Regulation of FMO and PON detoxication systems in ALS human tissues.

Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, and fatal neurodegenerative disease with unknown etiology. Recent evidence suggests an association between the exposure to toxic environmental factors and sporadic ALS. The flavin-containing monooxygenases (FMOs) and paraoxonase (PONs) genes encode enzymes involved in xenobiotic detoxication and are associated with ALS.

Flavin-containing monooxygenase mRNA levels are up-regulated in als brain areas in SOD1-mutant mice.

Flavin-containing monooxygenases (FMOs) are a family of microsomal enzymes involved in the oxygenation of a variety of nucleophilic heteroatom-containing xenobiotics. Recent results have pointed to a relation between Amyotrophic Lateral Sclerosis (ALS) and FMO genes. ALS is an adult-onset, progressive, and fatal neurodegenerative disease.

SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis.

The mutated Cu,Zn-superoxide dismutase gene (SOD1) (E.C. No.

Genetic modifiers of Hb E/beta0 thalassemia identified by a two-stage genome-wide association study.

Background: Patients with Hb E/beta0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/beta0 thalassemia and normal alpha-globin genes.

Methods: First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs) in pooled DNAs from different severity groups.

Immune defects in Alzheimer's disease: new medications development.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Abeta) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Abeta in the brain.

Catecholamine release-inhibitory peptide catestatin (chromogranin A(352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension.

Background: Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure.

Methods And Results: Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product.

Population-based sample reveals gene-gender interactions in blood pressure in White Americans.

The influence of genetic contributors, such as common single nucleotide polymorphisms, on blood pressure and essential hypertension may vary with the gender. We used the power of a large, community-based sample to probe whether gender interacts with genes in contributing to extremes of blood pressure in 611 male and 656 female age-matched white Americans within the top and bottom 5th percentiles of blood pressure among >53 000 people in a health maintenance program. This approach has >90% statistical power to detect genes contributing as little as 3% to trait (blood pressure) variation.

Using DNA pools for genotyping trios.

The genotyping of mother-father-child trios is a very useful tool in disease association studies, as trios eliminate population stratification effects and increase the accuracy of haplotype inference. Unfortunately, the use of trios for association studies may reduce power, since it requires the genotyping of three individuals where only four independent haplotypes are involved. We describe here a method for genotyping a trio using two DNA pools, thus reducing the cost of genotyping trios to that of genotyping two individuals.

Genome-wide SNP association: identification of susceptibility alleles for osteoarthritis.

The successful identification of genes involved in common human disorders is dependent upon availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology we have generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes, and a large DNA sample bank from more than 50,000 consented diseased (case) and healthy (control) individuals.

Complement factor H polymorphism and age-related macular degeneration.

Age-related macular degeneration (AMD) is a common, late-onset, and complex trait with multiple risk factors. Concentrating on a region harboring a locus for AMD on 1q25-31, the ARMD1 locus, we tested single-nucleotide polymorphisms for association with AMD in two independent case-control populations. Significant association (P = 4.

Evaluating a Model of an NRE Mediated Tissue-Specific Expression of Murine Renin Genes.

-We have used comparative sequence analysis to evaluate a putative silencer element that has been proposed to be involved in the differential tissue-expression of the murine renin genes: Ren-1 and Ren-2. In the mouse, these genes share a similar pattern of tissue-specific renin expression. One significant difference is seen in the submandibular gland (SMG) where renin expression from the Ren-2 locus is 100-fold greater than the expression from the Ren-1 locus.