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Alison P Klein

Publications and source records attributed to Alison P Klein.

16 recordsLinked to original sources
PubMed2007

Identification of novel genetic loci for intraocular pressure: a genomewide scan of the Beaver Dam Eye Study.

OBJECTIVE: To identify genetic loci that control intraocular pressure (IOP). METHODS: We performed a genomewide scan of IOP, using 486 pedigrees ascertained through a population-based cohort, the Beaver Dam Eye Study. Linkage analysis was performed using the modified Haseman-Elston regression models and variance components linkage analysis. RESULTS: Seven regions of interest were identified on chromosomes 2, 5, 6, 7, 12, 15, and 19. The novel linkage region on chromosome 19p had an empirical multipoint P value of 6.1 x 10(-5). Two of the regions (2 and 19) were especially interesting since each has been identified as a potential linkage region for blood pressure. CONCLUSIONS: The results of this genomewide scan provide evidence that a quantitative trait locus may influence elevated IOP and may colocalize with blood pressure loci. These loci may control systemic pressure reflected in the eye and vascular system. CLINICAL RELEVANCE: Glaucoma is a leading cause of blindness in the world, and the identification of genes that contribute to this disease is essential. Elevated IOP is a principal risk factor for primary open-angle glaucoma and an intriguing quantitative trait that may strongly influence the development of disease.

Adult↗
PubMed2007

Confirmation of linkage to ocular refraction on chromosome 22q and identification of a novel linkage region on 1q.

OBJECTIVE: To localize genes influencing ocular refraction in subjects in the Beaver Dam Eye Study. Previous studies establish that myopia clusters within families and linkage to myopia has been demonstrated on 2q, 4q, 12q, 17q, 18q, 22q, and Xq. Few studies have examined genetic effects across the entire range of refraction, though linkages to 1p, 3q, 4q, 8p, and 11p have been reported, and our previous analysis of the Beaver Dam Eye Study demonstrated substantial heritability for refraction (68%). METHODS: We conducted nonparametric sibling-pair and genome-wide linkage analyses on spherical equivalent adjusting for age, education, and nuclear sclerosis, in 834 sibling pairs in 486 extended pedigrees. RESULTS: We identified a novel region of suggestive linkage on 1q (multipoint, P<.00019) and replicated the 22q region (multipoint, P = .0033) previously linked to myopia. Additionally, there was some evidence of linkage to 7p (multipoint, P = .0023). CONCLUSION: Refraction is a complex trait influenced by both genes and environment. Our work confirms a previously reported linkage region on 22q and identifies 2 novel regions of linkage on 1q and 7p. CLINICAL RELEVANCE: Further, genetic research is needed to finemap this trait to identify the causative gene. Modifying the actions of such a gene might lead to a reduction in the risk of refractive error.

Adult↗
PubMed2006

Pancreatic cancer genetic epidemiology consortium.

We have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial pancreatic cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with pancreatic cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident pancreatic cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 (N = 72,700). The mean age +/- SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 +/- 11.8 and was 65.4 +/- 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 +/- 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all pancreatic cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in pancreatic cancer.

Age of Onset↗
PubMed2006

Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer.

We screened 116 patients with a strong family history of pancreatic cancer using a combination of endoscopic ultrasound and computed tomography. Ten of these patients underwent surgical resection at our institution, providing an opportunity to define the morphology of pancreatic precursor lesions in patients with a strong family history of pancreatic cancer. Eight of the 10 pancreata were available and these were entirely submitted for histologic examination. The number of pancreatic intraepithelial neoplasia (PanIN) lesions and intraductal papillary mucinous neoplasms (IPMNs) were compared with age-matched controls. Parenchymal changes were defined. Selected precursor neoplasms from 6 pancreata were microdissected and analyzed for KRAS gene mutations. PanINs were significantly more common in the 8 cases (mean of 10.7% of the duct profiles, range 1.0% to 27.3%) than in the controls (mean 1.9%, range 0% to 9.2%, P<0.01). Different KRAS gene mutations were identified in separately microdissected precursor lesions in 2 of 6 cases. IPMNs were identified in 4 of the 8 cases, including 2 pancreata each having 2 distinct IPMNs. Both the IPMNs and the PanINs, even the low-grade PanIN-1 lesions, were associated with lobular parenchymal atrophy. Some individuals with a strong family history of pancreatic cancer develop multifocal, noninvasive epithelial precursor lesions of the pancreas. PanINs and IPMNs produce obstructive lobular atrophy, and this atrophy is likely the source of the chronic pancreatitis-like changes seen in these patients. The multifocal nature of familial pancreatic neoplasia suggests that surveillance of these patients is warranted after partial pancreatectomy.

Adenocarcinoma, Mucinous↗
PubMed2005

Investigation of altering single-nucleotide polymorphism density on the power to detect trait loci and frequency of false positive in nonparametric linkage analyses of qualitative traits.

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed.

Alcoholism↗
PubMed2005

Identification of tag single-nucleotide polymorphisms in regions with varying linkage disequilibrium.

We compared seven different tagging single-nucleotide polymorphism (SNP) programs in 10 regions with varied amounts of linkage disequilibrium (LD) and physical distance. We used the Collaborative Studies on the Genetics of Alcoholism dataset, part of the Genetic Analysis Workshop 14. We show that in regions with moderate to strong LD these programs are relatively consistent, despite different parameters and methods. In addition, we compared the selected SNPs in a multipoint linkage analysis for one region with strong LD. As the number of selected SNPs increased, the LOD score, mean information content, and type I error also increased.

Chromosome Mapping↗
PubMed2005

Polygenic effects and cigarette smoking account for a portion of the familial aggregation of nuclear sclerosis.

Cataract is the most common cause of blindness worldwide. Nuclear cataract, an advanced stage of nuclear sclerosis, is the most common type of age-related cataract. The authors assessed data from 2,089 persons within 620 extended pedigrees who participated in the 1988-1990 Beaver Dam Eye Study in Wisconsin to determine whether the observed familial aggregation of nuclear sclerosis could be explained by inheritance of a major gene. Familial correlations were examined and segregation analyses were performed on nuclear sclerosis measurements adjusted for age, sex, and pack-years of cigarette smoking. There was modest correlation among close family members after adjustment for age, sex, and pack-years of cigarette smoking: 0.084 between parents and offspring, and 0.198 between sibling pairs. Although results do not support involvement of a single major locus in the etiology of nuclear sclerosis, models that allowed for familial correlation, attributable in part to polygenic effects, did provide a better fit to the observed data than models without a polygenic effect. This finding suggests that several genes of modest effect may influence development of nuclear lens opacity, possibly in conjunction with environmental factors. Cigarette smoking was an important covariate in these analyses. Overall, results highlight the complex etiology of nuclear sclerosis.

Adult↗
PubMed2005

Treatment of familial pancreatic cancer and its precursors.

Approximately 10% of pancreatic cancers are believed to have a familial basis. The familial aggregation of pancreatic cancers provides a unique opportunity to prevent the development of pancreatic cancer, to identify and treat precancerous lesions of the pancreas, and to advance our understanding of the genetic basis for the development of all forms of pancreatic cancer. After appropriate genetic counseling, individuals with a strong family history of pancreatic cancer can now be tested for inherited genetic alterations that are known to increase the risk of pancreatic cancer. These include germline BRCA2, STK11/LKB1, p16/CDKN2A and PRSS1 gene mutations. Individuals with one of these inherited genetic alterations and individuals with a strong family history of pancreatic cancer can be counseled on smoking cessation and possible dietary modifications. Selected individuals, even if they are asymptomatic, can be screened using a combination of endoscopic ultrasound and multidetector computed tomography. Patients found to have a mass lesion in the pancreas would then be candidates for surgical resection. The resection of noninvasive precancers will cure these lesions before they have the opportunity to spread and metastasize. Even with the best early detection efforts, some patients will still be diagnosed with an invasive cancer. Surgical resection of invasive pancreatic cancer is proven to be safe and can provide long-term survival in patients with small, node-negative, and margin-negative cancers. Chemotherapy and radiation therapy are effective in some patients with invasive pancreatic cancer, but these therapies do not usually result in long-term cures. Individuals with a family history of pancreatic cancer may also choose to join a research study such as the National Familial Pancreas Tumor Registry.

Journal Article↗
PubMed2005

A genetic contribution to intraocular pressure: the beaver dam eye study.

PURPOSE: To investigate a potential genetic contribution to intraocular pressure (IOP), we performed a complex segregation analysis on 2337 individuals in 620 extended pedigrees ascertained through a population-based cohort, the Beaver Dam Eye Study (BDES). IOP is a principal risk factor for primary open-angle glaucoma (POAG) a leading cause of blindness worldwide. METHODS: Segregation analysis is an analytical method that provides statistical evidence supporting the involvement of a major gene or polygenes in a particular phenotype. Detailed medical histories and eye examinations were performed on all participants. From the two eyes, the higher IOP measurement was used as a continuous trait after adjustment for covariates. A genome-wide scan (GWS) using affected sib pair linkage analysis was performed on 218 sibling pairs. RESULTS: In this segregation analysis the model that allowed for an unmeasured major environmental effect plus a polygenic/multifactorial effect provided the best fit and was the most parsimonious model. The lack of an adequate fit for the Mendelian single-gene models is consistent with a multifactorial model of inheritance that may include multiple genes and environmental factors that contribute to IOP. The results of the GWS yielded two novel loci as potential linkage regions for IOP on chromosomes 6 (P = 0.008) and 13 (P = 0.0007). Neither of these regions has previously been identified in GWS of POAG. CONCLUSIONS: The segregation and familial correlation analyses of IOP suggest a polygenetic component with environmental influences. The pilot linkage study further confirms the heterogeneity of IOP with the identification of two novel genetic loci.

Adult↗
PubMed2005

Support for polygenic influences on ocular refractive error.

PURPOSE: Refractive errors, myopia, and hyperopia are common conditions requiring corrective lenses. The familial clustering of myopia has been well established. Several chromosomal regions have been linked to high myopia (12q, 17q, and 18q), to quantitative refraction among twins (3q, 4q, 8p, and 11p), and to families with moderate myopia (22q). This study examined the familial aggregation and pattern of inheritance of ocular refraction in an adult population, by using data from the Beaver Dam Eye Study. METHODS: Familial correlations were examined and segregation analysis was performed on the average refractive error measurements in the right and left eyes after adjustment for age, sex, and education. Analyses were based on 2138 individuals in 620 extended pedigrees with complete data on age, sex, education, and spherical equivalent. RESULTS: Substantial positive correlation was found between siblings (0.33), parents and offspring (0.17), and cousins (0.10) and lower correlation among avuncular pairs (0.08) after adjustment for age, sex, and years of education. The results of this segregation analysis do not support the involvement of a single major locus throughout the entire range of refractive error. However, models allowing for familial correlation, attributable in part to polygenic effects, provided a better fit to the observed data than models without a polygenic component, suggesting that several genes of modest effect may influence refractive error, possibly in conjunction with environmental factors. CONCLUSIONS: These results support the involvement of genetic factors in the etiology of refractive error and are consistent with reports of linkage to multiple regions of the genome.

Family Health↗
PubMed2005

Overview of linkage analysis: application to pancreatic cancer.

Linkage analysis has aided in the identification of genes involved in many diseases, including several cancers. It relies on using family-based data to detect genetic loci that may harbor disease predisposing genes. Although linkage studies were first designed to find the genes responsible for simple Mendelian diseases (diseases caused by alterations in a single gene), today it is more common for investigators to use linkage analysis to locate genes involved in complex diseases (diseases caused by the independent and joint effects of multiple genes often in conjunction with environmental factors), such as pancreatic cancer. During the past decade linkage analysis has been key step in the identification of several cancer genes, including BRCA2 and STK11, which additional studies have shown also carry an increased risk of pancreatic cancer. However, these known genes explain very little of the observed familial aggregation of pancreatic cancer. While the foundations of linkage analysis are relatively straightforward, the actual implementation of linkage studies, especially for complex diseases such as pancreatic cancer, can be quite difficult. This chapter focuses on the basics of linkage analysis for qualitative traits (affected/unaffected) as could be applied to the study of pancreatic cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed2004

GeneLink: a database to facilitate genetic studies of complex traits.

BACKGROUND: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. RESULTS: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. CONCLUSIONS: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink.

Alleles↗
PubMed2004

Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.

Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5-16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22-6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2-74.7), two (6.4; CI, 1.8-16.4), or one (4.6; CI, 0.5-16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer.

Adult↗
PubMed2003

Importance sampling method of correction for multiple testing in affected sib-pair linkage analysis.

Using the Genetic Analysis Workshop 13 simulated data set, we compared the technique of importance sampling to several other methods designed to adjust p-values for multiple testing: the Bonferroni correction, the method proposed by Feingold et al., and naïve Monte Carlo simulation. We performed affected sib-pair linkage analysis for each of the 100 replicates for each of five binary traits and adjusted the derived p-values using each of the correction methods. The type I error rates for each correction method and the ability of each of the methods to detect loci known to influence trait values were compared. All of the methods considered were conservative with respect to type I error, especially the Bonferroni method. The ability of these methods to detect trait loci was also low. However, this may be partially due to a limitation inherent in our binary trait definitions.

Computer Simulation↗
PubMed2002

Evidence for a major gene influencing risk of pancreatic cancer.

Family history of pancreatic cancer, the fifth leading cause of cancer death in the United States, confers a 1.5-13-fold higher risk of developing pancreatic cancer. Pancreatic cancer is associated with several genetic syndromes, including hereditary breast cancer (BRCA2), familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer (HNPCC). However, these syndromes explain little of the observed familial aggregation of pancreatic cancer. We performed complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994 and December 31, 1999. We tested for the presence of a major gene controlling either the "age-at-onset of pancreatic cancer" of "susceptibility to pancreatic cancer," and incorporated smoking data on kindred members as a covariate. We found evidence for involvement of a major gene in the etiology of pancreatic cancer. Whether inheritance was modeled as "age-at-onset" or "susceptibility," nongenetic transmission models were strongly rejected. However, modeling "age-at-onset" provided a better fit to the observed data than did modeling "susceptibility." The most parsimonious models included autosomal-dominant inheritance of a rare allele. Under the age-at-onset model, approximately 0.7% of the population appears to be at high risk of developing pancreatic cancer due to this putative gene, whereas 0.4% of the population is at high risk under the susceptibility model. Inclusion of smoking as a covariate did not significantly improve the fit of these models. This hospital-based segregation analysis of pancreatic cancer found evidence supporting the role of a rare major gene influencing risk of pancreatic cancer.

Adenocarcinoma↗