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PubMed2006

Genes, ageing and longevity in humans: problems, advantages and perspectives.

Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative "longevity genes". Nevertheless, many discrepancies are reported, likely due to the population-specific interactions between gene pools and environment. New approaches, including large-scale studies using high-throughput techniques, are urgently needed to overcome the limits of traditional association studies performed on a limited number of polymorphisms in order to make substantial progress to disentangle the genetics of a trait as complex as human longevity.

Aged, 80 and over↗
PubMedDate not supplied

Metabolic gene polymorphisms and p53 mutations in healthy centenarians and younger controls.

To obtain insights into the genetic mechanisms of ageing, we studied the frequency of the simultaneous presence of polymorphisms in phase I and phase II genes and of several p53 germline mutations in a group of 66 nonagenarians and centenarians in good health, selected from a larger sample of a multicentre Italian study in Northern Italy, and in a sample of 150 young healthy volunteers of the same ethnic group. We found a statistically significant difference in the frequency of 1the GSTT1 deletion and the p53 genotypes: the absence of any p53 polymorphisms and of GSTT1 deletion, and the simultaneous presence of the three p53 polymorphisms and of GSTT1 deletion, were much more frequent in young subjects than in centenarians (41.5% versus 26.9% and 8.8% versus 3.8%, respectively). One hypothesis to explain this difference is that subjects with both GSTT1 deletion and p53 polymorphisms may accumulate carcinogens and may have reduced DNA repair ability, and thus are more at risk for cancer. Another possible explanation is that both metabolic genes and p53 act on pathways related to cell ageing and death, and therefore certain composite genetic patterns could represent a generic mechanism of protection against ageing, not just against the development of chronic diseases. It is likely that longevity is related to a complex genetic trait as well as to certain environmental exposures.

Adult↗
PubMedDate not supplied

Genetics of hypertension: lessons learnt from mendelian and polygenic syndromes.

This brief review discusses genetic and genomic aspects of hypertension. A special emphasis is given to currently available strategies for gene identifications, including studies of rare Mendelian hypertension, candidate gene evaluation, genome-wide scans and approaches based on the comparative genome analysis. We also discuss the growing potential for pharmacogenetic approaches and address briefly the issue of genetic testing in complex polygenic traits.

Genomics↗
PubMed1998

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.

Amino Acid Substitution↗
PubMed2000

Evidence for a new Graves disease susceptibility locus at chromosome 18q21.

Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.

Alleles↗
PubMed2000

Lifetime Reproductive Success and Heritability in Nature.

The observation that traits closely related to fitness ("fitness traits") have lower heritabilities than traits more distantly associated with fitness has traditionally been framed in terms of Fisher's fundamental theorem of natural selection-fitness traits are expected to have low levels of additive genetic variance due to rapid fixation of alleles conferring highest fitness. Subsequent treatments have challenged this view by pointing out that high environmental and nonadditive genetic contributions to phenotypic variation may also explain the low heritability of fitness traits. Analysis of a large data set from the collared flycatcher Ficedula albicollis confirmed a previous finding that traits closely associated with fitness tend to have lower heritability. However, analysis of coefficients of additive genetic variation (CVA) revealed that traits closely associated with fitness had higher levels of additive genetic variation (VA) than traits more distantly associated with fitness. Hence, the negative relationship between a trait's association with fitness and its heritability was not due to lower levels of VA in fitness traits but was due to their higher residual variance. However, whether the high residual variance was mainly due to higher levels of environmental variance or due to higher levels of nonadditive genetic variance remains a challenge to be addressed by further studies. Our results are consistent with earlier suggestions that fitness-related traits may have more complex genetic architecture than traits more distantly associated with fitness.

Ficedula albicollis↗
PubMed2001

International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16.

Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high-penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits.

Chromosome Mapping↗
PubMed2003

Genomewide linkage analysis identifies polymorphism in the human interferon-gamma receptor affecting Helicobacter pylori infection.

Helicobacter pylori is considered the most prevalent infectious agent among humans, and it causes gastric inflammation, gastroduodenal ulcers, and a risk of gastric cancer. We performed a genomewide linkage analysis among Senegalese siblings phenotyped for H. pylori-reactive serum immunoglobulin G. A multipoint LOD score of 3.1 was obtained at IFNGR1, the gene that encodes chain 1 of the interferon-gamma (IFN-gamma) receptor. Sequencing of IFNGR1 revealed -56C-->T, H318P, and L450P variants, which were found to be associated with high antibody concentrations. The inclusion of these in the linkage analysis raised the LOD score to 4.2. The variants were more prevalent in Africans than in whites. Our findings indicate that IFN-gamma signaling plays an essential role in human H. pylori infection, and they contribute to an explanation of the observations of high prevalences and relatively low pathogenicity of H. pylori in Africa. Moreover, they provide further support for the value of genomewide linkage studies in the analysis of susceptibility to infection and other complex genetic traits.

Antibodies, Bacterial↗
PubMed2004

Inherent bias toward the null hypothesis in conventional multipoint nonparametric linkage analysis.

Traditional nonparametric "multipoint" statistical procedures have been developed for assigning allele-sharing values at a locus of interest to pairs of relatives for linkage studies. These procedures attempt to accommodate a lack of informativity, nongenotyped loci, missing data, and related issues concerning the genetic markers used in a linkage study. However, such procedures often cannot overcome these phenomena in compelling ways and, as a result, assign relevant relative pairs allele-sharing values that are "expected" for those pairs. The practice of assigning expected allele-sharing values to relative pairs in the face of a lack of explicit allele-transmission information can bias traditional nonparametric linkage test statistics toward the null hypothesis of no locus effect. This bias is due to the use of expected values, rather than to a lack of information about actual allele sharing at relevant marker loci. The bias will vary from study to study on the basis of the DNA markers, sample size, relative-pair types, and pedigree structures used, but it can be extremely pronounced and could contribute to a lack of consistent success in the application of traditional nonparametric linkage analyses to complex human traits and diseases. There are several potential ways to overcome this problem, but their foundations deserve greater research. We expose many of the issues concerning allele sharing with data from a large affected-sibling-pair study investigating the genetic basis of autism.

Alleles↗
PubMed2004

Genetic variation in radiation-induced expression phenotypes.

Studies have demonstrated that natural variation in the expression level of genes at baseline is extensive, and the determinants of this variation can be mapped by a genetic-linkage approach. In this study, we used lymphoblastoid cells to explore the variation in radiation-induced transcriptional changes. We found that, among normal individuals, there is extensive variation in transcriptional response to radiation exposure. By studying monozygotic twins, we demonstrated that there is evidence of a heritable component to this variation. The postradiation variation in the expression level of several genes, including the ferredoxin reductase gene (FDXR) and the cyclin-dependent kinase inhibitor 1A gene (CDKN1A), is significantly greater (P<.001) among twin pairs than within twin pairs. The induction of FDXR by radiation showed a bimodal distribution. Our findings have important implications for understanding the genetic basis of radiation response, which has remained largely unknown due to the lack of family material needed for genetic studies. Our approach, which uses expression phenotypes in cell lines, allows us to expose cells from family members to radiation. Similar study design can be applied to dissect the genetic basis of other complex human traits.

Cell Cycle Proteins↗
PubMed2005

Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26.

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.

Australia↗
PubMed2006

Measuring the efficiency of sound production.

Sound production efficiency is a complex phenotypic trait that incorporates biochemical and mechanical events beginning with substrate oxidation and ending with the radiation of sound. Its accurate measurement is significant in understanding the mechanisms and energetics underlying acoustic signaling and sexual selection. I show that in the short-tailed cricket Anurogryllus arboreus Walker, acoustic performance is apparently the same in acoustic free fields and in the reverberant conditions of a respirometry chamber. I present three methods for simultaneous and nearly simultaneous determination of calling metabolic rate and acoustic power output. The new methods yielded metabolic rates 3%-6% lower than matched controls using traditional flow-through respirometry (mean=8.1 mW); however, none of theses differences were statistically significant. I also evaluate four methods for determining the efficiency of sound production. The means of an individual's efficiencies calculated using these methods vary between 0.50% and 0.60%, with no statistically significant differences between the methods. I conclude with a critical evaluation of these techniques.

Acoustics↗
PubMed2006

Analysis of HLA-DQA, HLA-DQB frequencies in a group of Sardinian centenarians.

Human leukocyte antigen (HLA) alleles, regulating type and intensity of the immune response, might influence life expectancy. In previous case-control studies the authors have demonstrated that both HLA-DR and -DQ alleles are not associated with longevity in the Sardinian population. On the other hand, association studies are subjected (as part of the homogeneity of the population in terms of geographic origin) to a number of possible confounding factors. Therefore, the authors typed the HLA-DQA1 and HLA-DQB1 alleles in 24 sibs (age range 85 to 97) of 17 centenarians by PCR-SSP. Sib pair analysis showed nonsignificant differences between the observed and expected percentage of DQA* or DQB1* allele sharing. Therefore, these data strengthen the view that class II HLA genes have a marginal effect, if any, on the complex longevity trait.

Aged, 80 and over↗
PubMed2000

Mathematica packages for simulation of experimental genetics.

UNLABELLED: This note describes add-on packages for the Mathematica software system (Wolfram 1996) which allow simulation and analysis of both Mendelian and complex genetic traits in experimental crosses of plants or animals. AVAILABILITY: The add-on packages are freely available at http://www.mathsource.com/cgi-bin/msitem?0209-30 4. SUPPLEMENTARY INFORMATION: A tutorial notebook file is included with the packages at the mathsource site.

Animals↗
PubMed2006

A Laplace mixture model for identification of differential expression in microarray experiments.

Microarrays have become an important tool for studying the molecular basis of complex disease traits and fundamental biological processes. A common purpose of microarray experiments is the detection of genes that are differentially expressed under two conditions, such as treatment versus control or wild type versus knockout. We introduce a Laplace mixture model as a long-tailed alternative to the normal distribution when identifying differentially expressed genes in microarray experiments, and provide an extension to asymmetric over- or underexpression. This model permits greater flexibility than models in current use as it has the potential, at least with sufficient data, to accommodate both whole genome and restricted coverage arrays. We also propose likelihood approaches to hyperparameter estimation which are equally applicable in the Normal mixture case. The Laplace model appears to give some improvement in fit to data, though simulation studies show that our method performs similarly to several other statistical approaches to the problem of identification of differential expression.

Arabidopsis↗
PubMed2003

Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis.

Autoimmune diseases such as multiple sclerosis are characterized by complex genetic traits and pathomechanisms that translate into clinical heterogeneity. This wide heterogeneity of multiple sclerosis as well as different biological responses to immunomodulatory drugs can be expected to contribute to differential treatment responses. Strategies that dissect the relationship between the treatment response and the biological characteristics in individual patients are valuable not only as a clinical tool, but also in leading to a better understanding of the disease. Here we address the in vitro and ex vivo RNA expression profile under one approved therapy of multiple sclerosis, interferon-beta (IFN-beta, Betaseron), by cDNA microarrays and demonstrate that non-responder and responder phenotypes to IFN-beta as assessed by longitudinal gadolinium-enhanced MRI scans and clinical disease activity differ in their ex vivo gene expression profile. These findings will help to better elucidate the mechanism of action of IFN-beta in relation to different disease patterns and eventually lead to optimized therapy.

Follow-Up Studies↗
PubMed2000

Cellular consequences in the brain and liver of age-specific selection for rate of development in mice.

Changes in cell number (hyperplasia) and cell size (hypertrophy) in the brain and liver are described for mice subjected to 24 generations of age-specific restricted index selection for rate of development in body weight. One selection treatment (E) altered rate of development between birth and 10 days of age, another treatment (L) involved changes in rate of development between 28 and 56 days of age, while a third control treatment (C) involved random selection. Each selection treatment was replicated three times. These age-specific selection treatments focused on intervals during ontogeny when different developmental processes (hypertrophy or hyperplasia) were more predominant in the control of growth. Significant changes in brain and liver weight occurred at both 28 and 70 days of age. Early selection (E) generated significant changes in the number of cells in the brain while later selection (L) had no effect since the brain had stopped growth before selection was initiated. For the liver, early and late selection produced significant effects on both cell number and cell size. These results describe the dynamic and multidimensional aspects of selection in terms of its ability to alter different cellular and developmental components of complex morphological traits.

Aging↗
PubMed2005

Angiotensin-converting enzyme (ACE) haplotypes and cyclosporine A (CsA) response: a model of the complex relationship between ACE quantitative trait locus and pathological phenotypes.

It is highly controversial to define the role of angiotensin-converting enzyme (ACE) polymorphisms in essential hypertension. We studied a group of patients in whom hypertension was the major side effect of treatment by cyclosporine A (CsA). This study group comprised 227 Italian patients with nephrotic syndrome, 103 of which were treated with CsA and had different outcome. Forty-nine patients developed serious hypertension that was reversed after withdrawal of drug. ACE haplotypes were determined by a combination of molecular and statistical methods after verifying genotypes of six intragenic single nucleotide polymorphisms in 304 Italian blood donors and assembling them in clades (A, B, C) that include 95% of observed haplotypes. The association between ACE clade combinations and serum enzymatic levels confirmed the previous results about a role of an unidentified genetic variant at the 5' of the intragenic recombination site located near intron 7. ACE clades were then determined in patients, and regression methods were used to analyze variables associated with CsA responsivity and progression to renal failure. ACE genotype and responsiveness to CsA were strictly associated, because homozygosis for ACE B clade was able to influence CsA sensitivity. This highlights the role of 5' variants, which differentiate clades B and C. Other genetic markers were tested to search for possible additive effects. We found that PAI-1 4G allele was associated with progression to renal failure in the group of CsA-treated patients. Our results are in agreement with the hypothesis, raised after experimental results obtained in mouse models, that the effect of ACE polymorphisms on blood pressure is detectable once environmental factors, like CsA treatment in our case, overcome physiological homeostatic mechanisms.

Adolescent↗