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PubMedDate not supplied

[The relation between the HLA-DRB1*1501 allele and the severity of multiple sclerosis in a sample of the Spanish population from the Balearic Islands: the influence exerted by sex].

INTRODUCTION: There is some controversy about the possible relation between HLA-DR2 (DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602) and the severity of multiple sclerosis (MS), which could be due, at least in part, to methodological differences among the different studies dealing with this subject and/or to a lack of phenotypic homogeneity within the series of patients. AIMS: This study aims to contribute information about the possible relation between DR2 (more specifically the HLA-DRB1*1501 allele) and the severity of MS. PATIENTS AND METHODS: We conducted a study of 43 individuals with clinically defined MS, whose degree of severity was determined using Kurtzke's EDSS, and 107 controls from a similar ethnic origin. DETERMINATIONS: HLA typing by PCR-SSO and PCR-SSP, analysis of oligoclonal IgG bands in CSF by isoelectric focusing, and quantification of the intrathecal synthesis of IgG (IgG index, IgG ratio, Reiber's formula and Tourtellotte's formula). STATISTICS: Chi2 test, Mann-Whitney test and Kendall correlation coefficient. RESULTS: DRB1*1501 is associated with the presence of MS only in females and with lower severity of the disease only in males. These associations do not appear to depend on any kind of effect exerted by DRB1*1501 on the intrathecal synthesis of IgG that differs between the two sexes. CONCLUSIONS: The absence of a relation between DRB1*1501 and the severity of MS reported in many studies could be due to not stratifying the patients according to sex. Our findings emphasise how important it is in genetic studies of complex traits to reduce the phenotypic heterogeneity of patients as much as possible.

Adolescent↗
PubMed2004

[Genetic susceptibility to metabolic syndrome].

The metabolic syndrome(MS) is a multifactorial complex trait that is influenced by both environmental and genetic factors. Factor analyses of several large population-based studies have shown that MS is genetically composed of at least 3-4 independent components. Mutations and polymorphisms in the genes associated with insulin resistance, adipocyte abnormality, chronic inflammation, or autonomic imbalance may underlie the etiological basis of MS. Above all, genes for several transcription factors such as PPARs and SREBPs and adipocytokines such as leptin and adiponectin are promising candidates. Genome-wide linkage analyses with affected sib-pairs have identified several chromosomal regions where major susceptible genes to MS may exist and have indicated that the underlying genes would differ among the races.

Disease Susceptibility↗
PubMed2004

Integrating genomics into Eucalyptus breeding.

The advent of high throughput genomic technologies has opened new perspectives in the speed, scale and detail with which one can investigate genes, genomes and complex traits in Eucalyptus species. A genomic approach to a more detailed understanding of important metabolic and physiological processes, which affect tree growth and stress resistance, and the identification of genes and their allelic variants, which determine the major chemical and physical features of wood properties, should eventually lead to new opportunities for directed genetic modifications of far-reaching economic impact in forest industry. It should be kept in mind, however, that basic breeding strategies, coupled with sophisticated quantitative methods, breeder's experience and breeder's intuition, will continue to generate significant genetic gains and have a clear measurable impact on production forestry. Even with a much more global view of genetic processes, genomics will only succeed in contributing to the development of improved industrial forests if it is strongly interconnected with intensive fieldwork and creative breeding. Integrated genomic projects involving multi-species expressed sequence tag sequencing and quantitative trait locus detection, single nucleotide polymorphism discovery for association mapping, and the development of a gene-rich physical map for the Eucalyptus genome will quickly move toward linking phenotypes to genes that control the wood formation processes that define industrial-level traits. Exploiting the full power of the superior natural phenotypic variation in wood properties found in Eucalyptus genetic resources will undoubtedly be a key factor to reach this goal.

Breeding↗
PubMed2004

Gene mapping and identification for osteoporosis.

Osteoporosis is a disease characterized by fragile bones and high susceptibility to low trauma fractures. It is a serious health problem, especially in elderly women. Bone mineral density (BMD) has been employed most commonly as the index for defining and studying osteoporosis. In this presentation, we use examples of our studies in both Caucasians and Chinese to illustrate the approaches used and some main results obtained on 1) characterizing the degree and the inheritance mode of genetic determination of a complex trait such as BMD; 2) identifying and mapping genes for osteoporosis. The purpose of the presentation is to introduce to the medical researchers how and what modern genetics can do to disentangle the mist of an array of genetics factors, the major determinants, for BMD.

Asian People↗
PubMed2005

An autosome-wide scan for linkage disequilibrium-based association in sporadic breast cancer cases in eastern Finland: three candidate regions found.

Breast cancer is the most common of cancers among women in industrialized countries. Many of breast cancer risk factors are known, but the majority of the genetic background is still unknown. Linkage disequilibrium-based association is a powerful tool for mapping disease genes and is suitable for mapping complex traits in founder populations. We report the results of a two-stage, autosome-wide scan for LD with breast cancer. Our aim was to identify genetic risk factors for sporadic breast cancer in an eastern Finnish population. Our case-control set is from the province of northern Savo in the late-settlement area of eastern Finland. This population is relatively young and genetically homogeneous. We used 435 autosomal microsatellite markers spaced by an average of 10 cM in a set of 49 breast cancer cases and 50 controls. In the first-stage scan, we found 21 markers in LD with breast cancer (Ps = 0.003-0.046, Fisher's exact test). In the second-stage scan with markers flanking 21 positive loci, four significant markers were found (Ps = 0.013-0.046, Fisher's exact test). Haplotype analysis using global score method with two, three, or four markers also revealed four positive marker combinations (simulated P for global score = 0.003-0.021). Our results suggest breast cancer-associated regions on 3p26, 11q23, and 22q13.1 in an eastern Finnish population.

Adult↗
PubMed2004

Progress towards identifying inflammatory bowel disease susceptibility genes.

Genomewide searches have identified about a dozen genomic regions potentially containing inflammatory bowel disease (IBD) susceptibility loci. Although some were observed in more than one genome scan or in replication studies, no one locus has been identified in all studies. This apparent lack of consistency is explained by the modest effect of most genetic loci in complex traits and by the modest power and the sampling variance of individual family-based studies. Despite these challenges, the field of IBD genetics found convincing evidence of linkage and, more recently, of genetic sequence variants that are strongly associated with disease. The first example was that of the IBD1 locus on chromosome 16, a linkage region confirmed by a large multicentre study, for which the CARD 15 gene was identified--using independent association strategies-as being a gene contributing to Crohn's disease susceptibility. Despite these advances, a number of questions still remain: (1) What is the best approach to identify the remaining IBD susceptibility loci? (2) How do we prove causality for any given gene or genetic variant? (3) How can we best use this information to obtain an understanding of the biological mechanisms underlying disease susceptibility and to identify useful markers of disease progression and response to therapy?

Chromosomes, Human, Pair 16↗
PubMed2002

Genetic regulation of bone mineral density in mice.

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations and effects of the individual genes contributing to natural variation in this trait are all unknown. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Genetically distinct animal strains raised under strict environmental control are critical tools for defining genetic regulation. The availability of inbred strains, combined with its relative fecundity, has established the mouse as the best model system for the study of mammalian genetics and physiology. Importantly, genes identified in murine analyses can usually be readily mapped to particular human chromosomal regions because of the high degree of synteny that exists between the mouse and human genomes. We employed quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (BXD RI). The distribution of BMD values among these strains clearly indicated the presence of strong genetic influences, with an estimated narrow sense heritability of 35%. The differences in peak whole body BMD in the BXD strains were integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL locations. This QTL analysis provisionally identified a number of chromosomal sites linked to BMD. In the second phase of our BMD QTL mapping efforts, we used three independent mouse populations (all derived from B6 and D2 progenitor strains) to confirm and narrow the genetic locations of 4 QTLs (on chromosomes 1, 2, 4, and 11) that strongly influence the acquisition of peak BMD in mice. Using a novel, fine-mapping approach (recombinant inbred segregation testing), we have succeeded in narrowing two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.

Journal Article↗
PubMed2004

PPARs: molecular targets in the pharmacogenomics era.

The recent global increase in prevalence of diseases like obesity, type 2 diabetes and hypertension in westernized societies is unfortunately not paralleled by our full understanding of the causative mechanisms. It is now firmly established that the interacting genetic and environmental (diet, smoking) components together determine the development and severity of the particular condition, which makes detailed dissection of such complex traits even more complicated. In effect, there is an unmet urgent need for molecular targets so we can directly modulate the causative factors and devise effective preventive and therapeutic algorithms. Among the most promising molecular targets for treatment of metabolic syndrome-related conditions identified so far, the group of three lipid-sensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology.

Animals↗
PubMed1992

A new test for linkage in the presence of locus heterogeneity.

The detection of linkage in complex traits, although potentially of the greatest value, has proved very difficult. One reason may be the drastic effect that locus heterogeneity has on statistical power. We propose a new test for linkage in the presence of heterogeneity, based upon the sum of individual pedigree maximum lod scores, combined with a bootstrap method for estimating the null-hypothesis distribution. The technique is designed to exploit modern computer capability and to avoid reliance on asymptotic-distribution theory. Numerical comparisons indicate that for small pedigrees this new test can detect linkage with 30%-50% less data than are required by standard methods. A computer program for simulating the distribution and for performing the test of linkage is available from the authors.

Female↗
PubMed2005

[Disease gene identification: opportunities and challenges].

The recent achievements of the Human Genome Project make it increasingly feasible to determine the genetic basis of human diseases, especially complex traits. Genomics will provide powerful means to discover hereditary elements that interact with environmental factors leading to diseases. However, the expected transformation toward genomics-based medicine will occur over decades, which requires the joint efforts of many scientists and physicians. Such transformation provides both opportunities and challenges to everyone involved in this field.

Genetic Diseases, Inborn↗
PubMed2005

Potential effect of inter-genic action on peak bone mass (PBM) in Chinese females.

Peak bone mass (PBM) is a complex trait, determined by both genetic and environmental factors and also their interactions. Vitamin D receptor (VDR) estrogen receptor alpha (ERalpha), interleukin 6 (IL6), parathyroid hormone (PTH), collagen type I alpha 2 (COL1A2), bone Gla protein (BGP), alpha2-HS glycoprotein (AHSG) are among the important candidate genes of bone metabolism. The study aims to detect significant effect of potential inter-genic action underlying PBM in Chinese females. 361 unrelated healthy premenopausal Chinese females (aged 20 -44 years) with Han ethnicity were recruited from the Shanghai city in China. Bone mineral density (BMD) at the hip and the lumbar spine (L1-4) was measured using a Hologic QDR 2000 + dual-energy X-ray absorptiometry (DXA) scanner. Eight polymorphisms among the seven genes were genotyped, i. e. Apa I in VDR, Pvu II and Xba I in ERa (ERX and ERP, respectively), BsrB I in IL6, BstB I in PTH, Msp I in COL1A2, Hind III in BGP, and Sac I in AHSG, using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) methods. Two-way analysis of variance (ANOVA) showed significant effects of IL6 x ERP interaction on PBM at the total hip (P = 0.019), intertrochanter (P = 0.016), and femoral neck (P =0. 019). The BMD difference between GGPp carriers and GGpp subjects (at these two loci) amounted to 18.0%, 19.5%, and 14.8% at the hip,intertrochanter,and femoral neck,respectively. The potential interaction effect of AHSG x IL6 was observed on femoral neck PBM (P = 0.046). GGSS individuals (at these two loci) had, on average, 18.8% higher femoral neck BMD than those subjects with GGSs genotype. The population-level statistical analysis indicates that IL6 x ERP and AHSG x IL6 have significant inter-genic effect on the genetic determination of PBM in Chinese females.

Absorptiometry, Photon↗
PubMedDate not supplied

Identifying genetic risk factors for osteoporosis.

Over the past decades epidemiological research of so-called "complex" diseases, i.e., common age-related disorders such as cancer, cardiovascular disease, diabetes, and osteoporosis, has identified anthropometric, behavioural, and serum parameters as risk factors. Recently, genetic polymorphisms have gained considerable interest, propelled by the Human Genome Project and its sequela that have identified most genes and uncovered a plethora of polymorphic variants, some of which embody the genetic risk factors. In all fields of complex disease genetics (including osteoporosis) progress in identifying these genetic factors has been hampered by often controversial results. Because of the small effect size for each individual risk polymorphism, this is mostly due to low statistical power and limitations of analytical methods. Genome-wide scanning approaches can be used to find the responsible genes. It is by now clear that linkage analysis is not suitable for this, but genome-wide association analysis has much better possibilities, as is illustrated by successful identification of risk alleles for several complex diseases. Candidate gene association analysis followed by replication and prospective multi-centred meta-analysis, is currently the best way forward to identify genetic markers for complex traits, such as osteoporosis. To accomplish this, we need large (global) collaborative studies using standardized methodology and definitions, to quantify by meta-analysis the subtle effects of the responsible gene variants.

Animals↗
PubMed2006

Mutation analysis of the MSX1 gene exons and intron in patients with nonsyndromic cleft lip and palate.

UNLABELLED: Cleft lip with or without cleft palate and cleft palate (CL/CLP/CP) is one of the most common malformations among newborns. The estimated prevalence in Latvia is 1/700. Nonsyndromic CL/CLP/CP is a complex trait determined by multiple, interacting genetic and environmental factors. MSX1 gene is one of the most important candidate-genes, which had been analyzed in relation with nonsyndromic CL/CLP/CP. The objective of our study was to examine the etiologic role of MSX1 gene mutations in the development of nonsyndromic CL/CLP/CP in Latvian population. MATERIALS AND METHODS: DNA was extracted from venous blood of 53 patients with cleft lip with or without palate. Polymerase chain reaction (PCR) was performed of selected segments of MSX1 gene. These were sequenced and analysed by comparison with reference sequence, accession Nr. AF426432 (NCBI). RESULTS: 16 DNA sequence variations were identified in 53 patient samples; 6 of them have not been previously described. Identified sequence variations localized in coding regions do not cause amino acid substitutions, therefore they are not considered as mutations with an etiological role in CL/CLP/CP development. Baltic-Taiwan joint research project "Identification of genes involved in craniofacial morphogenesis and susceptibility to orofacial clefting in a human genome scan 2004-2006".

Adenine↗
PubMed2006

[Power estimation for in silico mapping].

A fundamentally new approach to gene mapping of complex traits was suggested recently. It consists in computer analysis of existing databases on the phenotypes and single nucleotide polymorphisms (SNPs) in inbred mouse strains and was termed in silico mapping. The power of this method has been studied by simulating quantitative traits controlled by one, two, or three genes. The results have demonstrated that the power of in silico mapping is high in the case of a monogenic trait. The probability of mapping all genes determining a digenic or, especially, trigenic trait is low. If two or three genes make equal phenotypic contributions to a trait, the proportions of experiments where none of them is localized are 17 and 25%, respectively. In the case of a major gene effect, when the phenotypic contribution of one gene considerably exceeds those of the other genes, the probability to map the major gene is 0.95 and 0.80 for the digenic and trigenic models, respectively. This shows that, in the case of polygenic control, the new method could localize only the genes with major effects, while most genes involved in the control of the trait would not be mapped.

Animals↗
PubMed2006

Transferability of tag SNPs to capture common genetic variation in DNA repair genes across multiple populations.

Genetic association studies can be made more cost-effective by exploiting linkage disequilibrium patterns between nearby single-nucleotide polymorphisms (SNPs). The International HapMap Project now offers a dense SNP map across the human genome in four population samples. One question is how well tag SNPs chosen from a resource like HapMap can capture common variation in independent disease samples. To address the issue of tag SNP transferability, we genotyped 2,783 SNPs across 61 genes (with a total span of 6 Mb) involved in DNA repair in 466 individuals from multiple populations. We picked tag SNPs in samples with European ancestry from the Centre d'Etude du Polymorphisme Humain, and evaluated coverage of common variation in the other samples. Our comparative analysis shows that common variation in non-African samples can be captured robustly with only marginal loss in terms of the maximum r2. We also evaluated the transferability of specified multi-marker haplotypes as predictors for untyped SNPs, and demonstrate that they provide equivalent coverage compared to single-marker tests (pairwise tags) while requiring fewer SNPs for genotyping. The efficacy of a tagging-based approach in studying genotype-phenotype correlations in complex traits is strongly supported by our empirical results.

Computational Biology↗
PubMed1991

Cuban AIDS control.

In an item on a "dog genome project" (Science, 19 April, p. 382), we failed to say that while Eric Lander of MIT and David Botstein of Stanford University developed methods for mapping the genes for complex traits, the test of the method on tomatoes was done (with Lander's collaboration) at Steven D. Tanksley's lab at Cornell University.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The power of identity-by-state methods for linkage analysis.

The affected-sib-pair method has been widely utilized for mapping. This methodology is aimed at mapping complex traits which have been observed to be familial but for which Mendelian segregation, even after allowing for partial penetrance, is not apparent. Indications of linkage are based on the observation of nonrandom segregation at a marker locus in two affected siblings. We extend this methodology to more distant genetic relationships and examine the power of identity-by-state methods for mapping when marker information is only available on pairs of affected relatives. The power depends on the polymorphism of the marker, the probability of identity by descent at the trait locus, and the recombination fraction between the trait and the marker loci.

Female↗
PubMed1983

The concept of "productive adaptability" of domestic animals in tropical and subtropical regions.

The complex trait "productive adaptability" is shown to be a useful parameter for selection work in tropical climates. Characters such as rectal temperature in poultry and hair colour and structure in cattle used as indicators of heat tolerance prove to be of little value. "Productive adaptability" is also genetically more suited for selection procedures. Our results confirm that body size is a significant indicator of an animal's productive adaptability and that it is a suitable criterion for use in improving the genetic potential of livestock in warm climates. The special use of major genes in breeding programmes to improve productive adaptability is demonstrated.

Acclimatization↗