Biomedical subjects

D L Duffy

Publications and source records attributed to D L Duffy.

At least 37 records · Page 2Linked to original sources

PubMed2001

Mutations in the follicle-stimulating hormone receptor and familial dizygotic twinning.

Concentrations of follicle-stimulating hormone (FSH) have an important role in multiple ovulation. An association has been reported between mutations in the FSH receptor (FSHR) in a family with increased twinning frequency. We sequenced the transmembrane region of FSHR (located on chromosome 2) in 21 unrelated mothers of dizygotic twins and found no differences to the published sequence. A linkage study of 183 sister pairs and trios, in which all sisters had given birth to spontaneous dizygotic twins, excluded linkage to this region of chromosome 2. We conclude that mutations in FSHR are not a common cause of familial dizygotic twinning.

Chromosomes, Human, Pair 2↗

PubMed2001

Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma.

MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype.

Alleles↗

PubMed2001

Applying statistical approaches in the dissection of genes versus environment for asthma and allergic disease.

Now that some of the genes involved in asthma and allergy have been identified, interest is turning to how genetic predisposition interacts with exposure to environmental risk factors. These questions are best answered by studies in which both genotypes and other risk factors are measured, but even simpler studies, in which family history is used as a proxy for genotype, have made suggestive findings. For example, early breast feeding may increase the risk of allergic disease in genetically susceptible children, and decrease the risk of 'sporadic' allergy. This review also addresses the overall importance of genetic causes of allergic disease in the general population.

Asthma↗

PubMed2001

Natural selection and quantitative genetics of life-history traits in Western women: a twin study.

Whether contemporary human populations are still evolving as a result of natural selection has been hotly debated. For natural selection to cause evolutionary change in a trait, variation in the trait must be correlated with fitness and be genetically heritable and there must be no genetic constraints to evolution. These conditions have rarely been tested in human populations. In this study, data from a large twin cohort were used to assess whether selection will cause a change among women in a contemporary Western population for three life-history traits: age at menarche, age at first reproduction, and age at menopause. We control for temporal variation in fecundity (the "baby boom" phenomenon) and differences between women in educational background and religious affiliation. University-educated women have 35% lower fitness than those with less than seven years education, and Roman Catholic women have about 20% higher fitness than those of other religions. Although these differences were significant, education and religion only accounted for 2% and 1% of variance in fitness, respectively. Using structural equation modeling, we reveal significant genetic influences for all three life-history traits, with heritability estimates of 0.50, 0.23, and 0.45, respectively. However, strong genetic covariation with reproductive fitness could only be demonstrated for age at first reproduction, with much weaker covariation for age at menopause and no significant covariation for age at menarche. Selection may, therefore, lead to the evolution of earlier age at first reproduction in this population. We also estimate substantial heritable variation in fitness itself, with approximately 39% of the variance attributable to additive genetic effects, the remainder consisting of unique environmental effects and small effects from education and religion. We discuss mechanisms that could be maintaining such a high heritability for fitness. Most likely is that selection is now acting on different traits from which it did in pre-industrial human populations.

Age Factors↗

PubMed2001

Increasing the response rate to a mailed questionnaire by including more stamps on the return envelope: a cotwin control study.

Twins taking part in two unrelated studies were sent a questionnaire together with a self-addressed envelope that either carried one or multiple (up to 5) stamps to the same value. The unprompted proportion of questionnaires returned (before commencement of telephone reminder calls) was increased from 62% to 71% in one study, and from 43% to 52% in the other study (test for common odds ratio in studies, p = 0.04).

Humans↗

PubMed2001

Variation in alcohol pharmacokinetics as a risk factor for alcohol dependence.

BACKGROUND: The significant association between alcohol dehydrogenase (ADH)-2 genotype and alcohol-dependence risk, demonstrated in both Asian and non-Asian populations, suggests a link between the metabolism of alcohol (ethanol) and individual differences in susceptibility to dependence. METHODS: We tested this hypothesis by following up on subjects who took part in the Alcohol Challenge Twin Study conducted in 1979-1981 and comparing the blood and breath alcohol results in that study between subjects who subsequently did or did not meet diagnostic criteria for lifetime alcohol dependence in 1992-1993. RESULTS: Subjects who met DSM-III-R criteria for lifetime alcohol dependence at follow-up had higher blood and breath alcohol values after alcohol challenge than never-dependent subjects. Multivariate analysis showed independent effects of susceptibility to alcohol dependence and smoking status on blood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood or breath alcohol concentrations in the highest quartile than in the lowest quartile. CONCLUSIONS: In view of this association and the known genetic influences on both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than the known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.

Adolescent↗

PubMed2000

Genetic analysis of the age at menopause by using estimating equations and Bayesian random effects models.

Multi-wave self-report data on age at menopause in 2182 female twin pairs (1355 monozygotic and 827 dizygotic pairs), were analysed to estimate the genetic, common and unique environmental contribution to variation in age at menopause. Two complementary approaches for analysing correlated time-to-onset twin data are considered: the generalized estimating equations (GEE) method in which one can estimate zygosity-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modelled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the freeware package BUGS.

Adult↗

PubMed2000

Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins.

The aim of this study was to assess and to compare the role of HFE polymorphisms and other genetic factors in variation in iron stores. Blood samples were obtained from 3,375 adult male and female twins (age range 29-82 years) recruited from the Australian Twin Registry. There were 1,233 complete pairs (562 monozygotic and 571 dizygotic twins). Serum iron, transferrin, transferrin saturation with iron, and ferritin were measured, and the HFE C282Y and H63D genotypes were determined. The frequency of the C282Y allele was.072, and that of the H63D allele was.141. Significant sources of variation in the indices of iron status included age, sex, age-sex interaction, body-mass index, and both the C282Y and H63D genotypes. The iron, transferrin, and saturation values of CC and CY subjects differed significantly, but the ferritin values did not. After correction for age and body-mass index, 23% and 31% of the variance in iron, 66% and 49% of the variance in transferrin, 33% and 47% of the variance in transferrin saturation, and 47% and 47% of the variance in ferritin could be explained by additive genetic factors, for men and women, respectively. HFE C282Y and H63D variation accounted for <5% of the corrected phenotypic variance, except for saturation (12% in women and 5% in men). We conclude that HFE CY and HD heterozygotes differ in iron status from the CC and HH homozygotes and that serum transferrin saturation is more affected than is serum ferritin. There are highly significant effects of other as-yet-unidentified genes on iron stores, in addition to HFE genotype.

Adult↗

PubMed2000

Seasonal changes in courtship song and the medial preoptic area in male European starlings (Sturnus vulgaris).

In male starlings (Sturnus vulgaris) courtship song plays a critical role in mate attraction. During the breeding season courtship song occurs prior to copulation and appears to reflect male sexual arousal. Outside the breeding season starlings sing, but song appears unrelated to reproduction. The aromatization of testosterone (T), likely within the medial preoptic nucleus (POM), is critical for the expression of male sexual arousal. The present study was performed to determine whether seasonal changes in the POM might relate to seasonal changes in courtship singing behavior in male starlings. T concentrations, the volume of the POM, and aromatase within the POM were examined both during and outside of the breeding season in male starlings. Song was also recorded at these times both with and without a female present. The POM was largest and contained dense aromatase immunostaining only during the spring breeding season, when T concentrations were highest and males responded to a female with an increase in courtship song. Outside the breeding season the volume of the POM was small, T concentrations were low, and males displayed no changes in song expression in response to female conspecifics. Song bout length was positively related to POM volume, and males sang longer songs in spring. Only males with nestboxes in spring responded to a female, and the POM tended to be larger in these males, suggesting that nestbox possession might influence neuroplasticity within the POM. Overall, the findings suggest that T-dependent plasticity and aromatase activity within the POM might regulate courtship singing in a wild songbird.

Animals↗

PubMed2000

Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.

Data Interpretation, Statistical↗

PubMed2000

Dizygotic twinning is not linked to variation at the alpha-inhibin locus on human chromosome 2.

Natural multiple pregnancy in women leading to dizygotic (DZ) twins is familial and varies across racial groups, suggesting a genetic predisposition. Mothers of DZ twins have a higher incidence of spontaneous multiple ovulation and elevated FSH concentrations. FSH release is controlled by feedback of inhibin peptides from the ovary, and immunization against inhibin alpha-subunit results in an increased ovulation rate in animals. The inhibin alpha-subunit is therefore a candidate gene for mutations that may increase the frequency of DZ twinning. Restriction digests of a PCR product from exon 1 with the enzyme SpeI detects a C/T polymorphism at bp 128 with two alleles of 447 and 323/124 bp. The polymorphism was typed in 1,125 individuals from 326 pedigrees with 717 mothers of spontaneous DZ twins. The alpha-inhibin locus mapped within 3 centimorgans of D2S164, and linkage with DZ twinning was excluded [decimal log odds ratio (LOD) score, -2.81 at theta = 0]. There was complete exclusion of linkage (LOD, less than -2) of a gene conferring relative risk 1.8 (lambdas, >1.8) across the chromosome, except at the p-terminus region and a small peak (maximum LOD score, 0.6) in the region of D2S151-D2S326. Analysis using either recessive or dominant models excluded linkage with DZ twinning in this population (LOD score, less than -2.5) across chromosome 2. We conclude that dizygotic twinning is not linked to variation in the alpha-inhibin locus. The results also suggest that mutations in other candidates on chromosome 2, including the receptor for FSH and the betaB-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.

Chromosome Mapping↗

PubMed1999

Does sex or photoperiodic condition influence ZENK induction in response to song in European starlings?

Variables such as the photoperiod a bird experiences, or its sex, affect behavioral responses to song. The present experiment investigated whether song-induced expression of the immediate-early gene ZENK is also influenced by sex or photoperiod. We examined the expression of the protein product of ZENK in wild-caught male and female European starlings (Sturnus vulgaris) in different photoperiodic conditions. In the first experiment, adult reproductively active male and female starlings were presented with either conspecific male song or no song in experimental chambers. In the second experiment, conspecific male song was presented to reproductively active and reproductively inactive adult female starlings. Localization of the ZENK protein product revealed that song stimulation resulted in a significant increase in the number of ZENK immunoreactive (-ir) cells in the caudomedial neostriatum (NCM) and the caudomedial hyperstriatum ventrale (cmHV) compared with unstimulated birds. No differences in the number of ZENK-ir neurons were observed between males and females or between reproductively active and inactive females. Thus, the present data indicate that the number of cells expressing ZENK in NCM and cmHV following song playback does not vary with sex or photoperiod in starlings.

Age Factors↗

PubMed1999

Validation of a new antiserum directed towards the synthetic c-terminus of the FOS protein in avian species: immunological, physiological and behavioral evidence.

In the past 10 years, the study of the expression of immediate early genes, such as c-fos, in the brain has become a common method for the identification of brain areas involved in the regulation of specific physiological and behavioral functions. The use of this method in avian species has been limited by the paucity of suitable antibodies that cross-react with the FOS protein in birds. We describe in this paper the preparation of an antibody directed against a synthetic fragment of the protein product of the c-fos gene in chickens (Gallus domesticus). We demonstrate that this new antibody can be used in several avian species to study FOS expression induced by a variety of pharmacological, physiological and behavioral stimuli. Western blot studies indicated that this antibody recognizes a protein of the expected size (47 kDa) but also cross reacts to some extent with proteins of lower molecular weight that share sequence homology with FOS (Fos-related antigens). FOS immunocytochemistry was performed with this antibody in four species of birds in three different laboratories utilizing diverse variants of the immunocytochemical procedure. In all cases the antibody provided a reliable identification of the FOS antigen. The new antibody described here appears to be suitable for the study of FOS expression in several different avian species and situations. It is available in substantial amounts and will therefore make it possible to use FOS expression as a tool to map brain activity in birds as has now been done for several years in mammalian species.

Animals↗

PubMed1999

No common major gene for apolipoprotein A-I and HDL3-C levels: evidence from bivariate segregation analysis.

Apolipoprotein A-I (apo A-I) is the most abundant protein in high-density lipoprotein (HDL) particles, and it plays an important role in HDL metabolism. Both apo A-I and HDL cholesterol (HDL-C) levels are inversely associated with risk of cardiovascular disease. Segregation analyses suggest apo A-I levels are under the control of one or more major loci. Since HDL particles are heterogeneous in their composition and size, genetic influence on its subfractions (i.e., HDL2 and HDL3) could vary. A previous report showed evidence of a major locus controlling HDL3-C levels in a subset of the current study population. Because quantitative trait loci involved in complex diseases are likely to have pleiotropic effects on several related traits, it is possible to have a common major gene involved in regulating apo A-I and HDL3-C levels. We performed a bivariate segregation analysis of apo A-I and HDL3-C levels in 1,006 individuals from 137 families ascertained through probands undergoing elective, diagnostic coronary angiography at the Johns Hopkins Hospital. The results showed significant genetic correlation between these two traits, but the hypothesis of a common major gene was rejected. Bivariate segregation analysis favored a model with two genes controlling apo A-I and a third gene independently controlling HDL3-C, and the genetic correlation between these two traits is due to residual additive polygenes. Overall, results from this study suggest that there are distinct genetic mechanisms for apo A-I and HDL3-C levels. Future studies, especially linkage analysis, should consider distinct genetic mechanisms and multiple major gene loci.

Adult↗

PubMed1999

Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy.

BACKGROUND: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease. OBJECTIVE: To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG ) and one of the signal transducers and activators of transcription (STAT6 ), we conducted further linkage studies among 33 multiplex families. METHODS: We characterized 528 subjects from Barbados for asthma; 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning approximately 79 centimorgan) was performed. RESULTS: Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P <.05 to.002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P =.002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P =.01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric linkage analysis score at D12S326 (nonparametric linkage score = 3.8, P =.0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P =.036). CONCLUSIONS: Our findings suggest that (1) one or more loci in the chromosome 12q13. 12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.

Adult↗

PubMed1999

A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs.

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.

Child↗

PubMed1998

Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome-wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study on the Genetics of Asthma (CSGA).

BACKGROUND: Dermatophagoides pteronyssinus (Der p) is one of the most frequently implicated allergens in atopic diseases. Although HLA could play an important role in the development of the IgE response to the Der p allergens, genetic regulation by non-HLA genes influences certain HLA-associated IgE responses to complex allergens. OBJECTIVE: To clarify genetic control for the expression of Der p-specific IgE responsiveness, we conducted a genome-wide search for genes influencing Der p-specific IgE antibody levels by using 45 Caucasian and 53 African American families ascertained as part of the Collaborative Study on the Genetics of Asthma (CSGA). METHODS: Specific IgE antibody levels to the Der p crude allergen and to the purified allergens Der p 1 and Der p 2 were measured. Multipoint, nonparametric linkage analysis of 370 polymorphic markers was performed with the GENEHUNTER program. RESULTS: The best evidence of genes controlling specific IgE response to Der p was obtained in 2 novel regions: chromosomes 2q21-q23 (P = .0033 for Caucasian subjects) and 8p23-p21 (P = .0011 for African American subjects). Three regions previously proposed as candidate regions for atopy, total IgE, or asthma also showed evidence for linkage to Der p-specific IgE responsiveness: 6p21 (P = .0064) and 13q32-q34 (P = 0.0064) in Caucasian subjects and 5q23-q33 (P = 0.0071) in African American subjects. CONCLUSIONS: No single locus generated overwhelming evidence for linkage in terms of established criteria and guidelines for a genome-wide screening, which supports previous assertions of a heterogeneous etiology for Der p-specific IgE responsiveness. Two novel regions, 2q21-q23 and 8p23-p21, that were identified in this study merit additional study.

Adult↗

PubMed1998

Linkage analysis of Dermatophagoides pteronyssinus-specific IgE responsiveness with polymorphic markers on chromosome 6p21 (HLA-D region) in Caucasian families by the transmission/disequilibrium test. Collaborative Study on the Genetics of Asthma (CSGA).

BACKGROUND: Recently, we have obtained evidence for linkage between Der p 1-specific IgE antibodies and markers on chromosome 6p21 (HLA-D region) in a genome-wide screening in Caucasian families recruited as a part of the Collaborative Study on the Genetics of Asthma (CSGA). OBJECTIVE: Specific IgE antibodies toward different Dermatophagoides pteronyssinus (Der p) polypeptides were detected by immunoblotting analysis, and the transmission/disequilibrium test (TDT) was performed between specific IgE responsiveness toward each different Der p polypeptide and markers on chromosome 6p21 to better clarify the genetic contribution of HLA-D genes. METHODS: We studied 299 individuals in 45 Caucasian families participating in the CSGA. Serum samples from 137 individuals that showed elevated specific IgE antibodies toward the Der p crude allergen (> -0.5 log IU/mL) by ACCESS immunoassay were subjected to immunoblotting analysis. TDT was conducted between the presence of specific IgE antibodies toward each of 12 different Der p polypeptides and 4 polymorphic markers on chromosome 6p21. RESULTS: The 196-bp allele of D6S1281 and the 104-bp allele of DQCAR showed significant excess transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 55 kd, 45 kd, or 37 kd). In contrast, the 200-bp allele of D6S1281 and the 204-bp allele of D6S291 showed significantly decreased transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 90 kd, 52 kd, or 45 kd). Deviation from the expected 50% transmission in heterozygous parents was statistically significant after correcting for multiple comparisons. CONCLUSION: This study supported our previous findings that genes on chromosome 6p21 (HLA-D region) may influence the expression of Der p-specific IgE responsiveness in this Caucasian population. Our results, however, reveal the complexity of genetic regulations of Der p-specific IgE responsiveness by HLA-D genes, suggesting the strong influence of non-HLA loci and perhaps environmental factors for the development of Der p-specific IgE responsiveness.

Alleles↗