ABSTRACT
Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.
Subject(s)
HLA-DP beta-Chains/genetics , HLA-DRB1 Chains/genetics , Liver Cirrhosis, Biliary/genetics , Liver Cirrhosis, Biliary/immunology , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Italy , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Risk Factors , White People/geneticsABSTRACT
To assess the relationship between ethnicity and hypertension using individual admixture and blood pressure measurements, we performed a cross-sectional study of African American and Hispanic American (HA) women enrolled in the Women's Health Initiative. The admixture odds ratio for systolic and diastolic hypertensive risk was determined using linear regression models in which the proportional measurements of European (EUR), sub-Saharan African (AFR) and Amerindian (AMI) admixture was analyzed using ancestry informative markers. In both African-American women (n=10,147) and HA women (n=4908) there was a significant positive association between hypertension and African admixture (P<10(-4)). This relationship was observed for both systolic and diastolic hypertension examined as a continuous or dichotomous trait, and whether age, body mass index, years since menopause and a measurement of socioeconomic status were used as covariates. The odds ratio associated with AFR admixture in a dichotomous model of hypertension was 3.06 (95% confidence interval 2.72-3.45). AMI admixture was associated with lower odds of hypertension and appeared to be more protective, relative to EUR admixture. These data show that African admixture increases the risk for hypertension and provide additional support for evaluating therapeutic efficacy and conducting genetic analyses of hypertension in different ethnic groups.
Subject(s)
Black or African American , Hispanic or Latino , Hypertension/ethnology , Aged , Female , Humans , Hypertension/etiology , Middle Aged , Postmenopause , Risk , Social ClassABSTRACT
OBJECTIVE: The objective of this study was to investigate whether differences in admixture in African-American (AFA) and Hispanic-American (HA) adult women are associated with adiposity and adipose distribution. DESIGN: The proportion of European, sub-Saharan African and Amerindian admixture was estimated for AFA and HA women in the Women's Heath Initiative using 92 ancestry informative markers. Analyses assessed the relationship between admixture and adiposity indices. SUBJECTS: The subjects included 11 712 AFA and 5088 HA self-identified post-menopausal women. RESULTS: There was a significant positive association between body mass index (BMI) and African admixture when BMI was considered as a continuous variable, and age, education, physical activity, parity, family income and smoking were included covariates (P<10(-4)). A dichotomous model (upper and lower BMI quartiles) showed that African admixture was associated with a high odds ratio (OR=3.27 (for 100% admixture compared with 0% admixture), 95% confidence interval 2.08-5.15). For HA, there was no association between BMI and admixture. In contrast, when waist-to-hip ratio (WHR) was used as a measure of adipose distribution, there was no significant association between WHR and admixture in AFA but there was a strong association in HA (P<10(-4); OR Amerindian admixture=5.93, confidence interval=3.52-9.97). CONCLUSION: These studies show that: (1) African admixture is associated with BMI in AFA women; (2) Amerindian admixture is associated with WHR but not BMI in HA women; and (3) it may be important to consider different measurements of adiposity and adipose distribution in different ethnic population groups.
Subject(s)
Adiposity/ethnology , Black or African American/statistics & numerical data , Body Mass Index , Hispanic or Latino/statistics & numerical data , Obesity/ethnology , White People/statistics & numerical data , Adipose Tissue , Africa South of the Sahara , Body Composition , Cohort Studies , Female , Genotype , Humans , Indians, North American/statistics & numerical data , Middle Aged , Obesity/epidemiology , Odds Ratio , Phenotype , United States/epidemiology , Waist-Hip Ratio , Women's HealthSubject(s)
Antiviral Agents/therapeutic use , Glomerulonephritis, Membranoproliferative/drug therapy , Hepatitis B/complications , Hepatitis C/complications , Interferon-alpha/therapeutic use , Ribavirin/therapeutic use , Biopsy , Drug Therapy, Combination , Female , Follow-Up Studies , Glomerulonephritis, Membranoproliferative/diagnosis , Glomerulonephritis, Membranoproliferative/etiology , Hepacivirus/genetics , Hepatitis B/diagnosis , Hepatitis B/virology , Hepatitis B virus/genetics , Hepatitis C/diagnosis , Hepatitis C/virology , Humans , Microscopy, Fluorescence , Middle Aged , RNA, Viral/analysisABSTRACT
Several studies have identified the PTPN22 allelic variant 1858 C/T that encodes the R620W amino-acid change as a putative susceptibility factor in autoimmune diseases. The current study was undertaken to examine a large cohort of Finnish rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) subjects using both population control and, importantly, family-based association methods. The latter is particularly important when, as is the case for the 1858 C/T polymorphism, the frequency of the variant allele (T) differs in both major ancestral populations and in subpopulations. The analysis of rheumatoid factor-positive 1030 RA probands from Finland provides strong support for association of this variant in both population studies (allele specific odds ratio (OR)=1.47, 95% confidence interval (CI)=1.27-1.70, P=3 x 10(-7)) and in family studies (P<10(-6)). In contrast, no allelic association was seen with JIA (230 probands) and only weak evidence for a genotypic effect of 1858T homozygotes was observed in this population.
Subject(s)
Arthritis, Juvenile/genetics , Arthritis, Rheumatoid/genetics , Polymorphism, Genetic , Protein Tyrosine Phosphatases/genetics , Risk Factors , Alleles , Arthritis, Juvenile/epidemiology , Arthritis, Rheumatoid/epidemiology , Case-Control Studies , Cohort Studies , Confidence Intervals , Finland/epidemiology , Gene Frequency , Genetic Variation , Genetics, Population , Nuclear Family , Odds Ratio , Protein Tyrosine Phosphatase, Non-Receptor Type 22ABSTRACT
Alternative splicing is a major source of variety in mammalian mRNAs, yet many questions remain on its downstream effects on protein function. To this end, we assessed the impact of gene structure and splice variation on signal peptide and transmembrane regions in proteins. Transmembrane proteins perform several key functions in cell signaling and transport, with their function tied closely to their transmembrane architecture. Signal peptides and transmembrane regions both provide key information on protein localization. Thus, any modification to such regions will likely alter protein destination and function. We applied TMHMM and SignalP to a nonredundant set of proteins, and assessed the effects of gene structure and alternative splicing on predicted transmembrane and signal peptide regions. These regions were altered by alternative splicing in roughly half of the cases studied. Transmembrane regions are divided by introns slightly less often than expected given gene structure and transmembrane region size. However, the transmembrane regions in single-pass transmembranes are divided substantially less often than expected. This suggests that intron placement might be subject to some evolutionary pressure to preserve function in these signaling proteins. The data described in this paper is available online at http://www.affymetrix.com/community/publications/affymetrix/tmsplice/.
Subject(s)
Alternative Splicing , Computational Biology , Membrane Proteins/genetics , Animals , Artificial Intelligence , Codon, Nonsense , Exons , Genome , Membrane Proteins/chemistry , Mice , Proteomics , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/geneticsABSTRACT
Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.
Subject(s)
Arthritis, Rheumatoid/genetics , Autoimmune Diseases/genetics , Genetic Predisposition to Disease/genetics , Genetic Testing , Genome, Human , Alleles , Chromosome Mapping , Chromosomes, Human/genetics , Female , HLA Antigens/genetics , Humans , Lod Score , Male , Matched-Pair Analysis , Microsatellite Repeats/genetics , Middle Aged , Nuclear Family , Software , Statistics, Nonparametric , United States , White People/genetics , X Chromosome/geneticsABSTRACT
Friedreich's ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The structure of human frataxin, which we have determined at 1.8-A resolution, reveals a novel protein fold. A five-stranded, antiparallel beta sheet provides a flat platform, which supports a pair of parallel alpha helices, to form a compact alphabeta sandwich. A cluster of 12 acidic residues from the first helix and the first strand of the large sheet form a contiguous anionic surface on the protein. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Additional conserved residues create an extended 1008-A(2) patch on a distinct surface of the protein. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein-iron binding.
Subject(s)
Iron-Binding Proteins , Phosphotransferases (Alcohol Group Acceptor)/chemistry , Amino Acid Sequence , Cloning, Molecular , Crystallography, X-Ray , Friedreich Ataxia/genetics , Humans , Iron/metabolism , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Phosphotransferases (Alcohol Group Acceptor)/genetics , Protein Binding , Protein Folding , Protein Structure, Secondary , Sequence Homology, Amino Acid , FrataxinABSTRACT
BACKGROUND: Profilins are small eukaryotic proteins involved in modulating the assembly of actin microfilaments in the cytoplasm. They are able to bind both phosphatidylinositol-4,5-bisphosphate and poly-L-proline (PLP) and thus play a critical role in signaling pathways. Plant profilins are of interest because immunological cross-reactivity between pollen and human profilin may be the cause of hay fever and broad allergies to pollens. RESULTS: The determination of the Arabidopsis thaliana profilin isoform I structure, using multiwavelength anomalous diffraction (MAD) to obtain structure-factor phases, is reported here. The structure of Arabidopsis profilin is similar to that of previously determined profilin structures. Conserved amino acid residues in profilins from plants, mammals, and lower eukaryotes are critically important in dictating the geometry of the PLP-binding site and the overall polypeptide fold. The main feature distinguishing plant profilins from other profilins is a solvent-filled pocket located in the most variable region of the fold. CONCLUSIONS: Comparison of the structures of SH3 domains with those of profilins from three distinct sources suggests that the mode of PLP binding may be similar. A comparison of three profilin structures from different families reveals only partial conservation of the actin-binding surface. The proximity of the semi-conserved actin-binding site and the binding pocket characteristic of plant profilins suggests that epitopes encompassing both features are responsible for the cross-reactivity of antibodies between human and plant profilins thought to be responsible for type I allergies.
Subject(s)
Arabidopsis/chemistry , Contractile Proteins , Microfilament Proteins/chemistry , Actins/chemistry , Actins/metabolism , Allergens/chemistry , Allergens/immunology , Allergens/pharmacology , Amino Acid Sequence , Arabidopsis Proteins , Binding Sites , Conserved Sequence/genetics , Crystallography, X-Ray , Hydrogen Bonding , Immunoglobulin E/chemistry , Immunoglobulin E/immunology , Microfilament Proteins/classification , Microfilament Proteins/metabolism , Models, Molecular , Molecular Sequence Data , Peptides/chemistry , Peptides/metabolism , Plant Proteins/chemistry , Pollen/immunology , Pollen/metabolism , Profilins , Protein Structure, Secondary , Protein Structure, Tertiary , Rhinitis, Allergic, Seasonal/metabolism , Sequence Homology, Amino Acid , Water/metabolismABSTRACT
An isomorphous derivative of pertussis toxin crystals was prepared using a 2-alpha-mercuric analog of N-acetyl neuraminic acid in a method analogous to the use of inhibitors labelled with heavy atoms to solve crystal structures of enzymes. This derivative exploits the specific binding between pertussis toxin and terminal sialic acid residues on receptor glycoproteins. Difference Patterson maps yielded heavy-atom sites which refined with good statistics, indicating that the protein probably does not undergo a conformational change on receptor binding. Mercuric analogs of other monosaccharides should be easily obtainable using the same synthetic strategy, suggesting a general method for derivatizing crystals of carbohydrate-binding proteins.
ABSTRACT
Ascorbate-reduced dopamine beta-hydroxylase (DBH) is inhibited by CO in a competitive manner with respect to molecular O2. Measurement of the stoichiometry of CO binding indicates 0.50 CO bound per Cu(I), which provides the first evidence that the Cu(I) centers in the reduced enzyme are structurally inequivalent. FTIR spectroscopy has been used to detect an infrared absorption band characteristic of coordinated CO, with v(CO) = 2089 cm-1. Comparison of this frequency with those of other Cu(I)-carbonyls in both inorganic and protein systems suggests a coordination site with fewer or less basic ligands than the 3-histidine site of carbon-monoxy hemocyanin.