Home About us Contact
|
Home About us Contact | ||
|
|
||
Unrelated Controls (unrelated + control)
Selected AbstractsCandidate-gene association studies with pedigree data: Controlling for environmental covariatesGENETIC EPIDEMIOLOGY, Issue 4 2003S.L. Slager Abstract Case-control studies provide an important epidemiological tool to evaluate candidate genes. There are many different study designs available. We focus on a more recently proposed design, which we call a multiplex case-control (MCC) design. This design compares allele frequencies between related cases, each of whom are sampled from multiplex families, and unrelated controls. Since within-family genotype correlations will exist, statistical methods will need to take this into account. Moreover, there is a need to develop methods to simultaneously control for potential confounders in the analysis. Generalized estimating equations (GEE) are one approach to analyze this type of data; however, this approach can have singularity problems when estimating the correlation matrix. To allow for modeling of other covariates, we extend our previously developed method to a more general model-based approach. Our proposed methods use the score statistic, derived from a composite likelihood. We propose three different approaches to estimate the variance of this statistic. Under random ascertainment of pedigrees, score tests have correct type I error rates; however, pedigrees are not randomly ascertained. Thus, through simulations, we test the validity and power of the score tests under different ascertainment schemes, and an illustration of our methods, applied to data from a prostate cancer study, is presented. We find that our robust score statistic has estimated type I error rates within the expected range for all situations we considered whereas the other two statistics have inflated type I error rates under nonrandom ascertainment schemes. We also find GEE to fail at least 5% of the time for each simulation configuration; at times, the failure rate reaches above 80%. In summary, our robust method may be the only current regression analysis method available for MCC data. Genet Epidemiol 24:273,283, 2003. © 2003 Wiley-Liss, Inc. [source] Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate,,HUMAN MUTATION, Issue 1 2004F. Pezzetti Abstract The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investigated 110 sporadic CL/P patients, their parents and 289 unrelated controls for c.665C>T (commonly known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala) polymorphism in the MTHFR gene. Transmission disequilibrium test (TDT) showed no distortion in allele transmission. Nevertheless, association studies revealed significant differences in allele frequencies between mothers of CL/P patients and controls. This work supports the hypothesis that a lower MTHFR enzyme activity in pregnant women, mostly related to the c.665C>T variant form, is responsible for a higher risk of having CL/P affected offspring. © 2004 Wiley-Liss, Inc. [source] The increase in the frequency of MICA gene A6 allele in oral squamous cell carcinomaJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 6 2002Liu Chung-Ji Abstract Background: Oral squamous cell carcinoma (OSCC) was reported to be associated with immune function. The MICA (MHC class I chain-related gene A) is expressed by keratinocytes and other epithelial cells, and its encoded protein interacts with ,/, T cells localized in submucosa. The MICA also influences the heat shock protein function. We speculated that the alterations of MICA might influence the pathogenesis of OSCC through the aberration in presenting tumor antigens or heat shock protein. MICA gene has a triplet repeat (GCT) polymorphism in the transmembrane domain, resulting in five distinctive allelic patterns. Methods: We analysed this MICA polymorphism in 67 OSCC patients and 351 randomly selected unrelated controls. By using the ABI Prism 377,18 DNA sequencer (Applied Biosystems, Foster City, CA, USA) to analyse the sample DNA PCR products. The number of micro-satellite repeats was estimated with Genescan 672 software (Applied Biosystems) with a standard size marker of GS-350 TAMRA (N,N,N,N-tetramethyl-6-carbohydroxyl rhodamine; Applied Biosystems). Results: The phenotype frequency of allele A6 of MICA in subjects with OSCC was significantly higher than that in controls (RR = 3.46, 95% CI = 1.73,6.94, P = 0.0002), as was the frequency of allele (RR = 2.64, 95% CI = 1.39,5.02, P = 0.002). Conclusion: The results suggest that allele A6 in MICA might confer the risk of OSCC. [source] Parkinson's disease and LRRK2: Frequency of a common mutation in U.S. movement disorder clinicsMOVEMENT DISORDERS, Issue 4 2006Denise M. Kay PhD Abstract The G2019S mutation in the LRRK2 gene is reportedly a common cause of familial Parkinson's disease (PD) and may also have a significant role in nonfamilial PD. The objective of this study was to assess mutation carrier frequency in PD patients from movement disorder clinics in the United States, stratified by family history, age at onset, and geography; to determine carrier frequency in a large and well-characterized control population; to examine segregation of mutation in families of patients; and to correlate genotype with clinical phenotype. One thousand four hundred twenty-five unrelated PD patients from movement disorder clinics in Oregon, Washington, and New York and 1,647 unrelated controls were studied. The G2019S mutation was detected using a TaqMan assay and verified by sequencing. Eighteen of 1,425 patients and one of 1,647 controls had the mutation. Carrier frequency (± 2SE) in patients was 0.013 ± 0.006 overall, 0.030 ± 0.019 in familial PD, 0.007 ± 0.005 in nonfamilial PD, 0.016 ± 0.013 in early-onset PD, and 0.012 ± 0.007 in late-onset PD. Geographic differences were insignificant. Age at onset of mutation carriers ranged from 28 to 71 years. Mutation carriers were clinically indistinguishable from idiopathic PD. LRRK2 G2019S is the single most common pathogenic mutation linked to neurodegenerative disease to date. © 2005 Movement Disorder Society [source] Duration of breast feeding and bovine serum albumin antibody levels in type 1 diabetes: a case-control studyPEDIATRIC DIABETES, Issue 4 2003Francisco Pérez-Bravo Abstract:,Objective:, To compare the levels of bovine serum albumin (BSA) antibodies and their relationship with duration of breast feeding, age of exposure to cow's milk, and human leukocyte antigen (HLA-DQ) genotype in children with and without type 1 diabetes. Methods:, Serum samples from 143 (0.3,14.7 yr) newly diagnosed children with type 1 diabetes and 107 unrelated control children (0.8,13.5 yr) were evaluated for BSA antibodies. Duration of breast feeding and exposure to cow's milk were recorded on questionnaires. HLA-DQ typing was determined by polymerase chain reaction. Results:, One hundred percent of the diabetic children were positive for BSA antibodies compared to 1.9% for healthy controls (p < 0.001). Diabetic children also had higher levels of immunoglobulin G antibodies than unrelated controls (55.1 vs. 17.8 ng/mL, p < 0.0001). Duration of breast feeding (5.4 vs. 7.6 months, p < 0.02), but not age of exposure to cow's milk (8.3 vs. 9.2 months, p = 0.11), differed between cases and controls. There was no difference in antibody titer by duration of breast feeding or age of exposure to cow's milk in the cases or controls. Conclusion:, Higher levels of antibodies to BSA were found in children recently diagnosed with type 1 diabetes compared to the controls, particularly those with high or moderate HLA-DQ genotypes. The BSA profile, however, does not seem to depend on duration of breast feeding or age of exposure to cow's milk in this population. [source] Mixed-effects Logistic Approach for Association Following Linkage Scan for Complex DisordersANNALS OF HUMAN GENETICS, Issue 2 2007H. Xu Summary An association study to identify possible causal single nucleotide polymorphisms following linkage scanning is a popular approach for the genetic dissection of complex disorders. However, in association studies cases and controls are assumed to be independent, i.e., genetically unrelated. Choosing a single affected individual per family is statistically inefficient and leads to a loss of power. On the other hand, because of the relatedness of family members, using affected family members and unrelated normal controls directly leads to false-positive results in association studies. In this paper we propose a new approach using mixed-model logistic regression, in which associations are performed using family members and unrelated controls. Thus, the important genetic information can be obtained from family members while retaining high statistical power. To examine the properties of this new approach we developed an efficient algorithm, to simulate environmental risk factors and the genotypes at both the disease locus and a marker locus with and without linkage disequilibrium (LD) in families. Extensive simulation studies showed that our approach can effectively control the type-I error probability. Our approach is better than family-based designs such as TDT, because it allows the use of unrelated cases and controls and uses all of the affected members for whom DNA samples are possibly already available. Our approach also allows the inclusion of covariates such as age and smoking status. Power analysis showed that our method has higher statistical power than recent likelihood ratio-based methods when environmental factors contribute to disease susceptibility, which is true for most complex human disorders. Our method can be further extended to accommodate more complex pedigree structures. [source] Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitisARTHRITIS & RHEUMATISM, Issue 5 2009W. P. Maksymowych Objective Alterations in antigen processing have been proposed to play a significant role in the pathogenesis of ankylosing spondylitis (AS). A non,major histocompatibility complex gene encoding an endoplasmic reticulum aminopeptidase, ERAP1, has been implicated recently. This study assessed 13 coding single-nucleotide polymorphisms (SNPs) from 5 genes involved in antigen processing (ERAP1, TAP1, TAP2, LMP2, and LMP7) in 3 Canadian cohorts of patients with AS, to address the possibility of gene interactions in disease susceptibility. Methods The study involved 992 AS cases and 1,437 controls from 3 centers (472 cases and 451 controls from Alberta, 138 cases and 392 controls from Newfoundland, and 382 cases and 594 controls from Toronto). Most of the patients with AS and healthy, unrelated controls were Caucasians of northern European descent. Single-marker and haplotype associations were determined using an allelic likelihood ratio test in UNPHASED, version 3.0.12, and the WHAP program, respectively. P values for significance of haplotype associations were calculated using a permutation test. Results A specific ERAP1 haplotype, rs27044/10050860/30187-CCT, was strongly associated with increased risk of AS in all 3 case,control cohorts (pooled odds ratio [OR] 1.81, 95% confidence interval [95% CI] 1.46,2.24; P = 7 × 10,8), while a second specific ERAP1 haplotype, rs30187/26618/26653-CTG, reduced the disease risk (pooled OR 0.77, 95% CI 0.67,0.88; P = 9 × 10,5). Significant associations were also noted for 3 ERAP1 SNP variants (rs10050860, rs30187, and rs26653), although no significant haplotype interaction between ERAP1 and TAP/LMP loci was evident. Conclusion These data indicate that an AS disease locus may reside on a specific ERAP1 haplotype, and its effect is not multiplicative with contributions from TAP and LMP genes. [source] Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS geneACTA OPHTHALMOLOGICA, Issue 3 2010Kaja Kristine Selmer Abstract. Purpose:, This study aimed to identify the genetic cause of autosomal dominant pericentral retinal dystrophy (adPRD) in a large Norwegian family with 35 affected members. Methods:, The family was characterized by clinical ophthalmological examination along with fundus photography, dark adaptometry and electroretinography. We performed a genome-wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease. Results:, The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis. Linkage analysis showed a linkage peak covering the most recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a novel missense mutation, c.1205a>c, resulting in an amino acid substitution p.Q402P, was detected in all affected members. The mutation showed complete co-segregation with the disease in this family, with a LOD score of 7.3. It is located in a highly conserved region and alignment with the appropriate DNA sequence from other species shows complete conservation of this amino acid. The mutation was not detected in 207 healthy, unrelated controls of Norwegian origin. Conclusions:, We present a novel mutation in the TOPORS gene co-segregating with a distinct phenotype of adPRD in a large Norwegian family. [source] Molecular analysis of the CART gene in overweight and obese Italian children using family-based association methodsACTA PAEDIATRICA, Issue 5 2010L Rigoli Abstract Aim:, In our study, we evaluated if CART gene A1475G and ,A1457 polymorphisms could be associated with obesity. Patients and methods:, We recruited 133 Italian trios from among 103 (50 males and 53 females) overweight children (mean age 10.5 years, range 6,14 years; mean BMI 26.1 ± 3.2 kg/m2), and 30 (16 males and 14 females) obese children (mean age 9.0 years, range 6,11 years; mean BMI 32.3 ± 2.0 kg/m2). We also selected 187 non-obese unrelated controls. Results:, The allele frequencies of the A1475G single nucleotide polymorphism (SNP) were significantly higher in overweight children (0.07) than in control children (0.02) (p = 0.03) and control adults (0.02) (p = 0.02). Moreover, the allele frequencies were significantly different between obese children (0.08) and control children (0.02) (p = 0.03), and between obese children (0.08) and control adults (0.02) (p = 0.02). The ,A1457 SNP showed no significant association with overweight/obesity. TDT statistic revealed a preferential transmission of the 1475G allele from heterozygous parents to overweight children (p < 0.01) and to obese children (p < 0.05). No statistically significant excess transmission of the ,A1457 allele was found. Conclusion:, Our results supported the hypothesis that inherited variations of the CART gene could influence the development of obesity also in Italian children. [source] A novel mutation of the WRN gene in a Chinese patient with Werner syndromeCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2008N. Zhao Summary Werner syndrome (WS) is an autosomal recessive inherited disease characterized by features of premature ageing. It is caused by mutations of the WRN gene encoding a protein with both exonuclease and helicase activities. The aim of this study was to identify gene mutations in a Chinese patient with WS. A 31-year-old Chinese man with typical features of WS was diagnosed as having probable WS. We performed PCR to scan 33 exons of the WRN gene of the patient, six members of his family, and 50 unrelated controls. Automated DNA sequencing identified the mutation in the patient as 3250delG. The proband's parents, son, younger brother and paternal grandmother were heterozygous. We did not find this heterozygous mutation in the proband's maternal grandmother or in any of 50 normal controls. The novel mutation in the WRN gene is responsible for the pathogenesis of WS and genetic detection is a useful method to confirm the diagnosis. [source] | |||||||||||||