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OBJECTIVE: Recent studies of 2 complex diseases, rheumatoid arthritis (RA) and Crohn's disease (CD), showed associations with genes mapping to the cytokine gene cluster on 5q31. In particular, a functional single-nucleotide polymorphism (SNP) mapping to intron 1 of the organic cation transporter 1 (OCTN1; SLC22A4) gene was associated with RA in a Japanese population, and a haplotype of a different SNP in the same gene and one in an adjacent gene, OCTN2 (SLC22A5), was associated with CD. The purpose of this study was to investigate the association between the OCTN locus and RA in a Caucasian population. METHODS: Association with 11 SNPs spanning the SLC22A4 and SLC22A5 genes, including a putative RA-causing functional polymorphism (rs3792876 [slc2f2]) and a functional haplotype previously associated with CD, was investigated in 909 RA cases and 594 population controls in the UK. Genotyping was performed using 5'-allele discrimination assays. Estimated haplotype frequencies were generated using the expectation-maximization algorithm and were compared between cases and controls. RESULTS: All SNPs were in Hardy-Weinberg equilibrium. We found no evidence for an association between RA and either the SNP (rs3792876 [slc2f2]) or the haplotype previously reported to be associated with RA in a Japanese population. Similarly, no association between RA and the haplotype associated with CD was detected. CONCLUSION: Functional polymorphisms of the OCTN gene locus that have previously been associated with RA and CD were not found to be associated with RA in a UK population. The findings do not provide support for a major role of these genes in the etiology of RA in this population.
BACKGROUND: To develop screening strategies for identification of individuals at increased genetic risk for type 1 diabetes in three populations with variable disease incidence rates and distinct ethnic origin. METHODS: A stepwise HLA DQB1-DQA1-DRB1-based screening approach was evaluated. Patients with childhood-onset type 1 diabetes were recruited from Finland (n = 1739), Hungary (n = 149), and Greece (n = 119). Consecutive newborns (2568 from Finland and 1047 from Greece) or healthy schoolchildren (n = 177 from Hungary) served as controls. RESULTS: The DQB1*02/0302 genotype conferred the highest disease risk in all populations. The DQB1*02/y (y not equal DQB1*0301,*0302,*0602,*0603, *0604) genotypes were more common and conferred a higher disease risk in the Greek population (OR 4.9) compared to the Finns (OR 1.2). DQB1*0302/x (x not equal DQB1*02, *0301, *0602, *0603, *0604) genotypes were, in contrast, more prevalent among Finnish cases (32.7%) as compared to Hungarians (18.1%) or Greeks (13.5%). The protective DQB1*0602 or *0603 positive genotypes were most common in the Finns, while DQB1*0301 was more common in Hungarians and Greeks. In all groups, DQA1 and DRB1*04 typing considerably increased the sensitivity of the DQB1-based screening. The different high-risk genotype combinations present in about 10% of the background population had a diagnostic sensitivity of 60% in Finland and 80% in Hungary and Greece. CONCLUSIONS: HLA DR-DQ-based screening is a feasible tool for the identification of individuals at increased genetic risk for type 1 diabetes in populations with diverse genetic background. The risk markers should, however, be individually selected for the target population since the screening efficiency of various markers is highly dependent on the ethnic group studied.
Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1948. The frequencies of the common alleles of the apoE gene were (with 95% confidence intervals) epsilon 2 = 0.085 (0.068-0.105), epsilon 3 = 0.741 (0.712-0.769), and epsilon 4 = 0.174 (0.150-0.200). These frequencies were compared to findings in 45 other study populations around the world (n greater than 100). The Danish population was found to cluster with populations from Iceland, Norway, Iceland, Scotland, the Netherlands, Germany, France (Paris), and Caucasian populations in Canada and the USA. The compiled data further show that dissimilarities in apoE allele frequencies among Caucasian populations are comparable to dissimilarities between some Caucasian and Asian populations. Notably, the frequency of epsilon 4 appears to be higher in northern regions of Europe (the Nordic countries, Scotland, Germany, and the Netherlands) than in southern regions (Switzerland, Tyrol, France [Nancy], Italy, and Spain).
The prevalence of left ventricular systolic dysfunction (LVSD) in the general population is poorly defined. Specifically, the number of asymptomatic individuals with LVSD and, thus, the most appropriate strategy to identify and treat such subjects is still unknown. Therefore, the aim of this study was to document LV dysfunction in a middle-aged (25 to 75 years, mean 51.8+/-13.8) population - based sample in Germany (MONICA Augsburg, n=1678; echocardiography technically adequate n=1418) by M-mode and 2D-echocardiography and to analyze the importance of predisposing contributors. The overall prevalence of an ejection fraction (EF) less than 48% (mean minus 2 SD=LVSD) was 2.3% (n=33), with a slightly higher rate in men than in women (2.8% vs 1.9%, n.s.). LVSD rate increased with age: from 1.5% in individuals younger than 40 years to 4.0% among those older than 60 years of age (p<0.05). Of 33 participants with reduced left ventricular systolic function, 20 presented with at least one cardiovascular disease. The most frequent diagnoses were arterial hypertension, obesity and coronary heart disease. Only 13 subjects (0.9%) of the study population were asymptomatic without a history of cardiovascular disease. Furthermore, only 6 subjects (0.4%, 4 male) in this population presented with a moderate impairment of LV function (EF of 30 to 40%) and only 1 subject (0.07%, male) had severe LVSD (EF less than 30%). Almost all subjects with an EF less than 40% (6 of 7 individuals) had a known history of cardiovascular disease. In conclusion, LVSD is a relatively common finding in the general population. However, severe LVSD is rare in subjects without any concomitant cardiovascular disease. Thus, echocardiographic screening cannot be recommended in the unselected, middle-aged population to identify such patients.
Studies on polymorphisms of candidate genes and their association with bone mineral density (BMD) have been reported in many populations, but few have been reported in Chinese populations. We investigated polymorphisms of the following five commonly used markers of four prominent BMD candidate genes with the purpose of identifying useful genetic markers for osteoporosis genetic research in Chinese: the Sp1 and RsaI polymorphisms of the collagen type 1 alpha l (Col1a1) gene, the -174G/C promoter polymorphism of the interleukin 6 (IL-6) gene, the Asn363Ser polymorphism of the glucocorticoid receptor (GR) gene, and the T --> C polymorphism in intron 5 of the transforming growth factor beta(1) (TGF-beta(1)) gene. We evaluated these polymorphisms using PCR-RFLP in samples of at least 124 random individuals. We compared the polymorphisms of these five markers with other populations using the chi(2) test and Fisher's exact two-tailed test. For the RsaI polymorphism, only three heterozygotes but no variant homozygote were identified. For the -174G/C polymorphic site, only one GC heterozygote and no CC homozygote were found. Alleles s, Ser, and A(1) at the Sp1, Asn363Ser, and T --> C marker sites that have been found to be polymorphic in other populations were not found in Chinese. Significant differences of allele and genotype frequency distributions were observed at these polymorphisms ( P < 0.001) after comparing with other populations. Our results suggest that variant alleles of the five markers are absent or too rare to be useful genetic makers in Chinese, despite the fact that they have been commonly used as polymorphic markers in osteoporosis genetic research in other populations.
Selection responses of the laboratory stock Berlin wild (+60, +K) of Drosophila melanogaster to the mutagenic effects of high, accumulated exposures of X-rays were studied in several sub-populations with long irradiation histories. Interest was focussed on adaptive adjustments of mutation rates. In samples from the populations, radiosensitivities of immature oocytes were tested, by using dominant lethals (A), X-chromosome losses (B) and sex-linked recessive lethals (C) as end-points of genetic radiation damage. Populations RO II and RO V are similar to the previously studied population RO I and were exposed to 2100 R/generation, delivered to oocyte stages 6-14, mature sperm, and spermatids. RO II (first tests after 160 generations) is radioresistant relative to +60 (control). The resistance was characterized by dose-reduction factors (DRFs) of 1.72 (with respect to end-points A, B) and 1.53 (C), and these were similar to those previously obtained for RO I. The resistance of RO II was inherited semidominantly as was that of RO I, and the radiosensitivity of the hybrids RO I/RO II was similar to that of RO I and RO II with respect to end-points A and B. RO V did not become resistant within 25 generations of irradiation history (A). Populations RO III (6000 R/generation) and RO IV (7000 R/generation) have histories of irradiations given to oogonia and spermatogonia. Radiosensitivities of immature oocytes of RO III did not differ from those of +K after 55 generations, but after 105 and 135 generations of irradiation history, DRFs of 1.2 (A) and 1.44 (B) were observed. RO IV was characterized in generations 55-135 by DRFs of 1.31 (A) and 1.72 (B). Selection for relative radioresistance of immature oocytes was found (1) to be reproducible (RO II-RO IV), (2) not to require genetic pre-adaptation (RO V), and (3) to be, in part, also achieved by 'indirect' selection (RO III, RO IV). It is concluded that mutation rates in populations are selectively adjusted to evolutionary requirements.
To investigate the population genetic characteristics of VNTR polymorphisms in human populations, we have studied the allele frequency distribution of six VNTR loci (D1S57, RB1, D1S77, D1S61, alpha-globin 5'HVR, D1S76) in three well-defined populations (Kachari of Northeast India; Dogrib Indian of Canada; and New Guinea Highlander of Papua New Guinea). Even though the number of alleles sampled is limited, 48 to 92 alleles per locus per population, significant variation is noticed in the number of alleles per locus for all the populations. Using alternate summary measures, we have observed that genotype distributions at the six VNTR loci apparently conform to their respective Hardy-Weinberg predictions. Multilocus genotype profiles of the individuals in each of the three populations suggest that the VNTR alleles are independently segregating with the exception of the two linked loci D1S76 and D1S77. Lack of fit of all VNTR loci to one particular model of mutational change, either the Infinite Allele Model or the Stepwise Mutation Model, suggests more than one mechanism for production of new VNTR alleles. This study also indicates that increased heterozygosity at VNTR loci in comparison to protein and blood group loci may lead to more accurate estimates of genetic distance.
In population pharmacokinetic studies, the precision of parameter estimates is dependent on the population design. Methods based on the Fisher information matrix have been developed and extended to population studies to evaluate and optimize designs. In this paper we propose simple programming tools to evaluate population pharmacokinetic designs. This involved the development of an expression for the Fisher information matrix for nonlinear mixed-effects models, including estimation of the variance of the residual error. We implemented this expression as a generic function for two software applications: S-PLUS and MATLAB. The evaluation of population designs based on two pharmacokinetic examples from the literature is shown to illustrate the efficiency and the simplicity of this theoretic approach. Although no optimization method of the design is provided, these functions can be used to select and compare population designs among a large set of possible designs, avoiding a lot of simulations.
Samples of Phaulacridium marginale were taken from the North Island of New Zealand, together with further samples from three South Island populations. Seven of the North Island populations were found to be polymorphic for a small telocentric B chromosome. In only one case was the B chromosome significantly associated with an increase chiasma frequency. All three South Island populations contained B chromosomes. Seven of the nine N.I. populations were also polymorphic for extra segments on the centric end of the S11 chromosome. In six of them this polymorphism co-existed with that for B'S. A new polymorphism was encountered in two populations. This was for a large block of heterochromatic material located at the centric end of one of the smaller medium-sized chromosomes which thus becomes acro- rather than telocentric. Tt would appear that the New Zealand grasshopper, Ph. marginale, is able to tolerate many different polymorphisms for extra heterochromatin. However, this ability is perhaps restricted to central populations. In this context, the high level of occurence of these polymorphisms in the North Island could be due to the better climatological conditions existing there compared to most of the South Island.
Recently established, temperate tree populations combine a high level of differentiation for adaptive traits, suggesting rapid genetic evolution, with a high level of genetic diversity within population, suggesting a limited impact of genetic drift and purifying selection. To study experimentally the evolutionary forces in a recently established population, we assessed the spatial and temporal patterns of genetic diversity within a disjunct population of Cedrus atlantica established 140 years ago in south-eastern France from a North African source. The population is expanding through natural regeneration. Three generations were sampled, including founder trees. We analysed 12 isozyme loci, three of which were previously found in tight association with selected genes, and quantitative traits. No bottleneck effect was detected in the founder generation, but a simple test of allelic association revealed an initial disequilibrium which disappeared in the following generations. The impact of genetic drift during secondary evolution was limited, as suggested by the weak temporal differentiation. The genetic load was not reduced after 3 generations, and the quantitative variation for adaptive traits did not change either. Thus, initial genetic changes first proceed from a rapid re-organisation of the diversity through mating and recombination, whereas genetic erosion through drift and selection is delayed due to temporal and spatial stochasticity. Two life-history traits of trees contribute to slowing down the processes of genetic erosion: perenniality and large spatial scale. Thus, one would expect recently established tree populations to have a higher diversity than older ones, which seems in accordance with experimental surveys.
OBJECTIVES: To examine the relationship between microalbuminuria and incident stroke in the general population. DESIGN: Population-based prospective cohort study. SETTING: Participants were recruited in a primary care setting from 35 participating general practice units in Norfolk, UK. SUBJECTS AND MAIN OUTCOME MEASURES: The study population consisted of 23,630 individuals aged 40-79 years recruited between 1993 and 1997 for the EPIC-Norfolk Study and followed up for an average of 7.2 years. Random spot urine specimens were collected at baseline and albumin-to-creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria and macroalbuminuria groups. During follow-up, the main end point was stroke incidence (fatal and nonfatal), ascertained from the UK Office for National Statistics and from the National Health Service Health District database of all hospital admissions. RESULTS: A total of 246 stroke events occurred during follow-up [crude incidence rate of stroke, 1.5 per 1000 person years (pyrs)]. The age-adjusted incidence of stroke increased significantly across categories of baseline albuminuria (0.9, 1.1 and 1.4/1000 pyrs for tertiles of normoalbuminuria, 2.6/1000 pyrs for microalbuminuria, and 6/1000 pyrs for macroalbuminuria in the total population, P < 0.001 for trend). In all women and men, the multivariate hazard ratio [95% confidence interval (CI)] for stroke associated with microalbuminuria was 1.49 (1.13-2.14) and macroalbuminuria 2.43 (1.11-6.26). After stratifying by stroke subtype, microalbuminuria was only independently predictive of ischaemic stroke, with hazard ratio (95% CI) of 2.01 (1.29-3.31). CONCLUSION: Microalbuminuria is independently associated with approximately 50% increased risk of stroke in the general population. Microalbuminuria may be useful in identifying those at increased risk of stroke in the general population.
OBJECTIVES: To assess the dietary habits of Balearic Islands' consumers who are successful in meeting current nutritional recommendations, to find clues for the development of future food-based dietary guidelines (FBDG) that would be relevant to this population. DESIGN: Cross-sectional nutritional survey carried out in the Balearic Islands between 1999 and 2000. SUBJECTS AND METHODS: Dietary habits were assessed by means of 24-hour recall (two non-consecutive days: warm and cold season) and a food-frequency questionnaire in a random sample (n=1200, aged 16-65 years) living in private households. Differences in percentage of compliers with the intermediate nutritional objectives for the Spanish population and differences in food consumption patterns between genders and between high (above the upper quartile of intake) and low (below the lower quartile of intake) consumers of fat, saturated fatty acids (SFA), fibre, and fruit and vegetables were analysed. RESULTS: Gender differences were observed in nutrient and energy intakes, as well as in attainment of the recommendations. Less than 25% of the population reached the intermediate nutritional recommendations for iodine, fruit, carbohydrates, SFA, fibre and vegetables. Low fat/SFA and high fruit and vegetables/fibre consumers kept a diet in line with the traditional Balearic diet and prevailing dietary pyramids, which ensured better compliance with the nutritional goals. CONCLUSIONS: The intermediate nutritional objectives for the Spanish population could be achieved through maintenance of the traditional Balearic diet, a Mediterranean-type diet in the Balearic population. Therefore, this dietary model could be used to develop FBDG relevant to this population.
Previous studies based on allozyme variation have found little evidence for genetic differentiation in Drosophila simulans. On the basis of DNA sequence variation at two nuclear loci in four African populations of D. simulans, we show that there is significant structure to D. simulans populations within Africa. Variation at one of the loci, vermilion, appears to be neutral and supports an eastern African origin for European and American populations. Samples from the West Indies, Europe, and North America had a nucleotide diversity lower than that of African populations at vermilion and show nonequilibrium haplotype distributions at both vermilion and G6pd, consistent with a hypothesis of recent bottleneck and possibly also admixture in the history of these populations. Directional selection, previously documented at G6pd, appears to have occurred within the coalescence time of the species, obscuring deep population history.
BACKGROUND: Orthotopic liver transplantation in the United States is primarily limited by a shortage of donor organs. METHODS: To better understand the low rates of organ donation in the United States and identify areas for potential improvement, we analyzed detailed demographic and mortality-specific data from 10,689 adult cadaveric liver donors obtained from the United Network for Organ Sharing from April 1, 1994 to March 31, 1997. Comparative U.S. population demographic and economic data were obtained from the U.S. census. RESULTS: As compared with the U.S. population, we found there to be significantly fewer nonwhite (P=0.001) and foreign-born donors (P=0.001); 58.9% of liver donors were male (P=0.001). The mean age was 40.6 years; yet during the 3-year period analyzed, there was a significant trend toward increasing age of donors. Median household income was 18% to 32% lower in the donor population than in the general U.S. population. In 91.2% of cases, the donor cause of death was listed as cerebrovascular stroke or head trauma. Numerous significant interracial differences were found in both the donor mechanism and circumstance of death. These included black donors being more likely to have gunshot wound as the listed mechanism of death (P=0.001) and to have homicide as the listed circumstance of death (P=0.001). CONCLUSIONS: Nonwhites and foreign-born individuals are significantly underrepresented in the U.S. liver donor population. Furthermore, donors seem to be poorer than the general U.S. population. Increasing the liver donor pool, especially among minorities, will require creative and thoughtful public initiatives.
The effect of migration among different isolated virus quasispecies populations on their adaptation and diversity was analysed through experimental evolution. An in vitro cell system was employed to simulate migration of vesicular stomatitis virus between isolated homogeneous host cell populations. The results clearly demonstrated a positive correlation between the migration rate and the magnitude of the mean fitness reached by the virus quasispecies populations. The results also showed, although less clearly, that fitness differences among quasispecies decreased with the magnitude of migration. These results are in close agreement with predictions of standard population genetics theory. These results can be explained in terms of the spread of beneficial mutations, originating in a single isolated quasispecies, through the entire system formed by the different quasispecies populations contained in different host cell populations.