eye, hair, and skin, and dystopia canthorum. The phenotype is variable and affected individuals may exhibit only one or a combination of several of the associated features. To assess the relationship between phenotype and gene defect, clinical and genotype data on 48 families (271 WS individuals) collected by members of the Waardenburg Consortium were pooled. Forty-two unique mutations in the PAX3 gene, previously identified in these families, were grouped in five mutation categories: amino acid (AA) substitution in the paired domain, AA substitution in the homeodomain, deletion of the Ser-Thr-Pro-rich region, deletion of the homeodomain and the Ser-Thr-Pro-rich region, and deletion of the entire gene. These mutation classes are based on the structure of the PAX3 gene and were chosen to group mutations predicted to have similar defects in the gene product. Association between mutation class and the presence of hearing loss, eye pigment abnormality, skin hypopigmentation, or white forelock was evaluated using generalized estimating equations, which allowed for incorporation of a correlation structure that accounts for potential similarity among members of the same family. Odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the Pro-Ser-Thr-rich region compared to individuals with an AA substitution in the homeodomain. Odds ratios that differ significantly from 1.0 for these traits may indicate that the gene products resulting from different classes of mutations act differently in the expression of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for AA substitution in the paired domain compared with AA substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.

DNA-Binding Proteins↗

PubMed2006

Case-control and case-only designs with genotype and family history data: estimating relative risk, residual familial aggregation, and cumulative risk.

In case-control studies of inherited diseases, participating subjects (probands) are often interviewed to collect detailed data about disease history and age-at-onset information in their family members. Genotype data are typically collected from the probands, but not from their relatives. In this article, we introduce an approach that combines case-control analysis of data on the probands with kin-cohort analysis of disease history data on relatives. Assuming a marginally specified multivariate survival model for joint risk of disease among family members, we describe methods for estimating relative risk, cumulative risk, and residual familial aggregation. We also describe a variation of the methodology that can be used for kin-cohort analysis of the family history data from a sample of genotyped cases only. We perform simulation studies to assess performance of the proposed methodologies with correct and mis-specified models for familial aggregation. We illustrate the proposed methodologies by estimating the risk of breast cancer from BRCA1/2 mutations using data from the Washington Ashkenazi Study.

BRCA1 Protein↗

PubMed2000

Mutation analysis of 3 genes in patients with Leber congenital amaurosis.

OBJECTIVE: To assess the frequency of mutations in the CRX, GUCY2D, and RPE65 genes in patients with Leber congenital amaurosis (LCA). PATIENTS: One hundred seventy-six probands with a clinical diagnosis of LCA were from 9 countries, with the largest subgroup being 39 probands from India. METHODS: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. RESULTS: Of the 176 probands, 28 (15.9%) harbored possible disease-causing mutations. The relative contribution of each gene to the total number of mutations was as follows: CRX, 2.8%; GUCY2D, 6.3%; and RPE65, 6.8%. No patients who harbored mutations in these genes had associated systemic abnormalities. Molecular diagnosis allowed definitive genetic counseling in a family affected with Best disease and LCA. CONCLUSIONS: Molecular diagnosis may be of benefit to patients affected with LCA. The relative paucity of mutations found in this study suggests that more LCA-associated genes remain to be discovered. CLINICAL RELEVANCE: Molecular diagnosis can confirm and clarify the diagnosis of LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations will be established. This will facilitate the counseling of patients on their visual prognosis and the likelihood of associated systemic anomalies.

Adolescent↗

PubMed2001

Mutations in the CRB1 gene cause Leber congenital amaurosis.

OBJECTIVES: To test the hypothesis that mutations in the CRB1 gene cause Leber congenital amaurosis (LCA) and, if so, to describe the ocular phenotype of patients with LCA who harbor CRB1 sequence variations. PATIENTS: One hundred ninety probands with a clinical diagnosis of LCA were selected from a cohort of 233 probands ascertained in 5 different countries. The remaining 43 probands (18%) were excluded because they harbored sequence variations in previously identified LCA genes. METHODS: One hundred ninety unrelated individuals with LCA were screened for coding sequence mutations in the CRB1 gene with single-strand conformation polymorphism analysis followed by automated DNA sequencing. RESULTS: Twenty-one of the 190 probands (9% of the total cohort of 233) and 2 (1.4%) of 140 controls harbored amino acid-altering sequence variations in the CRB1 gene (P =.003). CONCLUSIONS: In our cohort of patients with LCA, coding sequence variations were observed in the CRB1 gene more frequently than in any of the other 5 known LCA-associated genes. Likely disease-causing sequence variations have now been identified in 64 (28%) of 233 subjects in this cohort. CLINICAL RELEVANCE: Molecular diagnosis can confirm and clarify the diagnosis in an increasing fraction of patients with LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations may be established. This will facilitate the counseling of patients regarding their visual prognosis and the likelihood of associated systemic anomalies.

Adolescent↗

PubMed1997

Expression of cytotoxic molecules in intestinal T-cell lymphomas. The German Study Group on Intestinal Non-Hodgkin Lymphoma.

Intestinal T-cell lymphoma (ITCL) represents a subgroup of peripheral T-cell lymphomas which is thought to arise from alpha beta intraepithelial T-lymphocytes. Since these lymphocytes may contain cytotoxic molecules, the question of whether this also holds true for ITCL arises. Twenty ITCL cases were examined for the presence of granzyme B, perforin, and T-cell-restricted intracellular antigen (TIA-1)/granule membrane protein of 17 kD (GMP-17). Two molecules with restricted expression in cytotoxic cells, granzyme B and perforin, were detected by immunocytochemistry and by in situ hybridization with an isotopically labelled RNA probe, respectively. Immunocytochemistry was also performed with the antibody 2G9, which recognizes two molecules, one expressed by cytotoxic cells (TIA-1) and the other found in granulocytes and cytotoxic cells (GMP-17). Granzyme B, TIA-1/GMP-17, and perforin were found in the neoplastic cells of 16/19 cases, 19/20 cases, and 16/17 cases, respectively, of ITCL, but not in the tumour cells of the control group, which consisted of intestinal B-cell lymphomas (five cases) and CD8-negative peripheral nodal T-cell lymphomas (six cases). At least one of these molecules was expressed in the tumour cells of all ITCL cases. 2G9 proved to be the most sensitive immunohistological marker, since reactivity with this antibody was not only observed in the highest number of cases, but also found in high numbers of neoplastic cells in positive cases. In conclusion, ITCL appears to show cytotoxic differentiation in all cases. In conjunction with immunophenotypic and genotypic data, our results support a uniform derivation of this tumour from intraepithelial alpha beta cytotoxic T-lymphocytes.

Adult↗

PubMed1999

Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study.

OBJECTIVE: To accurately determine the contributions of HLA-DRB1 alleles in explaining susceptibility to inflammatory polyarthritis in a large, true population-based cohort of new-onset cases. METHODS: A cohort of 680 consecutive patients with inflammatory polyarthritis, of whom 404 satisfied the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), was recruited from the population-based Norfolk Arthritis Register. All cases were compared with 286 local population controls. A standardized clinical assessment was performed on all patients. HLA-DRB1 phenotypes, including DR4 subtypes, were determined using a semiautomated, reverse dot-blot method. Results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: There was only a modest association (OR 1.8, 95% CI 1.4-2.4) between inflammatory polyarthritis and the presence of any shared epitope (SE) allele; the strongest individual risk was with DRB1*0404 (OR 3.5, 95% CI 1.8-6.8). Comparison of the genotypes demonstrated that the effect of being SE homozygous (OR 2.1, 95% CI 1.5-3.0) was only moderately greater than the effect of being SE heterozygous (OR 1.3, 95% CI 1.1-1.6). The exception to this was genotypic combinations that included HLA-DRB1*0404, which exhibited ORs ranging up to 18.0. There were no differences between either the phenotype or genotype data when the patients were stratified by RA status (defined by the ACR criteria). In contrast, the associations were substantially stronger in patients who were positive for rheumatoid factor. CONCLUSION: Previous studies had not been able to clarify whether the influence of HLA-DRB1 on RA was related to disease susceptibility or to disease severity and progression. These data on a unique population-based incident cohort suggest only weak effects on susceptibility, with the exception of the clearly distinct influence of HLA-DRB1*0404.

Alleles↗