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Biomedical subjects

Peter K Gregersen

Publications and source records attributed to Peter K Gregersen.

At least 19 recordsLinked to original sources
PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗
PubMed2007

Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits.

OBJECTIVE: To dissect the heterogeneity of rheumatoid arthritis (RA) through linkage analysis of quantitative traits, specifically, IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titers. METHODS: Subjects, 1,002 RA patients from 491 multiplex families recruited by the North American RA Consortium, were typed for 379 microsatellite markers. Anti-CCP titers were determined based on a second-generation enzyme-linked immunosorbent assay, and IgM-RF levels were quantified by immunonephelometry. We used the Merlin statistical package to perform nonparametric quantitative trait linkage analysis. RESULTS: For each of the quantitative traits, evidence of linkage, with logarithm of odds (LOD) scores of >1.0, was found in 9 regions. For both traits, the strongest evidence of linkage was for marker D6S1629 on chromosome 6p (LOD 14.02 for anti-CCP and LOD 12.09 for RF). Six other regions with LOD scores of >1.0 overlapped between the 2 traits, on chromosomes 1p21.1, 5q15, 8p23.1, 16p12.1, 16q23.1, and 18q21.31. Evidence of linkage to anti-CCP titer but not to RF titer was found in 2 regions (chromosomes 9p21.3 and 10q21.1), and evidence of linkage to RF titer but not to anti-CCP titer was found in 2 regions (chromosomes 5p15.2 and 1q42.3). Several covariates were significantly associated with 1 or both traits, and linkage analysis exploring the covariate effects revealed striking effects of sex in modulating linkage signals for several chromosomal regions. For example, sex had a striking impact on the linkage results for both quantitative traits on chromosome 6p (P = 0.0007 for anti-CCP titer and P = 0.0012 for RF titer), suggesting a sex-HLA region interaction. CONCLUSION: Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.

Adult↗
PubMed2006

Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.

Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3',5'-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Alleles↗
PubMed2006

European population substructure: clustering of northern and southern populations.

Using a genome-wide single nucleotide polymorphism (SNP) panel, we observed population structure in a diverse group of Europeans and European Americans. Under a variety of conditions and tests, there is a consistent and reproducible distinction between "northern" and "southern" European population groups: most individual participants with southern European ancestry (Italian, Spanish, Portuguese, and Greek) have >85% membership in the "southern" population; and most northern, western, eastern, and central Europeans have >90% in the "northern" population group. Ashkenazi Jewish as well as Sephardic Jewish origin also showed >85% membership in the "southern" population, consistent with a later Mediterranean origin of these ethnic groups. Based on this work, we have developed a core set of informative SNP markers that can control for this partition in European population structure in a variety of clinical and genetic studies.

Arthritis, Rheumatoid↗
PubMed2006

PTPN22: setting thresholds for autoimmunity.

The 620W allelic variant of the intracellular tyrosine phosphatase, PTPN22, is associated with a number of different autoimmune disorders, and this provides direct evidence for common mechanisms underlying many of these diseases. The associated allele appears to influence thresholds for T cell receptor signaling, and a variety of disease models involving both central and peripheral tolerance can be proposed. However, given the fact that PTPN22 is expressed in a variety of immunologically relevant cell types, the precise mechanisms for these associations remain unclear. In general, the PTPN22 620W allele appears to play a role in autoimmune disorders that have a prominent humoral component, suggesting that further investigation of PTPN22 activity in B cells will be useful. From a genetic perspective, the data highlights the genetic heterogeneity underlying autoimmunity in different ethnic groups.

Alleles↗
PubMed2006

A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Case-Control Studies↗
PubMed2006

Genome-wide meta-analysis for rheumatoid arthritis.

Meta-analysis is being increasingly used as a tool for integrating data from different studies of complex phenotypes, because the power of any one study to identify causal loci is limited. We applied a novel meta-analytical approach (Loesgen et al. in Genet Epidemiol 21(Suppl 1):S142-S147, 2001) in compiling results from four studies of rheumatoid arthritis in Caucasians including two studies from NARAC (Jawaheer et al. in Am J Hum Genet 68:927-936, 2001; Jawaheer et al. in Arthritis Rheum 48:906-916, 2003), one study from the UK (MacKay et al. in Arthritis Rheum 46:632-639, 2001) and one from France (Cornelis et al. in Proc Natl Acad Sci USA 95:10746-10750, 1998). For each study, we obtained NPL scores by performing interval mapping (2 cM intervals) using GeneHunter2 (Kruglyak et al. in Am J Hum Genet 58:1347-1363, 1996; Markianos et al. in Am J Hum Genet 68:963-977, 2001). The marker maps differed among the three consortium groups, therefore, the marker maps were aligned after the interval mapping was completed and the NPL scores that were within 1 cM of each other were combined using the method of Loesgen et al. (Genet Epidemiol 21(Suppl 1):S142-S147, 2001) by calculating the weighted average of the NPL score. This approach avoids some problems in analysis encountered by using GeneHunter2 when some markers in the sample are not genotyped. This procedure provided marginal evidence (P<0.05) of linkage on chromosome 1, 2, 5 and 18, strong evidence (P<0.01) on chromosomes 8 and 16, and overwhelming evidence in the HLA region of chromosome 6.

Arthritis, Rheumatoid↗
PubMed2006

Inferring causal relationships among intermediate phenotypes and biomarkers: a case study of rheumatoid arthritis.

MOTIVATION: Genetic association analysis is based on statistical correlations which do not assign any cause-to-effect arrows between the two correlated variables. Normally, such assignment of cause and effect label is not necessary in genetic analysis since genes are always the cause and phenotypes are always the effect. However, among intermediate phenotypes and biomarkers, assigning cause and effect becomes meaningful, and causal inference can be useful. RESULTS: We show that causal inference is possible by an example in a study of rheumatoid arthritis. With the help of genotypic information, the shared epitope, the causal relationship between two biomarkers related to the disease, anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) has been established. We emphasize the fact that third variable must be a genotype to be able to resolve potential ambiguities in causal inference. Two non-trivial conclusions have been reached by the causal inference: (1) anti-CCP is a cause of RF and (2) it is unlikely that a third confounding factor contributes to both anti-CCP and RF.

Arthritis, Rheumatoid↗
PubMed2006

Influence of male sex on disease phenotype in familial rheumatoid arthritis.

OBJECTIVE: To examine sex differences in clinical, demographic, and genetic characteristics among a large cohort of patients with familial rheumatoid arthritis (RA). METHODS: We studied 1,004 affected members of 467 Caucasian multicase RA families recruited from the North American Rheumatoid Arthritis Consortium. Standardized information about demographic and clinical characteristics was collected from all patients. Affected individuals also underwent radiography of the hands and were genotyped for markers in the HLA region. Sex differences were assessed using contingency table analysis (for categorical variables) and Student's t-tests for (continuous variables), and by multivariate logistic and linear regression analysis. RESULTS: Male patients had a significantly later onset of RA, were more likely to be seropositive for RF, and had significantly higher titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies compared with female patients, even after adjustment for covariates in multivariate analyses. Male patients were also significantly more likely to have a history of smoking and to be HLA-DRB1 shared epitope (SE) positive. Interestingly, female patients with an affected male sibling had significantly higher titers of anti-CCP antibodies and were more likely to be SE positive compared with female patients without affected male siblings. Multivariate analyses indicated that the presence of the SE did not fully explain the increased anti-CCP antibody titers observed in these families. CONCLUSION: Sex has an important influence on the disease phenotype in RA, including the age at disease onset and autoantibody production. Furthermore, families with affected male members are characterized by higher titers of autoantibodies, particularly anti-CCP antibodies. Our results indicate that these findings are not fully explained by differences in exposure to tobacco smoke, presence of the HLA-DRB1 SE, or other HLA region genetic variation. Thus, other genetic or nongenetic factors also contribute to sex differences in the RA phenotype.

Adult↗
PubMed2006

Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma.

OBJECTIVE: To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc). METHODS: Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups. RESULTS: The frequency of the -173*C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173*C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype. CONCLUSION: Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc.

Female↗
PubMed2006

Genetics of autoimmune diseases--disorders of immune homeostasis.

In the past few years, our extensive knowledge of the mammalian immune system and our increasing ability to understand the genetic causes of complex human disease have opened a window onto the pathways that lead to autoimmune disorders. In addition to the well-established role of genetic variation that affects the major histocompatibility complex, a number of rare and common variants that affect a range of immunological pathways are now known to have important influences on the phenotypic diversity that is seen among autoimmune diseases. Recent studies have also highlighted a previously unanticipated interplay between the innate and adaptive immune system, providing a new direction for research in this field.

Animals↗
PubMed2006

Genome-wide linkage scan for spontaneous DZ twinning.

In humans, spontaneous DZ twinning is known to have a genetic basis. A prior investigation in the Flemish and Dutch population showed that the phenotype of 'having DZ twins' was consistent with an autosomal monogenic dominant model, with a gene frequency of 3.5% and a female-specific lifetime penetrance of 10%. Recessive, X-linked, polygenic and sporadic models were rejected. This study reports on a genome-wide scan of 14 Flemish families containing 57 mothers of spontaneous DZ twins. Two-point linkage analysis using the autosomal dominant model showed nine chromosomal regions with a LOD score around 1. After multipoint linkage analysis, including heterogeneity, three chromosomes continued to give high LOD scores. These regions were further haplotyped with additional markers at 1 cM distance. The multipoint analysis was not in favour of linkage of the DZ twinning trait in most candidate genes and other regions (LOD score < -2) under the genetic model of autosomal dominance. To further evaluate the evidence for linkage given some uncertainty about the correct mode of inheritance of twinning susceptibility other models of inheritance were tested. Results of this analysis showed all models gave highest LOD scores under dominant models. If heterogeneity among the families is taken into account, the peaks that were observed on chromosome 2, 7 and 18 could well contain a potential gene contributing to DZ twinning. These results give suggestive evidence that the mode of inheritance of DZ twinning is probably more complex than was originally expected.

Belgium↗
PubMed2006

Gene expression profiling in human autoimmunity.

Human autoimmune diseases are well suited for the application of gene expression profiling. Sampling of blood cells and target tissues has already revealed many important pathways contributing to this spectrum of disorders, and many commonalities are emerging. For instance, clinically distinct diseases such as systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, and psoriasis all show evidence for dysregulation of the type I interferon pathway. These data suggest that autoimmune diseases will eventually be categorized at the level of gene expression. This work has led to advances in our understanding of disease pathogenesis and in the future promises to facilitate assessments of disease activity and improve targeting of therapies. Here, we review the literature on gene profiling in human autoimmune diseases and provide perspective on the current state of the art.

Autoimmune Diseases↗
PubMed2006

Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role for type I interferon (IFN) in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity. METHODS AND FINDINGS: We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity. CONCLUSIONS: These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus.

Adult↗
PubMed2005

Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.

Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P=.001) and PADI4 (PADI4_94, OR 1.24; P=.001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P=.0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P=.004) and that PTPN22 has a stronger effect in males than in females (P=.03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.

Adult↗