Biomedical subjects

K L Lunetta

Publications and source records attributed to K L Lunetta.

At least 19 recordsLinked to original sources

PubMed2006

Genetic association between endothelial nitric oxide synthase and Alzheimer disease.

Evidence suggests that vascular and inflammatory factors may be important in the etiology of Alzheimer disease (AD). The Glu/Glu genotype at the Glu298Asp variant of the endothelial nitric oxide synthase (NOS3) gene has been tested for association with AD in several Caucasian and Asian populations, with conflicting results. We tested the Glu298Asp variant for association in African American and Caucasian AD patients, unaffected siblings, and unrelated controls from the MIRAGE Study. To explore whether the inconsistent results in previous studies might be due to linkage disequilibrium with a polymorphism or haplotype not previously tested, we genotyped 10 additional NOS3 single nucleotide polymorphisms (SNPs) spanning 25.3 kb. Finally, we compiled results of previous studies of Glu298Asp using meta-analysis, to determine whether the aggregate studies support an association between Glu298Asp and AD. We found that the Glu298 allele was associated with higher risk of AD in the MIRAGE African American (p = 0.002) but not Caucasian (p = 0.9) groups. None of the additional SNPs were associated with AD in the Caucasians, whereas two showed evidence for association in the African Americans. The meta-analysis showed a small effect of the Glu298Asp GG genotype on AD risk across all studies (summary odds ratio = 1.15, 95% confidence interval: 0.97-1.35) and significant heterogeneity of this association among studies (p = 0.02).

Black or African American↗

PubMed2001

HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells.

To identify molecular alterations implicated in the initiating steps of breast tumorogenesis, we compared the gene expression profiles of normal and ductal carcinoma in situ (DCIS) mammary epithelial cells by using serial analysis of gene expression (SAGE). Through the pair-wise comparison of normal and DCIS SAGE libraries, we identified several differentially expressed genes. Here, we report the characterization of one of these genes, HIN-1 (high in normal-1). HIN-1 expression is significantly down regulated in 94% of human breast carcinomas and in 95% of preinvasive lesions, such as ductal and lobular carcinoma in situ. This decrease in HIN-1 expression is accompanied by hypermethylation of its promoter in the majority of breast cancer cell lines (>90%) and primary tumors (74%). HIN-1 is a putative cytokine with no significant homology to known proteins. Reintroduction of HIN-1 into breast cancer cells inhibits cell growth. These results indicate that HIN-1 is a candidate tumor suppressor gene that is inactivated at high frequency in the earliest stages of breast tumorogenesis.

Amino Acid Sequence↗

PubMed2001

Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients.

BACKGROUND: The importance of the bone marrow microenvironment in multiple myeloma is receiving increasing attention. Recent studies have suggested the importance of cytokine production and cell-cell contact by bone marrow stromal cells in the survival of myeloma cells. METHODS: In the current study, the authors examined bone marrow mesenchymal progenitor cell (MPC) cultures derived from eight multiple myeloma patients (mean age, 58 years) and nine normal donors (mean age, 61 years), with emphasis on cell surface antigens, cytokine, and growth factor expression. RESULTS: The authors have found, based on analysis of cellular receptors, growth factors, and cytokine expression, that myeloma MPCs are phenotypically and functionally distinguishable from normal donor MPCs. Immunofluorescence analysis of MPC monolayers shows that myeloma MPC cultures expressed reduced cell surface vascular cell adhesion molecule-1 and fibronectin, in contrast with the strong expression found on normal donor MPCs. Furthermore, a subset of myeloma MPCs strongly express intracellular receptor for hyaluronan-mediated motility, whereas normal MPCs do not. Cytokine expression in bone marrow MPC cultures was examined by reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Bone marrow MPCs constitutively express interleukin (IL)-1beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, stem cell factor (SCF), and tumor necrosis factor (TNF)-alpha. In comparison to normal MPCs, multiple myeloma MPCs express increased basal levels of IL-1beta and TNF-alpha. In vitro exposure of MPC cultures to dexamethasone resulted in the down-regulation of IL-6, G-CSF, and GM-CSF in both normal and myeloma MPC cultures. However, dexamethasone treatment significantly increased expression of SCF-1 in myeloma MPCs. CONCLUSIONS: In myeloma, bone marrow stromal cells provide paracrine factors, through cytokine production and cell-cell contact, which play a role in plasma cell growth and survival. The authors' data indicate differences in bone marrow MPCs, which may be biologically relevant to the growth and survival of myeloma plasma cells.

Adult↗

PubMed2001

On the validity of the TDT test in the presence of comorbidity and ascertainment bias.

Comorbidity, the association of two disorders, occurs commonly with complex diseases. In this paper, we investigate the effects of both true (within-family) comorbidity and spurious comorbidity due to ascertainment bias on the validity of both the parental and sibling control transmission/disequilibrium test. Specifically, we consider settings in which a candidate gene is unlinked to the target phenotype but is in linkage disequilibrium with a comorbid phenotype. We derive conditions under which the presence of true and/or spurious comorbidity will result in an artificial correlation between the target phenotype and the candidate gene.

Bias↗

PubMed2000

Phenol sulfotransferases: hormonal regulation, polymorphism, and age of onset of breast cancer.

In recent years, significant effort has been made to identify genes that influence breast cancer risk. Because the high-penetrance breast cancer susceptibility genes BRCA1 and 2 play a role only in a small fraction of breast cancer cases, understanding the genetic risk of the majority of breast cancers will require the identification and analysis of several lower penetrance genes. The estrogen-signaling pathway plays a crucial role in the pathophysiology of breast cancer; therefore, polymorphism in genes involved in this pathway is likely to influence breast cancer risk. Our detailed analysis of gene expression profiles of estrogen- and 4-OH-tamoxifen-treated ZR75-1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A) phenol sulfotransferase family as downstream targets of tamoxifen. On the basis of the induction of SULT1A by 4-OH-tamoxifen and the known inherited variability in SULT1A enzymatic activity, we hypothesized that polymorphism in sulfotransferase genes might influence the risk of breast cancer. Using an RFLP that distinguishes an arginine to histidine change in exon 7 of the SULT1A1 gene, we characterized SULT1A1 genotypes in relation to breast cancer risk. An analysis of 444 breast cancer patients and 227 controls revealed no effect of SULT1A1 genotype on the risk of breast cancer (P = 0.69); however, it did appear to influence the age of onset among early-onset affected patients (P = 0.04). Moreover, individuals with the higher activity SULT1A1*1 allele were more likely to have other tumors in addition to breast cancer (P = 0.004; odds ratio, 3.02; 95% confidence interval, 1.32, 8.09). The large number of environmental mutagens and carcinogens activated by sulfotransferases and the high frequency of the SULT1A1*1 allele in human populations warrants additional studies to address the role of SULT genes in human cancer.

Adult↗

PubMed2000

Implications of comorbidity and ascertainment bias for identifying disease genes.

Comorbidity, the co-occurrence of disorders, is frequently observed to occur at higher rates in clinically ascertained samples than in population-based samples. An explanation for this finding is that subjects suffering from multiple illnesses are more likely to seek medical care and receive a diagnostic evaluation. We refer to the component of the comorbidity between illnesses due to such ascertainment bias as "spurious comorbidity." When spurious comorbidity is present, an apparent association between a candidate locus and the phenotype of interest may actually be attributable to an association between the locus and a comorbid phenotype. This phenomenon, which we call "spurious comorbidity bias," could thus produce misleading association findings. In this article, we describe this phenomenon and demonstrate that it may produce marked bias in the conclusions of family-based association studies. Because of the extremely high rates of comorbidity among psychiatric disorders in clinical samples, this problem may be particularly salient for genetic studies of neuropsychiatric disorders. We conclude that ascertainment bias may contribute to the frequent difficulty in replicating candidate gene study findings in psychiatry. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:817-822, 2000.

Alleles↗

PubMed2000

Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.

Somatic mutations in mtDNA have recently been identified in colorectal tumours. Studies of oncocytic tumours have led to hypotheses which propose that defects in oxidative phosphorylation may result in a compensatory increase in mitochondrial replication and/or gene expression. Mutational analysis of mtDNA in thyroid neoplasia, which is characterised by increased numbers of mitochondria and is also one of the most common sites of oncocytic tumours. has been limited to date. Using the recently developed technique of two-dimensional gene scanning, we have successfully examined 21 cases of thyroid tumours, six cases of non-neoplastic thyroid pathology, 30 population controls, nine foetal thyroid tissues and nine foetal tissues of non-thyroid origin, either kidney or liver. We have identified three different somatic mutations (23%) in papillary thyroid carcinomas. In addition, we have found significant differential distributions of mtDNA sequence variants between thyroid carcinomas and controls. Interestingly, these variants appear to be more frequent in the genes which encode complex I of the mitochondrial electron transport chain compared to normal population controls. These findings suggest first, that somatic mtDNA mutations may be involved in thyroid tumorigenesis and second, that the accumulation of certain non-somatic variants may be related to tumour progression in the thyroid.

Adenoma↗

PubMed2000

Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions.

We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a phenotype and any number of predictors. We then construct a score statistic, using likelihoods for the distribution of phenotype, given genotype. The distribution of the score is computed as a function of offspring genotypes, conditional on parental genotypes and trait values for offspring and parents. This approach provides a natural extension of the transmission/disequilibrium test to any phenotype and to multiple genes or environmental factors and allows the study of gene-gene and gene-environment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one or more nuisance parameters. We suggest two approaches for obtaining parameter estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter and using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how covariates and gene-environment and gene-gene interactions can be incorporated.

Alleles↗

PubMed1999

Exploring linkage for alcoholism using affection status and quantitative event related potential phenotypes.

Using genome-scan data from the Collaborative Study on the Genetics of Alcoholism (COGA), we compared results of linkage analyses using a qualitative alcoholism phenotype to results of linkage analyses using event related potential (ERP) quantitative phenotypes, and compared our results to the results of Reich et al. [1998] and Begleiter et al. [1998]. We describe a general and simple strategy for identifying regions of the genome which may harbor genes involved in alcohol dependence which takes into consideration the results of both the affection status and ERP linkage analyses.

Alcoholism↗

PubMed1999

Using recursive partitioning for exploration and follow-up of linkage and association analyses.

We first conducted a genome-wide screen for association with discordant sibships using the multi allelic and diallelic SDT. Markers at D4S1628, D8S1109, D9S66 and D7S1797 showed multi-allelic association. Deleterious diallelic association was found for markers at D1S1613, D1S534, D3S2459, D7S1817, and D9S131. Protective association was found at markers D8S1109, D8S1136, and D9S66. We then incorporated these findings with previous linkage findings in the exploration of oligogenes and epistasis using recursive partitioning. We conclude that recursive partitioning can be a useful adjunct to traditional linkage and association analyses in the exploration of these effects.

Alcoholism↗

PubMed1999

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Abnormalities, Multiple↗

PubMed1998

Strategy for mapping minor histocompatibility genes involved in graft-versus-host disease: a novel application of discordant sib pair methodology.

We introduce a novel application for linkage analysis: using bone marrow donor-recipient sib pairs to search for genes influential in graft-versus-host disease (GVHD), a major cause of morbidity and mortality following allogeneic bone marrow transplantation. In particular, we show that transplant sib pairs in which the recipient developed severe GVHD can be used to map genes in the same way as traditional discordant (affected/unaffected) sib pairs (DSPs). For a plausible GVHD model, we demonstrate that the transplant/discordant sib pair analog of the "possible triangle test" [Holmans (1993) Am J Hum Genet 52:362-374] has similar power to that of the simpler "restricted test" proposed by Risch [(1990b) Am J Hum Genet 46:229-241; (1992) Am J Hum Genet 51:673-675]. Moreover, we show that the restricted test has superior power in much of the DSP possible triangle and significantly inferior power in only a small region. Thus, we conclude that the restricted test is preferable for localizing genes with transplant/discordant sib pairs. Finally, we examine the effects of heterogeneity on the power to detect GVHD loci and demonstrate the gain in efficiency by dividing the sample into genetically more homogeneous subgroups.

Chromosome Mapping↗

PubMed1998

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

Chromosome Mapping↗

PubMed1997

Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.

Chromosomes, Human, Pair 10↗

PubMed1996

Polymorphism of adhesion molecule CD31 is not a significant risk factor for graft-versus-host disease.

Mismatch between bone marrow transplant (BMT) patient and donor for an amino acid polymorphism within the adhesion molecule CD31 has recently been reported to increase risk for the development of graft-versus-host disease (GVHD). We further examined this association in a larger series of 301 BMT patients (227 with grade III/IV GVHD and 74 with grade 0 GVHD) and their HLA-identical sibling donors. CD31 genotypes were determined by polymerase chain reaction and restriction endonuclease digestion. The role of mismatch at the CD31 locus in the development of GVHD was assessed by analyzing the extent of CD31 identity and CD31 compatibility among the grade 0 GVHD and grade III/IV GVHD sibling pairs. No significant association between CD31 mismatch and the development of severe GVHD was detected in our overall patient population. Sixty-three percent of grade III/IV GVHD sibling pairs and 69% of grade 0 GVHD sibling pairs had CD31 genotypes that were identical (P = .36, odds ratio = 1.30). In addition, neither the grade 0 GVHD group (P = .10) nor the grade III/IV GVHD group (P = .27) differed significantly from the expected probability of identity between sibling pairs. Mismatch at the CD31 polymorphism between recipients and donors showed no consistent association with the development of GVHD. Current evidence does not support the value of CD31 mismatch in the selection of BMT donors.

Alleles↗

PubMed1996

Selected locus and multiple panel models for radiation hybrid mapping.

We develop two new types of models for whole-genome radiation hybrid mapping using the general multipoint framework. The first, selected locus models, are appropriate for mapping markers in the region of a selectable locus that was used in creation of the hybrids. The models allow for strong retention of the selectable locus, with retention rates decreasing with increasing distance from the selectable locus in both directions. We illustrate the application of these models with 10 chromosome 17 sequence-tagged site (STS) markers and the thymidine kinase (TK) locus typed on a whole-genome hybrid panel in which TK was used in the selection process. The second set of models are appropriate when loci typed on two or more independent panels are to be used to build maps. Maps can be built assuming interlocus distances are independent or proportional between the panels, and the hypothesis of proportional distances can be tested. We illustrate the application of these models by using 27 chromosome 21 STS markers typed on two hybrid panels created with radiation doses of approximately 10,000 and approximately 50,000 Rads.

Chromosome Mapping↗

PubMed1995

Statistical methods for polyploid radiation hybrid mapping.

Radiation hybrid mapping is a somatic cell technique for ordering genetic loci along a chromosome and estimating physical distances between adjacent loci. This paper presents a model of fragment generation and retention for data involving two or more copies of the chromosome of interest per clone. Such polyploid data can be generated by initially irradiating normal diploid cells or by pooling haploid or diploid clones. The current model assumes that fragments are generated in the ancestral cell of a clone according to an independent Poisson breakage process along each chromosome. Once generated, fragments are independently retained in the clone with a common retention probability. On the basis of this and less restrictive retention models, statistical criteria such as minimum obligate breaks, maximum likelihood ratios, and Bayesian posterior probabilities can be used to decide locus order. Distances can be estimated by maximum likelihood. Likelihood computation is particularly challenging, and computing techniques from the theory of hidden Markov chains prove crucial. Within this context it is possible to incorporate typing errors. The statistical tools discussed here are applied to 14 loci on the short arm of human chromosome 4.

Chromosome Mapping↗

PubMed1995

Experimental design and error detection for polyploid radiation hybrid mapping.

In this paper we consider issues of experimental design and error detection and correction for polyploid radiation hybrid mapping. Using analytic methods and computer simulation, we first consider the combinations of fragment retention rate, ploidy, and marker spacing that provide the best chance to order markers. We find that in general, combinations of ploidy and chromosome-specific retention rates that lead to a per-hybrid retention rate of approximately 50% result in the greatest power to order markers. We also find that analyzing polyploid radiation hybrids as if they were haploid does not compromise the ability to order markers but does result in less accurate intermarker distance estimates. Second, we examine the effect of typing errors on two-locus information, ability to order multiple loci, and estimation of intermarker distances and total map length. Even low levels of error result in large losses of information about breakage probabilities, markedly reduce ability to order loci, and inflate estimates of intermarker distances and total map length. We compare the ordering accuracy that results from duplicate typing of hybrids to that of single typing twice as many hybrids and find that duplicate typing results in a higher probability of identifying the true order as one of the best orders, but that single typing of twice as many hybrids results in stronger support for the true order. For low error rates, framework maps constructed from the larger single-typed panels are only slightly less likely to be correct and include substantially more markers than the smaller double-typed panels. Third, we develop a method to calculate the distribution of the number of obligate chromosome breaks for a polyploid radiation hybrid under a given locus order and discuss how this method may be used to identify hybrids with suspiciously large numbers of chromosome breaks.

Animals↗