Biomedical subjects

A R van der Slik

Publications and source records attributed to A R van der Slik.

8 recordsLinked to original sources

PubMed2002

HLA haplotypes and susceptibility to rheumatoid arthritis. More than class II genes.

Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

Arthritis, Rheumatoid↗

PubMed2001

Distribution of HERV-LTR elements in the 5'-flanking region of HLA-DQB1 and association with autoimmunity.

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.

Alleles↗

PubMed2001

The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci.

We have evaluated the possible contribution of genes besides DQ and DR to the association of HLA with rheumatoid arthritis (RA). To this end, we have looked at the allele distributions of six microsatellites, D6S1014, D6S2673, TNFalpha, MIB, C1-2-5, and C1-3-2 among 132 RA patients and 254 controls. We have defined 19 microsatellite clusters corresponding to previously described ancestral haplotypes. One of them was D6S1014*143-D6S273*139-TNFalpha*99-MIB*350-C1-2-5*196-C1-3-2*354, often found associated with DQB1*0201-DRB1*0301. As part of this microsatellite cluster, the allele MIB*350 was found to be a RA-predisposing factor, independent of DRB1*0301 and RA-predisposing haplotypes DQB1*03-DRB1*04 and DQB1*0501-DRB1*01. We conclude that the telomeric part of the HLA region contains a locus conferring predisposition to RA independently of HLA class II.

Arthritis, Rheumatoid↗

PubMed2001

Six microsatellite markers on the short arm of chromosome 6 in relation to HLA-DR3 and TNF-308A in systemic lupus erythematosus.

Differences in allelic distribution at loci surrounding the human HLA-DRB1 and tumor necrosis factor (TNF) genes have been observed in association with systemic lupus erythematosus (SLE). We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF-308A with SLE could be attributed to polymorphic markers in the chromosomal region encompassed by HLA-DRB1 and HLA-C. Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, microsatellites D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2 and the single nucleotide polymorphism at position -308 in the promoter of TNF. The independent contribution of alleles to disease susceptibility was estimated by cross-tabulation and multivariate logistic regression. Possession of TNF-308A was associated with susceptibility to SLE (odds ratio [95% confidence interval], 3.70 [2.24-6.11]). This remained present after stratification on possession of HLA-DR3 (pooled odds ratio, 2.53 [1.37-4.70]). Stratification revealed a possible association of possession of C1_2_5*192 with protection from SLE beyond the effects of HLA-DR3 and TNF-308A. A gene dosage effect was observed for -308A only (homozygotes, 7.75 [3.01-20.0], heterozygotes, 3.15 [1.85-5.37]). In multivariate analysis, possession of HLA-DR3, TNF-308A, and C1_2_5*192 remained independently associated with susceptibility to SLE (2.58 [1.29-5.18], 2.76 [1.43-5.31], and 0.26 [0.10-0.66], respectively). The association of possession of TNF-308A with susceptibility to SLE cannot be attributed to linkage to HLA-DR3 alone, nor to other polymorphic markers in the vicinity of the TNF gene. Further loci that are independently associated with SLE might be in the vicinity of marker C1_2_5.

Adult↗

PubMed2000

Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer.

The nature and frequency of human histocompatibility leukocyte antigen (HLA) class I loss mechanisms in primary cancers are largely unknown. We used flow cytometry and molecular analyses to concurrently assess allele-specific HLA phenotypes and genotypes in subpopulations from 30 freshly isolated cervical tumor cell suspensions.Tumor-associated HLA class I alterations were present in 90% of the lesions tested, comprising four altered pheno/genotype categories: (a) HLA-A or -B allelic loss (17%), mostly associated with gene mutations; (b) HLA haplotype loss, associated with loss of heterozygosity at 6p (50%). This category included cases with additional loss of a (third) HLA-A or -B allele due to mutation, as well as one case with an HLA class I-negative tumor cell subpopulation, caused by a beta2-microglobulin gene mutation; (c) Total HLA class I antigen loss and retention of heterozygosity (ROH) at 6p (10%); and (d) B locus or HLA-A/B downregulation associated with ROH and/or allelic imbalance at 6p (10%). Normal HLA phenotypes and ROH at 6p were observed in 10% of the cases. One case could not be classified (3%). Altered HLA class I antigen expression occurs in most cervical cancers, is diverse, and is mainly caused by genetic changes. Combined with widespread tumor heterogeneity, these changes have profound implications for natural immunity and T cell-based immunotherapy in cervical cancer.

Adenocarcinoma↗

PubMed2000

Subtyping for TNFa microsatellite sequence variation.

The microsatellite locus TNFa is frequently used as an additional genetic marker in studies of the major histocompatibility complex (MHC). Novel sequence variations at the TNFa locus have been described, and which may have implications for genetic analyses. In this study, we set up a nested polymerase chain reaction-sequence-specific primer (PCR-SSP) approach to type for these TNFa sequence variations. First, sequencing analysis of workshop B lymphoblastoid cell lines (n=13) showed the presence of three sequence variations upstream of the dinucleotide repeat at TNFa. Using nested PCR-SSP, we were able to detect these variations in a larger B lymphoblastoid cell line panel (n=34). Furthermore, we were able to show that TNFa alleles a7 and a10 are present in two distinct conformations leading to "splitting" of TNFa alleles exhibiting identical fragment lengths. To establish the frequency of the TNFa alleles and their variants, we performed microsatellite typing of a large panel of random individuals from the Dutch population (n=272). Subsequent nested PCR-SSP typing showed the presence of three previously described sequence variations in the Dutch population. Furthermore, the presence of a fourth subtype was established. The described variations of allele TNFa7 and TNFa10 are present in the random population with significant frequencies. Haplotyping analysis between HLA-DR, TNFa, and HLA-B showed that allele TNFa7.2 is present in an extended DR7-TNFa7.2-B13 haplotype. In this way, we were able to show that the additional sequence variations behave like distinct TNFa alleles.

Cell Line↗

PubMed1999

Frequent loss of heterozygosity on chromosome 6p in uveal melanoma.

Lack of expression of HLA class I antigens is frequently observed on primary uveal melanoma, and is correlated with improved patient survival. Several mechanisms may contribute to the observed loss of HLA class I expression, including changes at the DNA level. In this study, we used microsatellite analysis as a molecular genetic approach to examine loci on chromosome 6p for loss of heterozygosity (LOH). Three pairs of microsatellite markers were used to screen 20 formalin-fixed, paraffin-embedded uveal melanomas for LOH on the short arm of chromosome 6. In all cases, normal adjacent scleral tissue was used as a control. We identified LOH in eleven cases from microsatellite locus D6S105 to the telomere, in eight cases from microsatellite locus D6STNFa to the telomere (area includes D6S105), and in seven cases from microsatellite locus D6S291 to the end of chromosome 6p (includes D6STNFa and D6S105). In seven cases, retention of heterozygosity was found at all three loci using these primers. Our results suggest that loss of heterozygosity on chromosome 6p is a common feature in uveal melanoma. We did not find a correlation between the presence of LOH and locus-specific HLA-A and -B expression.

Choroid Neoplasms↗

PubMed1995

A novel G protein alpha subunit containing atypical guanine nucleotide-binding domains is differentially expressed in a molluscan nervous system.

We described the characterization of a novel G protein alpha subunit, G alpha a. cDNA encoding this subunit was cloned from the central nervous system of the mollusc Lymnaea stagnalis. The deduced protein contains all characteristic guanine nucleotide-binding domains of G alpha subunits but shares only a limited degree of overall sequence identity with known subtypes (approximately 30%). Moreover, two of the nucleotide-binding domains exhibit salient deviations from corresponding sequences in other G protein alpha subunits. The A domain, determining kinetic features of the GTPase cycle, contains a markedly unique amino acid sequence (ILIIGGPGAGK). In addition, the C domain is also clearly distinct (DVAGQRSL). The presence of a leucine in this motif, instead of glutamic acid, has important implications for hypotheses concerning the GTPase mechanism. In contrast to other G alpha subtypes, G alpha a has no appropriate N-terminal residues that could be acylated. It does contain the strictly conserved arginine residue that serves as a cholera toxin substrate in G alpha s and G alpha t but lacks a site for ADP-ribosylation by pertussis toxin. In situ hybridization experiments indicate that G alpha a-encoding mRNA is expressed in a limited subpopulation of neurons within the Lymnaea brain. These data suggest that G alpha a defines a separate class of G proteins with cell type-specific functions.

Amino Acid Sequence↗