Biomedical subjects

Eleftheria Zeggini

Publications and source records attributed to Eleftheria Zeggini.

At least 19 recordsLinked to original sources

PubMed2026

Elucidating shared genetic signals between type 2 diabetes and three neurodegenerative dementia phenotypes.

Type 2 diabetes (T2D) and dementia frequently co-occur, yet the biological mechanisms underlying this comorbidity remain incompletely understood. Here, we systematically investigate shared genetic signals between T2D and three forms of neurodegenerative dementia (Alzheimer disease, Lewy body dementia, and sporadic frontotemporal dementia) using large-scale genome-wide association studies of clinically diagnosed individuals. We identify five genomic regions harboring shared association signals between T2D and at least one dementia subtype. Among these, the APOE locus was common to all dementia subtypes, whereas the remaining four loci (GBA, CRY2/PEX16/MAPK8IP1, INO80E, and NSF) were each shared exclusively between T2D and one dementia subtype. Integrating multi-omics data across several disease-relevant tissues and orthogonal lines of functional evidence, we prioritize 26 candidate genes through which these shared genetic loci potentially mediate their effect. Pathway enrichment highlights lipid and lipoprotein regulatory biology as a central shared axis. Mendelian randomization analyses using genetically regulated gene expression in relevant tissues indicate pleiotropic mechanisms with divergent phenotypic consequences. Our findings identify shared genetic loci between T2D and neurodegenerative dementia, revealing systemic metabolic-neurodegenerative trade-offs and highlighting key genes that underpin the comorbidity, providing a framework for improved understanding of age-related multi-morbidity.

Alzheimer disease↗

PubMed2026

Diet-responsive proteogenomic effects following short-term restriction of animal products in humans.

The effect of diet on genetic regulation in humans remains largely unexplored. Here, we investigate gene-diet interactions in a unique group of healthy individuals (N = 200) who alternate between omnivory and dietary restriction of animal products for religious reasons. Using longitudinal proteomic and genotype data, we identify diet-responsive cis-pQTLs and highlight regulatory effects on LBR and MSRA, proteins involved in cholesterol and methionine metabolism respectively. LBR-associated cis-pQTL rs74148404 colocalizes with obesity exclusively under dietary restriction, suggesting diet-dependent modulation of genetic risk. We also show that a diet-dependent cis-pQTL for metabolic regulator FGF21 colocalizes with eosinophil and platelet traits pointing to diet-sensitive immunometabolic signalling. By parallel profiling of a continuously omnivorous control group (N = 211), we uncover seasonally dynamic genetic regulation for proteins linked to apoptosis in immune system pathways (MAVS, CASP3, PDLIM7, IL12RB1), effects likely masked by animal product restriction. These findings reveal dynamic diet- and season-sensitive regulatory mechanisms with implications for precision nutrition and individualized disease prevention strategies, and underscore the need to integrate environmental context into genetic studies of health and disease.

Humans↗

PubMed2006

Genetics of type 2 diabetes.

After several years of uncertain progress, the stage is now set for a transformation in understanding the genetic landscape of type 2 diabetes. Advances in genome informatics, genotyping technology, and statistical methodology, allied to availability of large-scale clinical material, are having a salutary effect on susceptibility gene discovery. The advent of genuinely genome-wide association scans and the prospects for combining genetics with high-throughput genomics are additional sources of optimism for the future.

Diabetes Mellitus, Type 2↗

PubMed2006

Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.

BACKGROUND: A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. CONCLUSIONS: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.

Adult↗

PubMed2006

Polymorphisms in the glucokinase-associated, dual-specificity phosphatase 12 (DUSP12) gene under chromosome 1q21 linkage peak are associated with type 2 diabetes.

Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5' end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from -8,379 to +10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P = 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker +7,580. Markers -8,379 and +7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P = 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size.

Black People↗

PubMed2006

Significant linkage of BMI to chromosome 10p in the U.K. population and evaluation of GAD2 as a positional candidate.

Obesity is a major health problem, and many family-based studies have suggested that it has a strong genetic basis. We performed a genome-wide quantitative trait linkage scan for loci influencing BMI in 573 pedigrees from the U.K. We identified genome-wide significant linkage (logarithm of odds = 3.74, between D10S208 and D10S196, genome-wide P=0.0186) on chromosome 10p. The size of our study population and the statistical significance of our findings provide substantial contributions to the body of evidence for a locus on chromosome 10p. We examined eight single nucleotide polymorphisms (SNPs) in GAD2, which maps to this linkage region, tagging the majority of variation in the gene, and observed marginally significant (0.01<P<0.05) associations between four common variants and BMI. However, these SNPs did not account for our evidence of linkage to BMI, and they did not replicate (in direction of effect) the previous associations. We therefore conclude that these SNPs are not the etiological variants underlying this locus. We cannot rule out the possibility that other untagged variations in GAD2 may, in part, be involved, but it is most likely that alternative gene(s) within the broad gene-rich region of linkage on 10p are responsible for variation in body mass and susceptibility to obesity.

Adult↗

PubMed2006

Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q.

The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.

Adult↗

PubMed2006

The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults.

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at -23HphI (odds ratio [OR] 0.42 [95% CI 0.31-0.58], P=2.4 x 10(-8)), A allele at +1,404Fnu4HI (0.50 [0.36-0.70], P=3.2 x 10(-5)), and C allele at +3,580MspI (0.55 [0.35-0.85], P=0.0046). As with type 1 diabetes, the -23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA.

Adult↗

PubMed2006

Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.

Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10(-11)). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P = 7 x 10(-5)) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is approximately 16%. The overall evidence for association for these variants (P = 4.4 x 10(-14) combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance.

Adult↗

PubMed2005

Will the real disease gene please stand up?

A common dilemma arising in linkage studies of complex genetic diseases is the selection of positive signals, their follow-up with association studies and discrimination between true and false positive results. Several strategies for overcoming these issues have been devised. Using the Genetic Analysis Workshop 14 simulated dataset, we aimed to apply different analytical approaches and evaluate their performance in discerning real associations. We considered a) haplotype analyses, b) different methods adjusting for multiple testing, c) replication in a second dataset, and d) exhaustive genotyping of all markers in a sufficiently powered, large sample group. We found that haplotype-based analyses did not substantially improve over single-point analysis, although this may reflect the low levels of linkage disequilibrium simulated in the datasets provided. Multiple testing correction methods were in general found to be over-conservative. Replication of nominally positive results in a second dataset appears to be less stringent, resulting in the follow-up of false positives. Performing a comprehensive assay of all markers in a large, well-powered dataset appears to be the most effective strategy for complex disease gene identification.

Chromosome Mapping↗

PubMed2005

An evaluation of HapMap sample size and tagging SNP performance in large-scale empirical and simulated data sets.

A substantial investment has been made in the generation of large public resources designed to enable the identification of tag SNP sets, but data establishing the adequacy of the sample sizes used are limited. Using large-scale empirical and simulated data sets, we found that the sample sizes used in the HapMap project are sufficient to capture common variation, but that performance declines substantially for variants with minor allele frequencies of <5%.

Chromosome Mapping↗

PubMed2005

Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition.

BACKGROUND: The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. RESULTS: Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. CONCLUSION: For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results.

Chromosomes, Human, Pair 17↗

PubMed2005

Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Adult↗

PubMed2005

MCP-1 gene haplotype association in biopsy proven giant cell arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is the most frequent vasculitis in European and North American countries. Increased expression of monocyte chemoattractant protein 1 (MCP-1) has been observed within the inflammatory infiltrates of blood vessels and serum of patients with GCA and in other autoimmune and inflammatory conditions. MCP-1 gene polymorphisms have been reported to contribute to susceptibility to several immune and inflammatory conditions. To investigate the clinical implication of MCP-1 polymorphisms in GCA, we examined the association of 3 single nucleotide polymorphisms (SNP) in a series of patients with GCA from Northwest Spain. METHODS: Seventy-nine patients with biopsy proven GCA and 99 ethnically matched controls were studied. Patients and controls were genotyped for MCP-1 polymorphisms. SNP included in this study (rs2857657, rs4586, rs139000) were located in intron 1(G/C), exon 2(T/C), and 3'UTR(C/T) region of MCP-1 gene. RESULTS: The distribution of the alleles and genotypes for each MCP-1 polymorphism showed no significant differences between GCA patients and controls. When we compared the overall distribution of haplotype frequencies between GCA cases and controls a significant difference was observed (p = 0.005, by chi-square test from 4 2 contingency table). In addition, haplotype C-C was significantly increased in GCA patients compared with controls (p = 0.03, OR 2.09, 95% CI 1.09-4.02). Similarly, haplotype T-T was overrepresented in GCA patients (p = 0.005). CONCLUSION: Significant differences in haplotype frequencies between GCA patients and controls may indicate a role for MCP-1 gene in susceptibility to GCA.

Biopsy↗

PubMed2004

Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

Arthritis, Rheumatoid↗

PubMed2004

A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis.

OBJECTIVE: To establish linkage and replicate the association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis (JIA). METHODS: Three hundred twenty-one Caucasian simplex families from the UK were genotyped for polymorphisms of MIF using SNaPshot ddNTP primer extension, or by a fluorescently labeled primer method, and capillary gel electrophoresis. The functional significance of the promoter polymorphisms was studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. RESULTS: MIF was linked and associated with JIA (P = 0.0016). Specifically, a 2-point promoter haplotype, CATT(7)-MIF-173*C, was found to be transmitted in excess (38 transmitted: 21 not transmitted) in the JIA patients. Conditional extended transmission disequilibrium test and pairwise extended transmission disequilibrium test predicted functional interaction between the 2 polymorphic positions. The interaction of the CATT repeat with MIF-173*G/C was found to be specific to the cell type. CONCLUSION: Replication of an association and linkage of MIF with JIA has been established. Functional interaction between the polymorphic positions on the linked haplotype has also been shown. The molecular mechanism of this interaction is currently being investigated.

Arthritis, Juvenile↗

PubMed2004

Evidence for a novel rheumatoid arthritis susceptibility locus on chromosome 6p.

OBJECTIVE: To investigate whether the large linkage peak on chromosome 6p harbors rheumatoid arthritis (RA) susceptibility loci in addition to the well-characterized HLA-DRB1 gene. METHODS: DNA samples obtained from 377 UK RA affected sibling pair (ASP) families, comprising test (181 ASPs) and replication (196 ASPs) cohorts, were used for linkage analysis. Three hundred eighty-four patients with RA derived from a subset of 192 ASPs were compared with a panel of 288 unrelated healthy controls for association studies. Samples were genotyped for 35 microsatellites and 25 single-nucleotide polymorphisms (SNPs). RESULTS: In the test cohort, the maximum logarithm of odds (LOD) score was obtained over D6S1260 (LOD 7.1). Evidence for linkage to the telomeric portion of the peak was increased in subsets of ASPs in which both individuals had erosive disease or both carried 2 copies of the shared epitope. HLA-A, HLA-DRB1, and 8 additional markers showed evidence of linkage in the presence of association with RA (using the extended transmission disequilibrium test [ETDT]). The positive ETDT result for 2 adjacent markers (D6S1665 and 210901-4) mapping to the telomeric end of the linked region ( approximately 11 Mb from DRB1) was replicated (for D6S1665) in the second cohort of ASPs. Haplotypic overtransmission of pairwise combinations between D6S1665*7 and 210901-4*4 was identified through the TDTPhase program. Multipoint conditional analysis showed this effect to be independent of HLA-DRB1. SNP-based association studies of the region identified a 4-marker haplotype in the DEK gene that was significantly associated with RA (P = 0.009). CONCLUSION: Evidence has been presented for an RA susceptibility locus mapping under the linkage peak on 6p, 11 Mb telomeric of HLA-DRB1. Preliminary association data implicate the gene DEK.

Arthritis, Rheumatoid↗

PubMed2004

Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype.

Differences in glucocorticoid (GC) sensitivity may underlie both common diseases (e.g. hypertension) and variability in response to treatment with GCs (e.g. asthma). We tested the potential involvement of the GC receptor (GR) gene in mediating GC sensitivity using haplotype analysis and a low-dose dexamethasone suppression test. Linkage disequilibrium across the GR gene was determined in 216 U.K. Caucasians, and 116 had a 0.25-mg overnight dexamethasone suppression test. Very strong linkage disequilibrium was observed across the GR gene with only four haplotypes accounting for 95% of those observed. Haplotype pattern mining and linear regression analyses independently identified a three-marker haplotype, across intron B, to be significantly associated with low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype occurred in 41% of the individuals with low postdexamethasone cortisol vs. 23% in the combined other quartiles (odds ratio 2.4, 95% confidence interval 0.9-6.3, P = 0.05). This is the first comprehensive, haplotype based analysis of the GR gene. A three-point haplotype, within intron B, is associated with enhanced sensitivity to GCs. This haplotype may help predetermine variation in clinical response to GC therapy and also assist the understanding of diseases related to GC production.

Adult↗