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Träfflista för sökning "WFRF:(Hirschhorn JN) ;srt2:(2005-2009)"

Sökning: WFRF:(Hirschhorn JN) > (2005-2009)

  • Resultat 1-4 av 4
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1.
  • Feigelson, HS, et al. (författare)
  • Haplotype analysis of the HSD17B1 gene and risk of breast cancer: A comprehensive approach to multicenter analyses of prospective cohort studies
  • 2006
  • Ingår i: Cancer Research. - 1538-7445. ; 66:4, s. 2468-2475
  • Tidskriftsartikel (refereegranskat)abstract
    • The 17 beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X-2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.
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2.
  • Florez, JC, et al. (författare)
  • High-density haplotype structure and association testing of the insulin-degrading enzyme (IDE) gene with type 2 diabetes in 4,206 people
  • 2006
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:1, s. 128-135
  • Tidskriftsartikel (refereegranskat)abstract
    • The insulin-degrading enzyme is responsible for the intracellular proteolysis of insulin. Its gene IDE is located on chromosome 10, in an area with suggestive linkage to type 2 diabetes and related phenotypes. Due to the impact of genetic variants of this gene in rodents and the function of its protein product, it has been proposed as a candidate gene for type 2 diabetes. Various groups have explored the role of the common genetic variation of IDE on insulin resistance and reported associations of various single nucleotide polymorphisms (SNPs) and haplotypes on both type 2 diabetes and glycemic traits. We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance. We assessed linkage disequilibrium, selected single-marker and multimarker tags, and genotyped these markers in several case-control and family-based samples totalling 4,206 Caucasian individuals. We observed no statistically significant evidence of association between single-marker or multimarker tests in IDE and type 2 diabetes. Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at, IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians.
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3.
  • Saxena, R, et al. (författare)
  • Comprehensive association testing of common mitochondrial DNA variation in metabolic disease
  • 2006
  • Ingår i: American Journal of Human Genetics. - 0002-9297. ; 79:1, s. 54-61
  • Tidskriftsartikel (refereegranskat)abstract
    • Many lines of evidence implicate mitochondria in phenotypic variation: ( a) rare mutations in mitochondrial proteins cause metabolic, neurological, and muscular disorders; ( b) alterations in oxidative phosphorylation are characteristic of type 2 diabetes, Parkinson disease, Huntington disease, and other diseases; and ( c) common missense variants in the mitochondrial genome ( mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy deficiency" diseases today. To test the hypothesis that common mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency > 1% in Europeans from > 900 publicly available European mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation ( except the hypervariable D-loop). Next, we evaluated the complete set of common mtDNA variants for association with type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of mtDNA variants with other metabolic traits ( body mass index, measures of insulin secretion and action, blood pressure, and cholesterol) was also tested in subsets of this sample. We did not find a significant association of common mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated.
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4.
  • Sun, MW, et al. (författare)
  • Haplotype structures and large-scale association testing of the 5 ' AMP-activated protein kinase genes PRK4A2, PRKAB1, and PRK4B1 with type 2 diabetes
  • 2006
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:3, s. 849-855
  • Tidskriftsartikel (refereegranskat)abstract
    • AMP-activated protein kinase (AMPK) is a key molecular regulator of cellular metabolism, and its activity is induced by both metformin and thiazolidinedione antidiabetic medications. It has therefore been proposed both as a putative agent in the pathophysiology of type 2 diabetes and as a valid target for therapeutic intervention. Thus, the genes that encode the various AMPK subunits are intriguing candidates for the inherited basis of type 2 diabetes. We therefore set out to test for the association of common variants in the genes that encode three selected AMPK subunits with type 2 diabetes and related phenotypes. Of the seven genes that encode AMPK isoforms, we initially chose PRKAA2, PRKAB1, and PRKAB2 because of their higher prior probability of association with type 2 diabetes, based on previous reports of genetic linkage, functional molecular studies, expression patterns, and pharmacological evidence. We determined their haplotype structure, selected a subset of tag single nucleotide polymorphisms that comprehensively capture the extent of common genetic variation in these genes, and genotyped them in family-based and case/control samples comprising 4,206 individuals. Analysis of single-marker and multi-marker tests revealed no association with type 2 diabetes, fasting plasma glucose, or insulin sensitivity. Several nominal associations of variants in PRKAA2 and PRKAB1 with BMI appear to be consistent with statistical noise.
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