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Biomedical subjects

A J MacGregor

Publications and source records attributed to A J MacGregor.

At least 37 records · Page 2Linked to original sources
PubMed2000

Twins. Novel uses to study complex traits and genetic diseases.

The challenge faced by research into the genetic basis of complex disease is to identify genes of small relative effect against a background of substantial genetic and environmental variation. This has focused interest on a classical epidemiological design: the study of twins. Through their precise matching for age, the common family environment and background environmental variation, studying diseases in non-identical twins provides a means to enhance the power of conventional strategies to detect genetic influence through linkage and association. The unique matching of identical twins provides researchers with ways to isolate the function of individual genes involved in disease together with approaches to understanding how genes and the environment interact.

Diseases in Twins↗
PubMed2000

Genetic influence on peripheral blood T lymphocyte levels.

T lymphocytes are a major component of the adaptive immune system. CD4 positive T cell subpopulations regulate B cell and macrophage effector function while CD8 positive T cells are largely responsible for anti-viral cytotoxic activity. The degree of natural variation in the levels and ratios of the various T cell subpopulations is a possible risk factor for the development of autoimmune disease, infectious disease and cancer. There is some evidence from studies of inbred strains of mice and humans which suggests that variation in T cell subpopulations is genetically influenced. However, family studies alone cannot distinguish between common environmental and shared genetic influences and provide less robust estimates of the heritability than twin studies. To comprehensively examine genetic influences on a selection of important T cell phenotypes, we investigated variation in levels of total lymphocytes, CD3+, CD4+, CD8+, CD3+CD4+, CD3+CD8+ lymphocytes and in CD4:CD8 ratio as a proportion of lymphocytes and of T cells using the classical twin model approach. Healthy female twin pairs were sampled from the St. Thomas' UK Adult Twin Registry. A maximum of 103 monozygotic (MZ) and 186 dizygotic (DZ) twins aged 18-80 years participated in the study. Whole blood samples were analysed for T cell subsets by flow cytometry. The relative genetic contribution to these phenotypes was estimated using a variance components model-fitting approach. Heritability estimates were calculated of 65% for CD4:CD8 T cell and lymphocyte ratios, around 50% for absolute lymphocyte, CD3+ and CD4+ counts, and 56% for CD8+ numbers. Unique (rather than shared) familial environment explains the remainder of the variance. Genetic factors have a major influence on the variation in peripheral T cell subset numbers. Polymorphism dictating such variation should be taken into account when assessing risk factors for T cell immune-mediated disease with a genetic background.

Adolescent↗
PubMed2000

A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs.

Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.

Aged↗
PubMed2000

Happy families: a twin study of humour.

The objective of this study was to estimate how much of an individual's appreciation of humour is influenced by genetic factors, the shared environment or the individual's unique environment. A population-based classical twin study of 127 pairs of female twins (71 monozygous (MZ) and 56 dizygous (DZ) pairs) aged 20-75 from the St Thomas' UK Adult Twin Registry elicited responses to five 'Far Side' Larson cartoons on a scale of 0-10. Within both MZ and DZ twin pairs, the tetrachoric correlations of responses to all five cartoons were significantly greater than zero. Furthermore, the correlations for MZ and DZ twins were of similar magnitude and in some cases the DZ correlation was greater than that of the MZ twins. This pattern of correlations suggests that shared environment rather then genetic effects contributes to cartoon appreciation. Multivariate model-fitting confirmed that these data were best explained by a model that allowed for the contribution of the shared environment and random environmental factors, but not genetic effects. However, there did not appear to be a general humour factor underlying responses to all five cartoons and no effect of age was seen. The shared environment, rather than genetic factors, explains the familial aggregation of humour appreciation as assessed by the specific 'off the wall' cognitive type of cartoons used in this study.

Adult↗
PubMed1999

Association between birth weight and adult blood pressure in twins: historical cohort study.

OBJECTIVES: To evaluate the associations in twins between within pair differences in birth weight and subsequent blood pressures as adults thereby removing the impact of potential parental confounding variables. DESIGN: Historical cohort study. SETTING: St Thomas's UK adult twin register, June 1992 to September 1995. PARTICIPANTS: 492 pairs of female twins (mean age 54 years). MAIN OUTCOME MEASURES: Mean within pair differences in adult blood pressure in each of four strata of within pair differences in birth weight (0, 1-500 g, 501-1000 g, >1000 g). Differences in blood pressure were analysed before and after adjustment for potential confounders between adult twins, after exclusion of those twin pairs including at least one twin taking antihypertensive drugs, and by zygosity. RESULTS: Reported mean birth weights of heavier and lighter twins were 2.51 (SD 0.61) v 2.12 (0.59) kg respectively. A graded inverse relation between strata of within pair differences in birth weight and differences in adult blood pressure was apparent, with an adjusted blood pressure range of 8.7/5.1 mm Hg across the four strata (test for trend: systolic, P=0.05; diastolic, P=0.09). After excluding those women taking antihypertensive drugs the significance of the association was similar (systolic, P=0.04; diastolic, P=0.10). When differences in blood pressure were stratified for zygosity similar but non-significant trends were apparent. CONCLUSION: It would seem that birth weight is inversely associated with adult blood pressure and that this association is independent of parental confounding variables probably including, in view of the findings in monozygotic twins, genetic factors. The observed blood pressure differences are likely to result from retarded intrauterine growth due to placental dysfunction rather than inadequate maternal nutrition.

Adult↗
PubMed1999

Genetic influences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins.

OBJECTIVE: Degenerative intervertebral disc disease is common; however, the importance of genetic factors is unknown. This study sought to determine the extent of genetic influences on disc degeneration by classic twin study methods using magnetic resonance imaging (MRI). METHODS: We compared MRI features of degenerative disc disease in the cervical and lumbar spine of 172 monozygotic and 154 dizygotic twins (mean age 51.7 and 54.4, respectively) who were unselected for back pain or disc disease. An overall score for disc degeneration was calculated as the sum of the grades for disc height, bulge, osteophytosis, and signal intensity at each level. A "severe disease" score (excluding minor grades) and an "extent of disease" score (number of levels affected) were also calculated. RESULTS: For the overall score, heritability was 74% (95% confidence interval [95% CI] 64-81%) at the lumbar spine and 73% (95% CI 64-80%) at the cervical spine. For "severe disease," heritability was 64% and 79% at the lumbar and cervical spine, respectively, and for "extent of disease," heritability was 63% and 63%, respectively. These results were adjusted for age, weight, height, smoking, occupational manual work, and exercise. Examination of individual features revealed that disc height and bulge were highly heritable at both sites, and osteophytes were heritable in the lumbar spine. CONCLUSION: These results suggest an important genetic influence on variation in intervertebral disc degeneration. However, variation in disc signal is largely influenced by environmental factors shared by twins. The use of MRI scans to determine the phenotype in family and population studies should allow a better understanding of disease mechanisms and the identification of the genes involved.

Adult↗
PubMed1999

Influence of current and past hormone replacement therapy on bone mineral density: a study of discordant postmenopausal twins.

There is controversy about the ideal timing of hormone replacement therapy (HRT) and duration of treatment. In this study we have examined intrapair differences in bone mineral density (BMD) in twins who were discordant for HRT use. Twin pairs in which only one co-twin had been exposed to HRT for more than 12 months continuously were selected from 365 postmenopausal monozygotic (MZ) and dizygotic (DZ) pairs recruited as part of the St Thomas' Adult UK Twin Registry of normal volunteers. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck. Intrapair differences in BMD between HRT users and non-users were compared. A total of 65 HRT-discordant pairs were identified, of which 36 were discordant for current HRT use (mean age: 55.3 years, median duration of HRT use: 36 months) and 29 were discordant for past HRT use (mean age: 60.4 years, median HRT duration: 30 months). Among current users BMD was consistently and significantly higher than in non-users at both sites (lumbar spine mean intrapair difference (IPD%): 12.3%, 95% confidence interval (CI): 7.1%, 17.5%; femoral neck IPD%: 8.6%, 95% CI: 3.4%, 13.7%). The intrapair differences were substantially smaller when past users and non-users were compared (lumbar spine IPD%: 2.4%, 95% CI: -3.7%, 8.6%; femoral neck IPD%: 0.4%, 95% CI: -5.3%, 6.0%). These differences remained little changed after adjusting for the potential confounding effects of the duration of HRT use, and intrapair differences in alcohol and tobacco consumption and physical exercise. The results confirm, in a closely matched design, the findings of other observational research that current use of HRT has a major effect on BMD at the lumbar spine and femoral neck. Past users of HRT do not, however, show the same benefits. The clinical implications of these findings are that HRT needs to be used continuously to influence BMD and that alternative treatments need to be considered in those who discontinue HRT.

Alcohol Drinking↗
PubMed1998

HLA haplotype sharing in rheumatoid arthritis sibships: risk estimates subdivided by proband genotype.

There is a well-known association between rheumatoid arthritis (RA) and HLA-DR4. Recent research has indicated that both DR4 haplotypes are important in disease predisposition (favoring a recessive mode of inheritance). Others have suggested that certain combinations of genotypes, in particular Dw4/Dw14 heterozygotes, may be more important than others. We examined the mode of inheritance of RA using data from the Arthritis and Rheumatism Council's national repository of family material [Worthington et al. (1994) Br J Rheumatol 33:970-976]. There were 85 affected sibships consisting of 77 sib pairs, 6 trios, 1 quintuplet, and 1 sextuplet. The affected sibs shared two, one, and zero parental HLA haplotypes in a ratio of 0.42:0.43:0.15, which was significantly different from random expectations (P = 0.00009). Risk estimates for RA to sibs were calculated based on an overall sibling recurrence risk of 3.9%. Risks for those sharing two, one, and zero parental HLA haplotypes were 6.5% [95% confidence interval (CI) = 5.1-7.9%], 3.3% (95% CI = 2.6-4.0%), and 2.5% (95% CI = 1.5-3.5%), respectively. We also examined the risk of RA based on the DRbeta1 genotype status of sib and proband. After excluding genotypic combinations with small numbers, the highest genotype-specific risks were seen for sibs sharing two haplotypes with either a DRbeta1*0401/DRbeta1*0404 (12.5%, 95% CI = 6.9-15.2%) or a DRbeta1*0401/DRbeta1*0408 (11.1%, 95% CI = 4.5-15.1%) proband. An independent assessment based on the AGFAP methodology confirmed the increase in risk for these genotypes, in particular for DRbeta1*0401/DRbeta1*0408. The excess being due to *0401/*0408 rather than to *0401/*0404 may explain why the Dw4/Dw14 effect is not always observed.

Alleles↗
PubMed1998

Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause.

A classical twin study was performed to assess the extent to which genetic factors explain individual differences in age at menopause and (indications for) hysterectomy. It was further examined whether a genetic effect on the timing of the menopause was mediated through a genetic effect on age at menarche. The subjects were 275 monozygotic and 353 dizygotic female twin pairs. Maximum likelihood model fitting was used to estimate genetic and environmental variance components, Kaplan-Meier survival analysis was used to account for censored data, and the Cox proportional hazards model was used to adjust for potential confounders. A model specifying additive genetic and unique environmental factors showed the best fit to the data, yielding a heritability (h2) for age at menopause of 63%. The significance of the genetic effect was confirmed by the survival analysis and was not affected by adjustment for confounders. Both early and late menopause were found to be significantly influenced by genetic factors. Hysterectomy also showed considerable heritability (h2 = 59%), as did its two main indications: fibroids (h2 = 69%) and menorrhagia (h2 = 55%). The genetic contribution to the variance in age at menarche was estimated to be 45%, with the majority (37%) being due to dominant genetic effects. No correlation was found between age at menopause and age at menarche, suggesting different genetic mechanisms. This study provides convincing evidence for the importance of genetic factors in determining natural and surgical menopause. Understanding how genes control the timing of menopause and exploring whether these genes are indirectly associated with disease are important areas for future study.

Age Factors↗
PubMed1997

Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment.

OBJECTIVE: To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). METHODS: Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence-specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. RESULTS: Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co-twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. CONCLUSION: Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

Adult↗
PubMed1996

Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins.

OBJECTIVE: To test the hypothesis that cigarette smoking is associated with susceptibility to rheumatoid arthritis (RA) by comparing smoking history between twins with RA and their unaffected co-twins. METHODS: Interview questionnaires on smoking history were administered to 79 identical (monozygotic [MZ]) and 71 same-sex nonidentical (dizygotic, [DZ]) twin pairs who were discordant for RA, recruited from the Arthritis and Rheumatism Council Twin Study. Results were expressed as odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Although most twin pairs were concordant for smoking history, there was a strong association between ever smoking and RA in the MZ pairs (OR 12.0, 95% CI 1.78-513), with a similar trend observed in the DZ pairs (OR 2.5, 95% CI 0.92-7.87). CONCLUSION: The discordance in cigarette smoking history for individuals who are at presumed identical genetic risk for RA supports other data suggesting the role of smoking in disease susceptibility.

Arthritis, Rheumatoid↗
PubMed1996

Unexpected HLA haplotype sharing in dizygotic twin pairs discordant for rheumatoid arthritis.

Dizygotic twins are generally believed to be no more genetically similar than sibs born from separate pregnancies. In the present study, a panel of 93 dizygotic twin pairs discordant for rheumatoid arthritis were typed for HLA-A, -B, -Cw, and -DR antigens. HLA haplotype sharing identical by descent between the twins showed a trend towards increased sharing of both HLA haplotypes; this increased sharing was statistically significant when the female/female twin pairs were considered separately. In contrast, the pattern of HLA haplotype sharing in sib pairs (n = 128) was consistent with a 1:2:1 ratio of 2, 1, or 0 haplotypes shared. An analysis of 16 normal dizygotic twin pairs was consistent with these results raising the possibility that dizygotic twins in general are genetically more similar at the HLA complex than sibs born from separate pregnancies.

Arthritis, Rheumatoid↗
PubMed1995

Classification criteria for rheumatoid arthritis.

The development of classification schemes for RA in the last 40 years has followed the increasingly precise understanding of the nature of the clinical disease and the recognition of the different requirements of classification methods in clinic and population settings. In published studies of RA in clinic patients the most widely used criteria sets have been the 1958 ARA (ACR) criteria and its 1961 adaptation (the Rome (active) criteria). These sets classified disease as 'classical', 'definite', 'probable' and 'possible' RA based on criteria comprising clinical, serological, radiological and histological features (the latter were dropped from the Rome criteria set because of their impracticality). More recently, a new criteria set (the 1987 ARA criteria) has been developed using statistical techniques. This set was derived using RA cases and controls attending hospital clinics. It is based on the earlier criteria sets but accommodates the characteristic pattern of joint involvement in RA more precisely. The criteria recognize only the single disease category of 'rheumatoid arthritis'. In validation studies, the 1987 criteria set has been found to have enhanced specificity over earlier schemes in clinic-based studies of RA. The sensitivity may, however, be reduced, in particular in studies of early disease. The application of classification criteria for case recognition in the population and family studies of RA has proved more problematic. In these settings, there is the additional requirement to recognize individuals with remitted and inactive disease as RA cases. The 1966 New York criteria were developed for this specific purpose, however their format proved cumbersome and they have not been widely adopted. The 1987 criteria set is insufficiently sensitive to recognize inactive disease if the criteria are applied exactly as they have been defined. The sensitivity of the 1987 criteria set is, however, substantially enhanced if the criteria are adapted to incorporate features of past disease activity, for example by allowing deformity to substitute for swelling and by incorporating data on the past occurrence of rheumatoid factor and rheumatoid nodules. Developments in the immunology and genetics of RA may in the future provide more accurate tools for classification and may lead to recognition of more precise disease subsets. At present, however, the 1987 ARA criteria provide the most appropriate basis for case recognition in both clinic and population-based studies.

Arthritis, Rheumatoid↗
PubMed1995

Heterogeneity of disease phenotype in monozygotic twins concordant for rheumatoid arthritis.

The objective of the study was to investigate the genetic contribution to the clinical expression of rheumatoid arthritis (RA) by comparison of disease features in RA-concordant monozygotic (MZ) twin pairs. Fourteen RA-concordant MZ twin pairs recruited from a nation-wide study were examined to determine the degree of similarity in: (a) age of disease onset; (b) pattern of joint involvement; (c) pattern of extra-articular disease; (d) toxic reactions to drugs; (e) disease course; and (f) serology for rheumatoid factor (RF) and antinuclear antibody. There was considerable within-pair diversity in the variables studied. Some similarity within twin pairs was observed for the ages at disease onset (R = 0.63), presence of erosive changes (kappa = 0.61) and the presence of IgM RF (R = 0.87). No important similarity was seen, however, in the pattern of joint involvement, the occurrence of extra-articular disease, adverse drugs reactions, clinical disease course and reported disability level. There is heterogeneity in the genetic contribution to the clinical expression of RA. The overall lack of similarity for the majority of clinical variables indicates the importance of non-genetic factors on the expression of disease.

Age Factors↗
PubMed1995

Rheumatoid factor isotypes in monozygotic and dizygotic twins discordant for rheumatoid arthritis.

OBJECTIVE: To examine the influence of genetic factors in determining the occurrence of rheumatoid factor (RF) isotypes. We investigated the hypothesis that, in twin pairs discordant for rheumatoid arthritis (RA), a genetic influence would be indicated by a higher rate of occurrence of RF among the unaffected monozygotic (MZ) when compared with the unaffected dizygotic (DZ) co-twins of seropositive affected twins. METHODS: IgM, IgA, and IgG RF were measured by ELISA in 70 MZ and 84 DZ disease discordant pairs using a cutoff for seropositivity defined using a normal control population. The risk of seropositivity in the unaffected twins of MZ when compared with DZ seropositive index twins was examined using odds ratios (OR). RESULTS: For all 3 RF isotypes, levels in the unaffected twins of seropositive index twins were higher than in the control population. MZ unaffected twins showed an increased risk for seropositivity for IgM and IgG RF when compared with DZ unaffected twins: IgM OR = 2.2 (95% CI 0.9-5.4), IgG OR = 2.4 (95% CI 0.9-6.6). The greatest excess risk for seropositivity occurred for IgM RF amongst the unaffected twin of an index twin with past or current documented evidence of RF seropositivity, OR = 3.4 (95% CI 1.4-8.5). For IgA RF, seropositivity risk in MZ unaffected twins was not increased, OR = 1.0 (0.3-3.1). The seropositivity risk for all 3 isotypes was independent of the age of the pair, the age of disease onset in the index twin, and the sex, HLA-DRB1*01 and DRB1*04 status of the unaffected twin. CONCLUSION: Genetic factors are important in determining the level of IgM and IgG RF. A genetic contribution to RA seropositivity exists that is independent of HLA-DR.

Adult↗
PubMed1994

"Homozygosity" for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins.

OBJECTIVE: To assess the contribution of HLA-DRB1 alleles in determining rheumatoid arthritis (RA) concordance in monozygotic twins. METHODS: Ninety-one monozygotic twins pairs in which at least 1 twin was affected were typed for HLA-DRB1 using both serologic methods and polymerase chain reaction amplification with sequence-specific oligonucleotide hybridization. The role of DR4 and of the shared epitope in disease concordance was investigated. Relative risks (RR) with 95% confidence intervals were determined. RESULTS: Increased concordance for RA was observed in both DR4 positive and shared epitope positive pairs (RR 3.4 and 3.7, respectively). A 5-fold risk for RA concordance was seen in twins who were "homozygous" for the shared epitope, compared with those negative for the shared epitope. CONCLUSION: In the absence of the shared epitope, RA concordance in monozygotic twins is rare. In contrast, "homozygosity" for the shared epitope is the most important factor in determining RA concordance.

Arthritis, Rheumatoid↗