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R A Kaslow

Publications and source records attributed to R A Kaslow.

At least 19 recordsLinked to original sources
PubMed2006

Conserved extended haplotypes of the major histocompatibility complex: further characterization.

Since the complete sequencing of a human major histocompatibility complex (MHC) haplotype, interest in non-human leucocyte antigen (HLA) genes encoded in the MHC has been growing. Non-HLA genes, which outnumber the HLA genes, may contribute to or account for HLA and disease associations. Most information on non-HLA genes has been obtained in separate studies of individual loci. To comprehensively address polymorphisms of relevant non-HLA genes in 'conserved extended haplotypes' (CEH), we investigated 101 International Histocompatibility Workshop reference cell lines and nine additional anonymous samples representing all 37 unambiguously characterized CEHs at MICA, NFKBIL1, LTA, NCR3, AIF1, HSPA1A, HSPA1B, BF, NOTCH4 and a single nucleotide polymorphism (SNP) at HLA-DQA1 as well as MICA, NOTCH4, HSPA1B and all five tumour necrosis factor short tandem repeat (STR) polymorphisms. This work (1) provides an extensive catalogue of MHC polymorphisms in all CEHs, (2) unravels interrelationships between HLA and non-HLA haplotypical lineages, (3) resolves reported typing ambiguities and (4) describes haplospecific markers for a number of CEHs. Analysis also identified a DQA1 SNP and segments containing MHC class III polymorphisms that corresponded with class II (DRB3 and DRB4) lineages. These results portray the MHC where lineages containing non-HLA and HLA variants in linkage disequilibrium may operate in concert and can guide more thorough design and interpretation of HLA-disease relationships.

3' Untranslated Regions↗
PubMed2006

Interleukin 18 and human immunodeficiency virus type I infection in adolescents and adults.

Interleukin (IL)-18, a proinflammatory cytokine, has been recognized recently as an important factor in both treated and untreated patients with human immunodeficiency virus type 1 (HIV-1) infection. Consistent with all earlier reports, our quantification of serum IL-18 concentrations in 88 HIV-1 seropositive, North American adolescents (14-18 years old) revealed a positive correlation with cell-free HIV-1 viral load at two separate visits (Spearman's r = 0.31 and 0.50, respectively, P < 0.01 for both), along with a negative correlation with CD4+ T cell counts (r = -0.31 and -0.35, P < 0.01 for both). In additional analyses of 66 adults (21-58 years old) from Zambia, HIV-1 seroconversion was associated uniformly with elevated IL-18 production (P < 0.0001). These epidemiological relationships were independent of other population-related characteristics, including age, gender and ethnicity. In neither study population could serum IL-18 concentrations be associated with the IL-18 gene (IL18) promoter genotypes defined by five major single nucleotide polymorphisms. Collectively, these findings suggest that circulating IL-18 rather than the IL18 genotype may provide a useful biomarker for HIV-1-related events or outcomes.

ADP-ribosyl Cyclase 1↗
PubMed2005

Interleukin (IL)-2 and IL-12 responses to Chlamydia trachomatis infection in adolescents.

Chlamydia trachomatis infects epithelial cells at the mucosal surface. While in vitro and animal studies have shown changes in mucosal T(H)1-associated cytokines in the presence of C. trachomatis infection and with its progression to the upper genital tract or clearance, in vivo cytokine responses to chlamydial infection in humans are not well understood. Using a quantitative enzyme-linked immunosorbent assay (ELISA), we examined the endocervical production of two T(H)1-associated cytokines, i.e. interleukin (IL)-2 and IL-12, in relation to C. trachomatis infection in adolescents. At a randomly selected visit for 396 females, median endocervical IL-2 levels were significantly lower (190 versus 283 pg/ml, P = 0.02) and median IL-12 levels significantly higher (307 versus 132 pg/ml, P < 0.001) in subjects testing positive versus negative for C. trachomatis. These divergent T(H)1-associated cytokine responses were: (1) confirmed in paired analyses of 96 individuals before and after infection within 6-month intervals, (2) reversible in 97 patients who cleared infection during consecutive visits, (3) not attributable to sociodemographic factors or other genital infections and (4) independent of common genetic variants at the IL2 and IL12B loci associated previously with differential gene expression. From these findings we infer that increased IL-12 and decreased IL-2, observed commonly during mucosal inflammation, are important features of mucosal immune defence against C. trachomatis infection.

Adolescent↗
PubMed2004

MICA and recovery from hepatitis C virus and hepatitis B virus infections.

The polymorphic MHC class I chain-related A (MICA) gene encodes a ligand that has different binding affinities for the NKG2D activating receptor of CD8+ T cells and natural killer (NK) cells. We hypothesized that MICA heterogeneity would affect recovery from hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To test the hypothesis, we initially typed known MICA polymorphisms for 228 persons who cleared HCV infection and 442 persons with persistent hepatitis C matched on other factors affecting viral persistence. Although MICA(*)015 was detected more than two-fold more often in persons with viral clearance (odds ratio 0.36, 95% confidence interval=0.19, 0.80), it occurred in fewer than 5% of the study population. In a similar analysis of 442 persons with chronic hepatitis B and 768 matched controls who recovered, MICA(*)015 was detected in 2.0% of persons with chronic hepatitis B and only 0.9% of controls. No significant associations were detected with other MICA polymorphisms. While further investigation may reveal a structural basis of the MICA(*)015 associations, these data provide little support for the hypothesis that differential distribution of MICA alleles substantially affects recovery from HCV and HBV infections.

Hepacivirus↗
PubMed2004

MICA intron 1 sequences of conserved extended HLA haplotypes: implications for sequencing-based typing.

The human major histocompatibility complex (MHC) class I chain-related gene A (MICA) has a high degree of genetic diversity. Several methods have been used in MICA typing. Recent studies reported different results for the same reference cell lines typed by different methods. By searching the GenBank, we found an indel polymorphism in MICA intron 1 corresponding to the area where one of the sequencing-based typing primers used by others is located. We investigated this polymorphism in 43 reference samples by primer cycle sequencing. This approach revealed three haplotype-specific patterns of polymorphisms in intron 1. This study provided evidence that one of the primers commonly used in MICA typing may fail to amplify both alleles in certain heterozygous combinations. Our data showed a correlation between the three patterns in MICA intron 1 and exon 5 short tandem repeat (STR) alleles. Being neutral ones, the intron 1 and STR polymorphisms appeared to mark the ancestral lineages better than the coding region polymorphisms.

Base Sequence↗
PubMed2004

Molecular typing of human leukocyte antigen and related polymorphisms following whole genome amplification.

Reliable, high-resolution genotyping of human leukocyte antigen (HLA) polymorphisms is often compromised by DNA samples of suboptimal quality or limited quantity. We tested the feasibility of molecular typing for variants at HLA and neighboring loci using whole genome amplification (WGA) strategy facilitated by the Phi29 DNA polymerase. With little (5-100 ng) starting genomic DNA of varying quality and source materials, WGA was deemed successful in 167 of 169 DNA from 47 cell lines, 100 European Americans, and 22 native Africans. The Phi29-processed DNA provided adequate templates for polymerase chain reaction (PCR)-based analyses of several HLA (A, B, C, DRB1, and DQB1) and related loci (HFE, MICA, and 10 microsatellites) in the 6p24.3-6p21.3 region, with PCR amplicons ranging from 92 to 2200 bp. Five different genotyping techniques resolved and confirmed 364 genotypes when both original and Phi29-processed DNA worked in PCRs. General population genetic analyses provided additional evidence that WGA may represent a reliable and simple approach to securing ample genomic DNA for typing HLA, MICA, and related variants.

Africa↗
PubMed2002

Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women: results from the Iowa Women's Health Study.

OBJECTIVE: To determine whether rheumatoid arthritis (RA) is associated with excess mortality among older women. METHODS: RA associated mortality was examined in a prospective cohort study that was started in 1986, and included 31 336 women aged 55-69 years without a history of RA at baseline. Up to 1997, 158 cases of RA were identified and validated against medical records. The relative risk (RR) and 95% confidence interval (CI) were calculated as measures of association between RA onset and subsequent mortality (overall and cause-specific) using Cox proportional hazards regression. RESULTS: Compared with non-cases, women developing RA during follow up had a significantly increased mortality risk (RR=1.52; 95% CI 1.05 to 2.20). Mortality was higher among rheumatoid factor (RF) positive cases (RR=1.90; 95% CI 1.24 to 2.92) than among RF negative cases (RR=1.00; 95% CI 0.45 to 1.99). There were trends towards increased proportions of RA related deaths from infection (RR=3.61; 95% CI 0.89-14.69) and circulatory disease (RR=1.46; 95% CI 0.76 to 2.81) but not malignancy (RR=0.97; 95% CI 0.46 to 2.04). CONCLUSIONS: RA was associated with significantly increased mortality in a cohort of older women, and the association appeared to be restricted to those with RF positive disease.

Aged↗
PubMed2001

Risk factors for acquisition of hepatitis C virus infection: a case series and potential implications for disease surveillance.

BACKGROUND: Transmission of hepatitis C virus (HCV) is strongly associated with use of contaminated blood products and injection drugs. Other "non-parental" modes of transmission including sexual activity have been increasingly recognized. We examined risk factors for acquiring HCV in patients who were referred to two tertiary care centers and enrolled in an antiviral therapy protocol. METHODS: Interviews of 148 patients were conducted apart from their physician evaluation using a structured questionnaire covering demographics and risk factors for HCV acquisition. RESULTS: Risk factors (blood products, injection/intranasal drugs, razor blades/ toothbrushes, body/ear piercing, occupational exposure, sexual activity) were identified in 141 (95.3%) of participants; 23 (15.5%) had one (most frequently blood or drug exposure), 41 (27.7%) had two, and 84 (53.4%) had more than two risk factors. No patient reported sexual activity as a sole risk factor. Body piercing accounted for a high number of exposures in women. Men were more likely to have exposure to street drugs but less exposure to blood products than women. Blood product exposure was less common in younger than older HCV patients. CONCLUSION: One and often multiple risk factors could be identified in nearly all HCV-infected patients seen in a referral practice. None named sexual transmission as the sole risk factor. The development of a more complete profile of factors contributing to transmission of HCV infection may assist in clinical and preventive efforts. The recognition of the potential presence of multiple risk factors may have important implications in the approach to HCV surveillance, and particularly the use of hierarchical algorithms in the study of risk factors.

Acute Disease↗
PubMed2001

Novel alleles at the lymphotoxin alpha (LTalpha) locus mark extended HLA haplotypes in native Africans.

Genetic variations at the closely related tumor necrosis factor alpha (TNFalpha or TNF) and lymphotoxin alpha (LTalpha, formerly TNFbeta) loci have been well documented in various human populations, and several haplotypes spanning the MHC class I and class II loci are known to carry specific TNF alleles. Genotyping of the TNFc microsatellite within the first intron of LTalpha in 285 Rwandans and 319 Zambians revealed two predominant alleles, c1 at frequencies of 0.598 and 0.683 and c2 at 0.384 and 0.307, respectively. Overall, the distribution of TNFc genotypes containing the major alleles conformed well to the Hardy-Weinberg equilibrium in both cohorts. Two previously unrecognized minor TNFc alleles were also detected: the first, designated c0, was found in 10 native Africans and was the only allele present in 10 chimpanzees; the second, designated c3, was seen in 6 other African patients. Further genotyping at loci for HLA class I, class II, and for transporters associated with antigen processing, subunit 1 (TAP1) in those 16 individuals suggested a tight, stable extended haplotype involving c0 and 26Asn (LTalpha)-TNF3 (TNF promoter -238A and -308G)-DRB1*1503-DQB1*0602-TAP1.2 (333Val)-TAP1.4 (637Gly). The c3 allele was observed on another extended haplotype with 26Thr (LTalpha)-TNF1 (TNF promoter -238G and -308G)-DQB1*0102-DQB1*0501-TAP1*0101 (333Ile and 637Asp). The c3-tagged haplotype further extended to Cw*15 at the HLA class I C locus, but no specific A or B alleles could be unambiguously assigned. Positive associations between c2 homozygosity and HIV-1 seronegative status in both Rwandans and Zambians (odds ratio = 2.03 and 2.00, p = 0.04 and 0.07, respectively) had little effect on the haplotype assignments. These findings suggest a preferential expansion of the human TNFc dinucleotide (CT/AG) repeat sequence and further imply the existence of two extended MHC lineages that have not been disrupted by recombinations.

Africa↗
PubMed2001

TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies.

Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Genotyping TAP2 variants in North American Caucasians, Brazilians, and Africans.

The protein forms of transporter associated with antigen processing, subunit 2 (TAP2), differ either by amino acid substitutions (Thr374Ala, Ile379Val, Ile467Val, Thr565Ala, Val577Met, Cys651Arg, and Ala665Thr) or by a truncation (Gln687Stop) of 17 amino acid residues at the C-terminus. Nonsynonymous single nucleotide polymorphisms (N-SNPs) causing these amino acid variations except 577Val were detected in genomic DNA samples from North American Caucasians (n = 76), Brazilians (n = 148), Rwandans (n = 285), and Zambians (n = 117). Exclusive (100%) and nearly exclusive (>95%) linkage disequilibrium was seen with a number of N-SNPs. The average heterozygosity at any given dimorphic site ranged from 7.3% to 44.6%, and at least four N-SNPs showed clear population specificity. N-SNP combinations alone led to the identification of 16 relatively common alleles, which appeared to form at least three lineages. Further analyses of 101 cDNA samples from Brazilians detected nine expressed TAP2 alleles, four of which matched the official assignments. Genetic complexity at the TAP2 locus was further enhanced by two out of five synonymous SNPs (S-SNPs), especially the GGT386GGG (Gly) that had similar heterozygosity rates in Caucasians (28.9%), Rwandans (33.3%), and Zambians (33.3%). Overall, distribution of both synonymous and nonsynonymous SNPs in the various ethnic groups examined here conformed well to the Hardy-Weinberg equilibrium, and between 57.9% and 77.0% of subjects in each ethnic group were heterozygous with two TAP2 alleles predicted to differ by at least one amino acid residue. Such complexity of TAP2 polymorphisms, in the form of SNPs as well as alleles, is likely to complicate the analyses of disease associations and haplotype structures in the HLA class II region.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection.

Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-alpha were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN + R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the -592A or the -819T SNP was associated with SR (odds ratio [OR] = 2.2; P =.016). The -592A/A and the exclusively linked -819T/T genotypes were also associated with SR (OR = 16.6; P =.013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and -3575T, -2763C, -1082A, -819T, -592A was also associated with SR (OR = 2.65; P =.01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR(crude) = 13.7; P =.025; stratified ORs = 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences -238G/A and -308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for -592A, -819T or the extended haplotype (108bp) - (-2575T) - (-2763C) - (-1082A) - (-819T) - (-592A) is associated with SR to IFN + R.

Alleles↗
PubMed2001

Polymorphisms in HLA class I genes associated with both favorable prognosis of human immunodeficiency virus (HIV) type 1 infection and positive cytotoxic T-lymphocyte responses to ALVAC-HIV recombinant canarypox vaccines.

Carriers of certain human leukocyte antigen class I alleles show favorable prognosis of human immunodeficiency virus type 1 (HIV-1) infection, presumably due to effective CD8(+) cytotoxic T-lymphocyte responses, but close relationships between class I variants mediating such responses to natural and to vaccine HIV-1 antigen have not been established. During 6 to 30 months of administration and follow-up in trials of ALVAC-HIV recombinant canarypox vaccines, cells from 42% of 291 HIV-1-negative vaccinated subjects typed at class I loci responded to an HIV-1 protein in a lytic bulk CD8(+) cytotoxic T-lymphocyte assay. By 2 weeks after the second dose, higher proportions of vaccinees carrying one of two alleles consistently associated with slower progression of natural HIV-1 infection reacted at least once: B*27 carriers reacted to Gag (64%; odds ratio [OR] = 10.3, P = 0.001) and Env (36%; OR = 4.6, P = 0.04), and B*57 carriers reacted to Env (44%; OR = 6.6, P < 0.05). By 2 weeks after the third or fourth dose, B*27 carriers had responded (two or more reactions) to Gag (33%; OR = 4.4, P < 0.05) and B*57 carriers had responded to both Gag (39%; OR = 5.3, P = 0.013) and Env (39%; OR = 9.5, P = 0.002). Homozygosity at class I loci, although conferring an unfavorable prognosis following natural infection, showed no such disadvantage for vaccine response. Individual class I alleles have not previously demonstrated such clear and consistent relationship with both the clinical course of an infection and cellular immunity to a vaccine against the infectious agent. This proof of principle that class I an alleles modulate both processes has implications for development of HIV-1 and presumably other vaccines.

AIDS Vaccines↗
PubMed2000

Association of DRB1*1501 with disseminated Mycobacterium avium complex infection in North American AIDS patients.

The HLA class II allele, DR2 (DRB1*1501), has been repeatedly found to be associated with development of tuberculosis and leprosy. We searched for associations of these and other class II alleles with disseminated Mycobacterium avium complex infection (DMAC) in North American Caucasian homosexual AIDS patients. Molecular typing for HLA-DRB1 and -DQB1 alleles in 176 cases of DMAC and 176 matched controls showed an association of accelerated onset of disease with DRB1*1501 (and the closely linked DQB1*0602) that was stronger upon adjustment for the degree and duration of CD4+ cell deficiency (P=0.04) and in multivariate analysis (P=0.02) than in unadjusted analysis. A similar trend was seen with DRB1*0701, and no other allele showed a relationship of similar magnitude. M. avium complex organisms may more effectively evade host defenses in individuals carrying an HLA polymorphism identical to that associated with M. tuberculosis and M. leprae.

AIDS-Related Opportunistic Infections↗
PubMed2000

Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection.

Pro-inflammatory cytokines including tumour necrosis factor (TNF) mediate the pathogenesis of hepatitis C virus (HCV) infection. The distribution of TNF gene polymorphisms was examined among cirrhotic and non-cirrhotic patients infected with HCV. Thirty Caucasians with cirrhosis due to chronic HCV infection and 114 HCV-infected patients histopathologically free of cirrhosis were genotyped for genetic variants in TNF, lymphotoxin alpha and TNF-receptor type I using PCR-based techniques. Variability in the progression of HCV-related cirrhosis was assessed in a multivariate model including genetic and non-genetic factors such as gender, estimated duration of infection, alcohol consumption, and viral genotype. Viral genotype and non-genetic host features were not independently related to the occurrence or rate of development of cirrhosis in the patient population. In contrast, the TNF promoter variants TNF2 (-238A) and TNF3 (-308A) conferred a 3.2-fold and 5.1-fold risk of cirrhosis respectively (P = 0.03 for both). Reciprocal effects were observed with several TNF alleles and haplotypes defined by the -238G/A and -308G/A dimorphic sequences. Polymorphisms in the TNF alpha promoter appear to be associated with variability in the histological severity of chronic hepatitis C infection.

Adolescent↗