Charles B. Foster

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies.

Abstract: The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases defined by chronic muscle inflammation and weakness associated with autoimmunity. We have performed low to high resolution molecular typing to assess the genetic variability of major histocompatibility complex loci (HLA-A, -B, -Cw, -DRB1, and -DQA1) in a large population of European American patients with IIM (n = 571) representing the major myositis autoantibody groups. We established that alleles of the 8.1 ancestral haplotype (8.1 AH) are important risk factors for the development of IIM in patients producing anti-synthetase/anti-Jo-1, -La, -PM/Scl, and -Ro autoantibodies. Moreover, a random forests classification analysis suggested that 8.1 AH-associated alleles B*0801 and DRB1*0301 are the principal HLA risk markers. In addition, we have identified several novel HLA susceptibility factors associated distinctively with particular myositis-specific (MSA) and myositis-associated autoantibody (MAA) groups of the IIM. IIM patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies have a unique HLA Class I risk allele, Cw*0304 (pcorr = 0.046), and lack the 8.1 AH markers associated with other anti-synthetase autoantibodies (for example, anti-Jo-1 and anti-PL-12). In addition, HLA-B*5001 and DQA1*0104 are novel potential risk factors among anti-signal recognition particle autoantibody-positive IIM patients (pcorr = 0.024 and p = 0.010, respectively). Among those patients with MAA, HLA DRB1*11 and DQA1*06 alleles were identified as risk factors for myositis patients with anti-Ku (pcorr = 0.041) and anti-La (pcorr = 0.023) autoantibodies, respectively. Amino acid sequence analysis of the HLA DRB1 third hypervariable region identified a consensus motif, 70D (hydrophilic)/71R (basic)/74A (hydrophobic), conferring protection among patients producing anti-synthetase/anti-Jo-1 and -PM/Scl autoantibodies. Together, these data demonstrate that HLA signatures, comprising both risk and protective alleles or motifs, distinguish IIM patients with different myositis autoantibodies and may have diagnostic and pathogenic implications. Variations in associated polymorphisms for these immune response genes may reflect divergent pathogenic mechanisms and/or responses to unique environmental triggers in different groups of subjects resulting in the heterogeneous syndromes of the IIM. Abbreviations: AH = ancestral haplotype, DM = dermatomyositis, EA = European Americans, HVR3 = third hypervariable region, IBM = inclusion body myositis, IIM = idiopathic inflammatory myopathies, MAA = myositis-associated autoantibodies, MHC = major histocompatibility complex, MSA = myositis-specific autoantibodies, PM = polymyositis, RF = random forests, RSP = restrictive supertype patterns, SRP = signal recognition particle.

Polymorphism analysis of six selenoprotein genes: support for a selective sweep at the glutathione peroxidase 1 locus (3p21) in Asian populations

BackgroundThere are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine. Since many selenoproteins have antioxidant properties, it is plausible that inter-individual differences in selenoprotein expression or activity could influence risk for a range of complex diseases, such as cancer, infectious diseases as well as deleterious responses to oxidative stressors like cigarette smoke. To capture the common genetic variants for 6 important selenoprotein genes (GPX1, GPX2, GPX3, GPX4, TXNRD1, and SEPP1) known to contribute to antioxidant host defenses, a re-sequence analysis was conducted across these genes with particular interest directed at the coding regions, intron-exon borders and flanking untranslated regions (UTR) for each gene in an 102 individual population representative of 4 major ethnic groups found within the United States.ResultsFor 5 of the genes there was no strong evidence for selection according to the expectations of the neutral equilibrium model of evolution; however, at the GPX1 locus (3p21) there was evidence for positive selection. Strong confirmatory evidence for recent positive selection at the genomic region 3p21 in Asian populations is provided by data from the International HapMap project.ConclusionThe SNPs and fine haplotype maps described in this report will be valuable resources for future functional studies, for population specific genetic studies designed to comprehensively explore the role of selenoprotein genetic variants in the etiology of various human diseases, and to define the forces responsible for a recent selective sweep in the vicinity of the GPX1 locus.

High Serum Selenium and Reduced Risk of Advanced Colorectal Adenoma in a Colorectal Cancer Early Detection Program

Background: Epidemiologic and animal studies suggest that selenium may reduce risk of colorectal cancer. However, the epidemiologic data is mainly from relatively small investigations, limiting their interpretation. Although substantial evidence suggests that smoking is a strong effect modifier for other antioxidative nutrients, little is known about smoking-selenium interactions in colorectal tumors. Methods: We studied the association of serum selenium and advanced colorectal adenoma, a cancer precursor, in 758 cases and 767 sex- and race-matched controls, randomly selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma (≥1 cm or villous elements, or high-grade dysplasia) of the distal colon, and controls had a negative sigmoidoscopy. Results: The multivariable odds ratio (OR) comparing participants in the highest quintile of serum selenium with those in the lowest quintile was 0.76 [95% confidence interval (95% CI), 0.53-1.10; Ptrend = 0.01]. The inverse association between serum selenium and advanced colorectal adenoma was significant among recent smokers (OR, 0.53; 95% CI, 0.27-1.01 for highest versus lowest tertile; Ptrend = 0.008). Serum selenium was unrelated to adenoma risk in nonsmokers and former smokers who quit smoking ≥10 years ago. Conclusion: Selenium may reduce the risk of developing advanced colorectal adenoma, particularly among the high-risk group of recent smokers. (Cancer Epidemiol Biomarkers Prev 2006;15(2):315–20)

Human Cytomegalovirus–Encoded α-Chemokines Exhibit High Sequence Variability in Congenitally Infected Newborns

Most congenital human cytomegalovirus (HCMV) infections are asymptomatic, but some lead to severe disease. We hypothesized that differences in disease manifestations may be partially explained by differences in viral strains. We recently reported an association between unique long (UL) 144 gene polymorphisms and clinical disease. We now report on the sequence heterogeneity of 2 potential HCMV virulence genes that encode alpha -chemokines: UL146 and UL147. These 2 genes were highly divergent in cultured isolates obtained from 23 newborns with congenital HCMV infection and were difficult to categorize. Unlike our findings for the contiguous UL144 gene, no specific UL146 or UL147 genotype was associated with disease outcome.

Loss of Linkage Disequilibrium and Accelerated Protein Divergence in Duplicated Cytomegalovirus Chemokine Genes

Human CMV (hCMV) encodes several captured chemokine ligand and chemokine receptor genes that may play a role in immune evasion. The adjacent viral alpha-chemokine genes UL146 and UL147 appear to have duplicated subsequent to a recent gene capture event. Sequence data from multiple hCMV isolates suggest accelerated protein evolution in one of the paralogues, UL146. Extensive sequence variation was noted throughout the more rapidly evolving paralogue, although significant variation was also observed within the more slowly evolving gene, especially within a region corresponding to a possible signal peptide. In contrast to the haplotype structure observed for other hCMV genes, the distribution of nucleotide variants indicates a marked loss of linkage disequilibrium within UL146 and to a lesser extent UL147. Despite evidence of accelerated protein evolution, the rate of nonsynonymous to synonymous substitutions (dN/dS) in the more rapidly evolving paralogue was not indicative of neutral evolution, but of moderate purifying selection. The data presented here provides a unique opportunity to study the mechanisms by which a recently duplicated pair of genes has diverged and suggests a role for recombination.

Serum Selenium, Selenoenzymes and Risk of Colorectal Cancer: Primary Analysis in the Women's Health Initiative and Meta-Analysis

Background: Selenium may prevent colorectal cancer. However, several previous studies are small and few investigated the association between selenium and colorectal cancer among women whose selenium metabolism may differ from men. Furthermore, genetic variants in selenoenzymes may be associated with colorectal cancer risk. Methods: This nested case–control study investigated whether serum selenium concentration and genetic variants in five selenoenzymes (glutathione peroxidase 1–4 and selenoprotein P) were associated with colorectal cancer risk in 804 colorectal cancer cases and 805 matched controls from the Womens Health Initiative (WHI) Observational Study. A meta-analysis was conducted to compare the WHI result with previous studies including 12 observational studies and two clinical trials on selenium. Results: Within the WHI, selenium concentrations were relatively high (mean = 135.6 μg/L) and were not associated with colorectal cancer risk (Ptrend = 0.10); the adjusted OR comparing the fifth with first quintile was 1.26 (95% CI, 0.91–1.73). Moreover, genetic variants in selenoenzymes were not significantly associated with colorectal cancer risk. Consistent with the finding in WHI, our meta-analysis showed no association between selenium and colorectal tumor risk in women (OR = 0.97; 95% CI, 0.79–1.18) comparing the highest quantile with the lowest); however, in men, there was a significant inverse association (OR = 0.68; 95% CI, 0.57–0.82) (P = 0.01). Conclusion: Consistent with previous studies, we observed no protective effect of selenium on colorectal cancer among women. Impact: Our analyses suggest that a population with relatively high selenium concentrations, especially women, would not benefit from increasing selenium intake. Cancer Epidemiol Biomarkers Prev; 20(9); 1822–30. ©2011 AACR.

A common genetic variant in FCGR3A-V158F and risk of Kaposi sarcoma herpesvirus infection and classic Kaposi sarcoma.

Associations of FCGR3A among men with HIV/acquired immunodeficiency syndrome suggest that host responses affect the pathogenesis of Kaposi sarcoma herpesvirus (KSHV) infection and risk of acquired immunodeficiency syndrome–associated Kaposi sarcoma. Using DNA from two HIV seronegative case-control populations in Italy, we examined whether the functional FCGR3A-V158F variant was associated with risk of KSHV infection or classic Kaposi sarcoma (CKS). In population I, we examined FCGR3A variants and risk of KSHV infection in 34 KSHV latent nuclear antigen (LANA)-seropositive and 120 LANA-seronegative adults from Sardinia (52% male; median age, 45 years; range, 31-60), whereas in population II, we examined risk of CKS from 133 CKS cases and 172 KSHV LANA-seropositive controls from Sicily, Rome, and Naples (70% males; median age, 74 years; range, 29-91). FCGR3A variants were determined by direct sequence analysis of a nested PCR of genomic DNA assay using allele-specific primers. KSHV LANA was determined by immunofluorescence assay. Overall, compared with the 158F allele, 158V was overrepresented among controls from both Mediterranean populations (frequency = 0.52 and 0.51, respectively). After controlling for age, 158V homozygous women were at increased risk of KSHV infection and CKS compared with 158F homozygous women [odds ratio (OR), 8.7; 95% confidence interval (95% CI), 0.8-98 and OR, 3.8; 95% CI, 1.0-14, respectively], whereas homozygous men were at decreased risk (OR, 0.4; 95% CI, 0.1-2.3 and OR, 0.4; 95% CI, 0.2-0.8, respectively). Significant gene-dose effects were observed among men and women at risk for CKS (Ptrend ≤ 0.05). Our findings suggest that gender differences could possibly modify the effect of FCGR3A on risk of KSHV infection and CKS. Additional studies are required to confirm these relationships and determine their etiologic significance.

A Haplotype-Based Test of Association Using Data from Cohort and Nested Case-Control Epidemiologic Studies

Haplotype-based risk models can lead to powerful methods for detecting the association of a disease with a genomic region of interest. In population-based studies of unrelated individuals, however, the haplotype status of some subjects may not be discernible without ambiguity from available locus-specific genotype data. A score test for detecting haplotype-based association using genotype data has been developed in the context of generalized linear models for analysis of data from cross-sectional and retrospective studies [1]. In this article, we develop a test for association using genotype data from cohort and nested case-control studies where subjects are prospectively followed until disease incidence or censoring (end of follow-up) occurs. Assuming a proportional hazard model for the haplotype effects, we derive an induced hazard function of the disease given the genotype data, and hence propose a test statistic based on the associated partial likelihood. The proposed test procedure can account for differential follow-up of subjects, can adjust for possibly time-dependent environmental co-factors and can make efficient use of valuable age-at-onset information that is available on cases. We provide an algorithm for computing the test statistic using readily available statistical software. Utilizing simulated data in the context of two genomic regions GPX1 and GPX3, we evaluate the validity of the proposed test for small sample sizes and study its power in the presence and absence of missing genotype data.

The Use of Artificial Neural Networks in Prediction of Congenital CMV Outcome from Sequence Data

A large number of CMV strains has been reported to circulate in the human population, and the biological significance of these strains is currently an active area of research. The analysis of complex genetic information may be limited using conventional phylogenetic techniques. We constructed artificial neural networks to determine their feasibility in predicting the outcome of congenital CMV disease (defined as presence of CMV symptoms at birth) based on two data sets: 54 sequences of CMV gene UL144 obtained from 54 amniotic fluids of women who contracted acute CMV infection during their pregnancy, and 80 sequences of 4 genes (US28, UL144, UL146 and UL147) obtained from urine, saliva or blood of 20 congenitally infected infants that displayed different outcomes at birth. When data from all four genes was used in the 20-infants’ set, the artificial neural network model accurately identified outcome in 90% of cases. While US28 and UL147 had low yield in predicting outcome, UL144 and UL146 predicted outcome in 80% and 85% respectively when used separately. The model identified specific nucleotide positions that were highly relevant to prediction of outcome. The artificial neural network classified genotypes in agreement with classic phylogenetic analysis. We suggest that artificial neural networks can accurately and efficiently analyze sequences obtained from larger cohorts to determine specific outcomes. The ANN training and analysis code is commercially available from Optimal Neural Informatics (Pikesville, MD).