Biomedical subjects

A M Valdes

Publications and source records attributed to A M Valdes.

At least 19 recordsLinked to original sources

PubMed2006

Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population-based study.

BACKGROUND: Although age is the strongest predictor of osteoarthritis, the exact mechanism underlying this disorder remains elusive. OBJECTIVE: To examine the association between leucocyte telomere length (LTL), a bio-indicator of ageing, and radiographic hand osteoarthritis. METHODS: An unselected, predominantly female sample from the TwinsUK Adult Twin Registry (Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, UK) was studied. Radiographs of both hands were obtained with a standard posteroanterior view and assessed for radiographic osteoarthritis according to the Kellgren/Lawrence (K/L) score. Individual radiographic features including osteophytes and joint space narrowing (JSN) were also assessed on a four-point scale using a standard atlas. Hand osteoarthritis was defined radiographically as having >or=3 osteoarthritis-affected joints of both hands (K/L score>or=2). Severity of hand osteoarthritis was indicated semiquantitatively by total K/L scores, osteophytes, JSN scores and proportion of joints affected. Mean LTL was measured by the terminal restriction fragment length using the Southern blot. RESULTS: A total of 1086 Caucasian subjects (mean (SD) age 55 (8.0) years) were studied. LTL was 6.95 (0.64) kb and was inversely correlated with age. After adjustment for age, sex, body mass index and smoking, LTL was significantly shorter by 178 bp in subjects with hand osteoarthritis (n = 160) than in those without (n = 926; p = 0.04). LTL was also significantly associated with semicontinuous measures of osteoarthritis (eg, total K/L score, JSN score, osteophyte score and proportion of joints affected) after adjustment (all p<or=0.02) in a dose-response fashion. CONCLUSION: Shorter LTL equivalent to around 11 years of annual loss in normal people is associated with radiographic hand osteoarthritis and disease severity, suggesting potential shared mechanisms between osteoarthritis and ageing, and implicating oxidative stress and low-level chronic inflammation in both conditions.

Adult↗

PubMed2006

The effects of social status on biological aging as measured by white-blood-cell telomere length.

Low socio-economic status (SES) is associated with a shortened life expectancy, but its effect on aging is unknown. The rate of white-blood-cell (WBC) telomere attrition may be a biological indicator of human aging. We tested the hypothesis that SES is associated with telomere attrition independent of known risk factors influencing the aging process. We studied 1552 female twins. A venous blood sample was taken from each twin and isolated WBCs used for extraction of DNA. Terminal restriction fragment length (TRFL) was measured. Questionnaire data were collected on occupation, education, income, smoking, exercise, height and weight. Standard multiple linear regression and multivariate analyses of variance tested for associations between SES and TRFL, adjusting for covariates. A discordant twin analysis was conducted on a subset to verify findings. WBC telomere length was highly variable but significantly shorter in lower SES groups. The mean difference in TRFL between nonmanual and manual SES groups was 163.2 base pairs (bp) of which 22.9 bp (approximately 14%) was accounted for by body mass index, smoking and exercise. Comparison of TRFL in the 17 most discordant SES twin pairs confirmed this difference. Low SES, in addition to the harmful effects of smoking, obesity and lack of exercise, appears to have an impact on telomere length.

Adolescent↗

PubMed2005

D6S26515 marks a DRB115, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk. METHODS: We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden. RESULTS: We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15-=0.017 (95% CI 0.005, 0.062), p<0.001]. CONCLUSIONS/INTERPRETATION: Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk.

Adult↗

PubMed2005

Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR.

The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior. In a study of smokers enrolled in an open-label, randomized effectiveness trial, we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling. Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months, respectively, following a target quit date. Compared to women who carry both A2 alleles, women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects (odds ratio (OR)=1.91, 95% confidence interval (CI)=1.01-3.60; P<0.04) and at 12 months were somewhat more likely to report smoking (OR=0.76, 95% CI=0.56-1.03; P<0.076). Significant associations or trends were not observed in men. In women, individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function.

Adult↗

PubMed2005

Extended DR3-D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians.

Human leukocyte antigen (HLA)-DR3 haplotypes are associated with susceptibility to type 1 diabetes (T1D). Reports from Northern European populations show that an allele (D6S273*2) at a microsatellite mapping to HLA class III marks an extended DR3-B18 haplotype associated with increased susceptibility to T1D. Consistent with previous reports, D6S273*2 marked a highly predisposing DR3 haplotype in European origin, multiplex families from the USA. Furthermore, we observed on DR3 haplotypes that other D6S273 alleles were also significantly associated with both increased transmission (D6S273*5; P < 0.02) and decreased transmission (D6S273*7; P < 0.05) to affected individuals. The differential transmission was most evident among DR3-B8 haplotypes. Neither HLA-B*1801 nor any alleles of D6S273 were associated with increased T1D predisposition on DR4 haplotypes. These data indicate that multiple alleles of D6S273 mark a susceptibility locus whose effect we were able to detect only among DR3 haplotypes but not limited to DR3-B18 haplotypes.

Diabetes Mellitus, Type 1↗

PubMed2004

The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4(+) T-cell epitope in human interferon-beta.

Human CD4(+) T-cell epitopes were identified in interferon-beta (IFN-beta)-1b. A prominent peptide epitope region was found that induced a proliferative response in 16% of all donors tested. Responses corresponded to the presence of the HLA-DR2 haplotype. Responsive donors expressing the HLA-DQ6 allele showed an increased level of proliferation to the epitope as compared to peptide-responsive HLA-DQ6 negative donors. A similar result was found for HLA-DR15-expressing donors. PBMC from donors expressing HLA-DR15 were more likely to proliferate in response to IFN-beta in a whole-protein in vitro assay than donors who did not carry this haplotype. It is striking that the common DQ6 allele HLA-DQB1(*)0602 is found in linkage disequilibrium with HLA-DRB1(*)1501, and this combination defines the HLA genotype associated with the development of multiple sclerosis. The HLA association between a response to IFN-beta and MS might explain the prevalence of neutralizing antibody development, and may underlie the etiology of the disease.

CD4-Positive T-Lymphocytes↗

PubMed2001

Modeling of HLA class II susceptibility to Type I diabetes reveals an effect associated with DPB1.

In this report, we present evidence that the HLA class II DPB1 locus (or a locus with alleles in linkage disequilibrium with DPB1) contributes to Type I diabetes (IDDM) susceptibility in addition to the contribution of the HLA DR and DQ loci. The marker association segregation chi-square (MASC) method, which fits both genotype frequency and affected sib-pair identity-by-descent (IBD) distributions, was applied to 257 sib pairs affected with IDDM. Fitting DR-DQ as the sole HLA susceptibility loci was strongly rejected. Next, we considered the DPB1 contribution to disease susceptibility. Published reports indicate a predisposing role for alleles DPB1*0301 and DPB1*0202, including our previous stratification analyses of association data on this sample. IDDM probands were stratified into those not carrying the alleles DPB1*0301 and DPB1*0202 (group DPB1-A), and those carrying at least one copy of either allele (group DPB1-B). Both groups of probands have almost identical frequencies of DR and DQ haplotypes but significantly different IBD distributions in the subset of families with probands who do not carry the highly predisposing DR3/DR4 genotype. In these data, DPB1 (or a locus in linkage disequilibrium), in addition to DR-DQ, is involved in IDDM susceptibility and affects IBD in the HLA region. Addition of DPB1 in a genetic model of IDDM gives a better fit to the data than consideration of DR-DQ alone. Our results are consistent with previous reports implicating DPB1 in IDDM susceptibility.

Alleles↗

PubMed2001

Association of traditional risk factors with coronary calcification in persons with a family history of premature coronary heart disease: the study of the inherited risk of coronary atherosclerosis.

BACKGROUND: Genetic factors strongly influence the risk of coronary heart disease (CHD), but their contribution to variation in coronary atherosclerosis beyond that measured by traditional CHD risk factors is uncertain. METHODS: We recruited healthy subjects with family histories of premature CHD. We assessed traditional risk factors and performed electron beam tomography (EBT) to quantitate coronary artery calcification (CAC), a marker of coronary atherosclerosis. Persons with significant risk factors that included diabetes, total cholesterol >300 mg/dL, active cigarette smoking, and poorly controlled hypertension were excluded from the study. In this paper, we report on the relationship between traditional risk factors and CAC in this cohort. RESULTS: The incidence of coronary calcification was significantly higher in this cohort than in the population-based Rochester Heart Study. In our cohort, most traditional risk factors were significantly associated with CAC on univariate analysis. On the other hand, in stepwise logistical regression, age and triglycerides were the only predictors of variation in CAC in men and accounted for only 30% of the variation; in women, age, body mass index (BMI), and triglycerides were the only traditional risk factors significantly associated with CAC variation and accounted for 22.2% of CAC variance. CONCLUSIONS: In a cohort of subjects specifically selected for the characteristic of a family history of premature CHD, traditional risk factors accounted for less than one-third of the variation in CAC, and the most important predictors of CAC after age were plasma triglycerides. This supports the opinion that other inherited risk factors have important effects on the variation in coronary atherosclerosis and that the strategy of using EBT to phenotype clinically asymptomatic subjects with regard to coronary atherosclerosis may be a useful tool for identification of genes that are associated with CHD.

Adult↗

PubMed2000

The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes.

HLA-DPB1 genotypes were determined for samples from 269 multiplex Caucasian families from the Human Biological Data Interchange. DRB1 and DQB1 loci were also characterized, allowing assignment of DPB1 alleles to haplotypes and calculation of linkage disequilibrium values. Frequencies for several DPB1 alleles differed significantly between patients and affected family-based control subjects. Some differences were attributable to linkage disequilibrium with DR and DQ alleles, whereas others were not. DPB1*0301 and DPB1*0202 alleles are predisposing for type 1 diabetes in these data, not only in analyses of individual alleles, but also in genotype analyses. DPB1*0402 appears protective; however, stratification analysis indicates that its protective effect is specific for DR3 haplotypes. A protective role for DPB1*0401 is suggested by genotype analysis. For increased statistical power, DPB1 alleles were pooled into three categories: susceptible, neutral, and protective after removal of effects due to linkage disequilibrium with DR-DQ. Analysis of these pools suggests that DPB1 primarily affects susceptibility to, rather than protection from, type 1 diabetes in a dominant fashion. This effect is more apparent in patients with genotypes other than the highest risk DR3/DR4-DQB1*0302 genotype. These data support a role for the DPB1 locus in conferring susceptibility to type 1 diabetes.

Alleles↗

PubMed1999

Evidence for linkage and association to alcohol dependence on chromosome 19.

An association study on markers showing suggestive evidence for linkage to severe alcoholism was performed on the Collaborative Study on the Genetics of Alcoholism (COGA) data set. Our linkage study was restricted to the autosomal markers on chromosomes 2, 3, 4, 13, and 19, with low homozygosity (below 30%) and high identity-by-state sharing in affected sib pairs (ASPs). We used a strict phenotype definition, only individuals diagnosed as affected both on the ALDX1 (COGA criterion) and ALDX2 (ICD-10) scales were used in the analyses. Linkage was assessed by excess identity-by-descent allele sharing in ASPs. The strongest evidence of linkage was detected on chromosome 19, in particular at markers D19S49 (p < 0.0001) and D19S431 (p < 0.002). An association study of allele and haplotype data was then carried out on chromosome 19 markers using affected-family-based controls. A haplotype defined by alleles at markers D19S49, D19S43, and D19S200 in chromosome 19 shows significant association (p < 0.003, odds ratio 2.82). Further, significant differences were observed in the distribution of the harm avoidance subscale among genotypes defined by D19S49 (p < 0.0001). These results provide evidence for the existence of a locus in chromosome 19 potentially involved in alcohol dependence susceptibility.

Alcoholism↗

PubMed1999

Codon usage bias and base composition in MHC genes in humans and common chimpanzees.

Codon bias and base composition in major histocompatibility complex (MHC) sequences have been studied for both class I and II loci in Homo sapiens and Pan troglodytes. There is low to moderate codon bias for the MHC of humans and chimpanzees. In the class I loci, the same level of moderate codon bias is seen for HLA-B, HLA-C, Patr-A, Patr-B, and Patr-C, while at HLA-A the level of codon bias is lower. There is a correlation between codon usage bias and G+C content in the A and B loci in humans and chimps, but not at the C locus. To examine the effect of diversifying selection on codon bias, we subdivided class I alleles into antigen recognition site (ARS) and non-ARS codons. ARS codons had lower bias than non-ARS codons. This may indicate that the constraint of codon bias on nucleotide substitution may be selected against in ARS codons. At the class II loci, there are distinct differences between alpha and beta chain genes with respect to codon usage, with the beta chain genes being much more biased. Species-specific differences in base composition were seen in exon 2 at the DRB1 locus, with lower GC content in chimpanzees. Considering the complex evolutionary history of MHC genes, the study of codon usage patterns provides us with a better understanding of both the evolutionary history of these genes and the evolution of synonymous codon usage in genes under natural selection.

Animals↗

PubMed1999

Locus and population specific evolution in HLA class II genes.

The population genetics of the HLA class II loci was studied with reference to variation in the frequency of (a) alleles at a locus and (b) amino acids at specific sites. Variation was surveyed at 4 loci (DRB1, DQA1, DQB1, and DPB1) in 22 populations from the Twelfth International Histocompatibility Workshop (Saint-Malo, 1996). Allele and amino acid variation was measured by computing heterozygosity and the effective number of alleles. Substantial variations in polymorphism were observed among the various populations and loci studied. In the majority of the populations, DRB1 has the highest heterozygosity and effective number of alleles. As previously shown, the Amerindian populations have lower levels of allelic diversity when compared to other populations. At the amino acid level, DRB1 antigen recognition sites (ARS) have the highest heterozygosities and effective number of alleles. For the other loci (DPB1, DQA1, and DQB1) for which there is no crystal structure and for which ARS sites were inferred from DRB1, non-ARS sites were often among the sites with highest levels of variation. It is possible that these putative non-ARS sites do play a role in antigen presentation. The homozygosity test for neutrality was applied to allele and amino acid data. Of the four HLA class II loci studied, only DPB1 failed to show evidence of balancing selection. DQB1 and DQA1 depart significantly from neutrality in the largest number of populations. Genetic distances between populations were computed based on frequency of alleles and amino acids at ARS sites.

Alleles↗

PubMed1999

Association between type 1 diabetes age of onset and HLA among sibling pairs.

In this study, we report type 1 diabetes age-of-onset association with HLA class II (DRB1, DQB1, and DPB1) and class I (A) genes in 222 multiplex families from the Human Biological Data Interchange. Linear regression showed a small (R2 = 0.26) but significant correlation in the ages of onset among sib pairs. A strong association in age of onset between members of sib pairs was observed when the analysis was performed using contingency tables that split sibs into three age-at-onset ranges (0-10, 11-20, and 21-36 years). The association is strongest for sib pairs that share both haplotypes and is nonsignificant for sib pairs that do not share any DR-DQ haplotypes. A goodness-of-fit test revealed that DR-DQ haplotype sharing cannot account for all the association in age of onset among sib pairs. The age-of-onset distribution of DR-DQ haplotypes is affected by the DPB1 and A alleles present. The strongest associations were found with the A locus: DR3/DR4 genotype frequency decreases with age of onset in this data set only among A*0101- individuals, and A*2402 is strongly associated with younger age of onset in many DR-DQ haplotypes.

Adolescent↗

PubMed1997

Detecting disease-predisposing variants: the haplotype method.

For many HLA-associated diseases, multiple alleles-- and, in some cases, multiple loci--have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some--compared with none--of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1#52 (Arg predisposing) DQB1#57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class II DRB1 data, the results were consistent with the shared-epitope hypothesis.

Amino Acids↗

PubMed1997

HLA class II DR-DQ amino acids and insulin-dependent diabetes mellitus: application of the haplotype method.

Insulin-dependent diabetes mellitus (IDDM) HLA class II DRB1-DQA1-DQB1 data from four populations (Norwegian, Sardinian, Mexican American, and Taiwanese) have been analyzed to detect the amino acids involved in the disease process. The combination of sites DRB1#67 and 86; DQA1#47; and DQB1#9, 26, 57, and 70 predicts the IDDM component in these four populations, when the results and criteria of the haplotype method for amino acids, developed in the companion paper in this issue of the Journal, are used. The following sites, either individually, or in various combinations, previously have been suggested as IDDM components: DRB1#57, 70, 71, and 86; DQA1#52; and DQB1#13, 45, and 57 (DQB1#13 and 45 correlates 100% with DQB1#9 and 26). We propose that DQA1#47 is a better predictor of IDDM than is the previously suggested DQA1#52, and we add DRB1#67 and DQB1#70 to the HLA DR-DQ IDDM amino acids. We do not claim to have identified all HLA DR-DQ amino acids-or highly correlated sites-involved in IDDM. The frequencies and predisposing/protective effects of the haplotypes defined by these seven sites have been compared, and the effects on IDDM are consistent across the populations. The strongest susceptible effects came from haplotypes DRB1 *0301/DQA1 *0501/ DQB1*0201 and DRB1*0401-5-7-8/DQA1*0301/ DQB1*0302. The number of strong protective haplotypes observed was larger than the number of susceptible ones; some of the predisposing haplotypes were present in only one or two populations. Although the sites under consideration do not necessarily have a functional involvement in IDDM, they should be highly associated with such sites and should prove to be useful in risk assessment.

Amino Acids↗

PubMed1996

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families.

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.

Adolescent↗

PubMed1994

Mutational processes of simple-sequence repeat loci in human populations.

Mutational processes of simple sequence repeats (SSRs) in complex genomes are poorly understood. We examined these processes by introducing a two-phase mutation model. In this model, most mutations are single-step changes, but infrequent large jumps in repeat number also occur. We used computer simulations to determine expected values of statistics that reflect frequency distributions of allele size for the two-phase model and two alternatives, the one-step and geometric models. The theoretical expectations for each model were tested by comparison with observed values for 10 SSR loci genotyped in the Sardinian population, whose genetic and demographic histories have been previously reconstructed. The two-phase model provided the best fit to the data for most of these loci in this population. In the analysis we assumed that the loci were neutral and that this population had undergone rapid population growth. Recent observations made for unstable trinucleotide repeats support our suggestion that frequent small changes and rare large changes in repeat number represent two distinct classes of mutation at SSR loci. We genotyped the same 10 loci in Egyptian and sub-Saharan African samples to assess the utility of SSRs for studying the divergence of populations and found that estimates of interpopulation distances from SSRs were similar to those derived from analysis of mitochondrial DNA.

Gene Frequency↗

PubMed1993

Allele frequencies at microsatellite loci: the stepwise mutation model revisited.

We summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. We show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. We show that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size.

Alleles↗