Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms

in Journal of Vascular Surgery (2005), 41(6), 1036-1042

Background: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells ... [more ▼]

Background: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs. Methods: DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs;2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFBI(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms; in male subjects. Results: Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P =.0047; rs2070584, P =.015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (x(2) p =.014 and empirical P =.009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (P=.037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (P =.0169) and TIMP3 (P =.0023) in cases with a family history of AAA. Conclusions: These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease. Clinical Relevance: Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase I (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA. [less ▲]

Genetic Analysis of Rwandan Patients With Cystic Fibrosis-Like Symptoms: Identification of Novel Cystic Fibrosis Transmembrane Conductance Regulator and Epithelial Sodium Channel Gene Variants.

in CHEST (2008)

Background The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CFTR loss of function and of an abnormal interaction between CFTR and ENaC. A few patients were ... [more ▼]

Background The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CFTR loss of function and of an abnormal interaction between CFTR and ENaC. A few patients were described with CF-like symptoms, a single CFTR mutation and an ENaC mutation. Methods To study African patients with CF-like symptoms and to relate the disease to gene mutations of both CFTR and ENaC genes, we collected clinical data and DNA samples from 60 African patients with a CF phenotype. The CFTR gene was first analyzed in all patients by dHPLC followed by direct sequencing, whereas the SCNN1A, SCNN1B and SCNN1G subunits of ENaC gene were analyzed by sequencing in the five patients who carried only one CF mutation. The frequency of all identified ENaC variants was established in a control group of 200 healthy individuals and in the 55 CF-like patients without any CFTR mutation Results Three CFTR mutants, including one previously undescribed missense mutation (p.A204T), and a 5T/7T variant were identified in five patients. ENaC gene sequencing in these 5 patients detected 8 ENaC variants: c.72T>C and p.V573I in SCNN1A; p.V348M, p.G442V, c.1473 + 28C>T, and p.T577T in SCNN1B; and p.S212S, c.1176 + 30G>C in SCNN1G. In the 55 CF-like patients without any CFTR mutation, we identified five of these eight ENaC variants, including the frequent p.G442V polymorphism, but we did not detect the presence of the p.V348M, p.T577T, and c.1176 + 30G>C ENaC variants. Moreover, these last three ENaC variants, p.V348M, p.T577T, and c.1176 + 30G>C, were not found in the control group. Conclusion Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations. [less ▲]

Genetic and biochemical characterization of cytoplasmic and mitochondrial ASN-tRNA synthetase functions in two mutans yeast strains.

Poster (1995)

Genetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition

in Proceedings of the National Academy of Sciences of the United States of America (2004), 101(8), 2398-2403

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait ... [more ▼]

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the DGAT1 K232A mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan BULGE30-BULGE9 interval containing the QTL and show that the association with milk fat percentage maximizes at the DGAT1 gene. We provide evidence that the K allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both DGAT1 alleles in Sf9 cells and show that the K allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher V-max in producing triglycerides than the A allele. [less ▲]

Genetic and historic evidence for climate-driven population fragmentation in a top cetacean predator: the harbour porpoises in European water.

in Proceedings of the Royal Society B : Biological Sciences (2010), 277(1695), 2829-37

Recent climate change has triggered profound reorganization in northeast Atlantic ecosystems, with substantial impact on the distribution of marine assemblages from plankton to fishes. However, assessing ... [more ▼]

Recent climate change has triggered profound reorganization in northeast Atlantic ecosystems, with substantial impact on the distribution of marine assemblages from plankton to fishes. However, assessing the repercussions on apex marine predators remains a challenging issue, especially for pelagic species. In this study, we use Bayesian coalescent modelling of microsatellite variation to track the population demographic history of one of the smallest temperate cetaceans, the harbour porpoise (Phocoena phocoena) in European waters. Combining genetic inferences with palaeo-oceanographic and historical records provides strong evidence that populations of harbour porpoises have responded markedly to the recent climate-driven reorganization in the eastern North Atlantic food web. This response includes the isolation of porpoises in Iberian waters from those further north only approximately 300 years ago with a predominant northward migration, contemporaneous with the warming trend underway since the 'Little Ice Age' period and with the ongoing retreat of cold-water fishes from the Bay of Biscay. The extinction or exodus of harbour porpoises from the Mediterranean Sea (leaving an isolated relict population in the Black Sea) has lacked a coherent explanation. The present results suggest that the fragmentation of harbour distribution range in the Mediterranean Sea was triggered during the warm 'Mid-Holocene Optimum' period (approx. 5000 years ago), by the end of the post-glacial nutrient-rich 'Sapropel' conditions that prevailed before that time. [less ▲]

Genetic and non genetic effects on growth traits of West African Dwarf sheep in Benin (West Africa)

in Livestock Production Science (2008)

Genetic aspects of abdominal aortic aneurysm.

in Annals of the New York Academy of Sciences (1996), 800

Genetic causes of familial pituitary adenomas

in Growth Hormone Related Diseases and Therapy - Contemporary Endocrinology (2011)

Genetic causes of pituitary diseases

Scientific conference (2010, October)

Genetic Characterization Of The Yeast Pichia Anomala (Strain K), An Antagonist Of Postharvest Diseases Of Apple

in Journal of Applied Microbiology (2005), 98(3),