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The genetics of viral infection pathology.

The genetic diversity of viruses and the genetic constitution (polygenic configuration) of susceptible organisms participate together in the determination of a virus disease and of its clinical forms. Genes of sensitivity to viral infection, genes of nonspecific defense (encoding for interferons, complement factors), immune response regulating genes and immunoglobulin genes would form the background of an intrinsic polygenic group involved in viral infection pathology.

Alleles↗

PubMed2006

Three allele combinations associated with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS. METHODS: 286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFbeta1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group. RESULTS: We identified two previously unknown MS-associated tri-allelic combinations:-509TGFbeta1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Delta32, DRB1*04 were also reidentified as MS-associated. CONCLUSION: These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles.

Adult↗

PubMed2005

Leaf tip necrosis, molecular markers and beta1-proteasome subunits associated with the slow rusting resistance genes Lr46/Yr29.

Resistance based on slow-rusting genes has proven to be a useful strategy to develop wheat cultivars with durable resistance to rust diseases in wheat. However this type of resistance is often difficult to incorporate into a single genetic background due to the polygenic and additive nature of the genes involved. Therefore, markers, both molecular and phenotypic, are useful tools to facilitate the use of this type of resistance in wheat breeding programs. We have used field assays to score for both leaf and yellow rust in an Avocet-YrA x Attila population that segregates for several slow-rusting leaf and yellow rust resistance genes. This population was analyzed with the AFLP technique and the slow-rusting resistance locus Lr46/Yr29 was identified. A common set of AFLP and SSR markers linked to the Lr46/Yr29 locus was identified and validated in other recombinant inbred families developed from single chromosome recombinant populations that segregated for Lr46. These populations segregated for leaf tip necrosis (LTN) in the field, a trait that had previously been associated with Lr34/Yr18. We show that LTN is also pleiotropic or closely linked to the Lr46/Yr29 locus and suggest that a new Ltn gene designation should be given to this locus, in addition to the one that already exists for Lr34/Yr18. Coincidentally, members of a small gene family encoding beta-1 proteasome subunits located on group 1L and 7S chromosomes implicated in plant defense were linked to the Lr34/Yr18 and Lr46/Yr29 loci.

Basidiomycota↗

PubMed2003

Gallbladder motility in agouti-yellow and leptin-resistant obese mice.

BACKGROUND: Obesity is a polygenic disorder that is associated with gallstone disease. We have previously shown that leptin deficiency in obese mice correlates with decreased gallbladder motility, suggesting that leptin plays a role in the link between gallstone disease and obesity. However, most obese humans are leptin-resistant, and relatively few are leptin-deficient. To confirm that leptin dysfunction is responsible for impaired gallbladder motility in obese mice, we hypothesized that leptin-resistant obese mice (Lep(db)) would have abnormal gallbladder motility while obese mice with intact leptin function (Agouti Yellow, A(y)) would have normal gallbladder motility. MATERIALS AND METHODS: Eighteen lean control (C57BL/6J), 10 A(y) and 12 Lep(db) female mice were fasted overnight, weighed, and livers and gallbladders were harvested. Liver weights and gallbladder volumes were measured. Gallbladder contractile responses (N/cm(2)) to acetylcholine (10(-5)M), neuropeptide Y (10(-8,-7,-6) M) and cholecystokinin (10(-10,-9,-8,-7)M) were determined in muscle bath chambers. Results were analyzed by analysis of various (ANOVA) and with the Mann-Whitney Rank Sum Test. RESULTS: Both Agouti yellow (A(y)) and leptin-resistant (Lep(db)) obese mice had body weights, liver weights and gallbladder volumes that were significantly greater (P < 0.01) than lean control mice. Leptin-resistant obese mice had gallbladder responses to acetylcholine, neuropeptide Y and cholecystokinin that were significantly less (P < 0.01) than both lean control and Agouti yellow obese mice. CONCLUSIONS: These data suggest that (1). leptin-resistant obese mice (Lep(db)) have abnormal gallbladder motility and (2). obese mice with normal leptin metabolism (A(y)) have normal gallbladder response to neurotransmitters. We conclude that leptin represents a link between obesity, gallbladder motility and gallstone formation.

Acetylcholine↗

PubMed2002

Investigation of bax, bcl-2, bcl-x and p53 gene polymorphisms in multiple sclerosis.

Clinical course, outcome, radiological features, severity, and histopathology are heterogenous in multiple sclerosis (MS). Since MS is considered to be a polygenic disease, the genetic background may at least partly be responsible for this variability. Some MS cases are histopathologically characterized by a dramatic oligodendrocyte loss that is in part caused by apoptosis. A dysregulated apoptotic elimination of self-reactive T cells may also contribute to disease susceptibility. To analyze genetic differences in the apoptosis regulating factors bcl-2, bax, bcl-x and p53 we investigated polymorphisms of these genes in 105 patients with a relapsing remitting disease course and 99 controls by PCR-SSCP and direct sequencing. We identified so far unpublished sequence alterations in the promotor region of the bxl-x gene, in exon 7 of the p53 gene, and in exon 1 of the bax gene. No differences were observed between MS patients and controls. Additional known polymorphisms were found in intron 3 of the bax gene and in exon 6 of the p53 gene. No significant differences in the frequency of gene sequence variations were found between MS patients and controls. The apoptosis genes studied here therefore appear less likely to be important effector genes in MS.

Apoptosis↗

PubMed2002

Coeliac disease candidate genes: no association with functional polymorphisms in matrix metalloproteinase 1 and 3 gene promoters.

BACKGROUND: Coeliac disease is polygenic with a large genetic component. Matrix metalloproteinase-1 (MMP-1) and MMP-3 degrade extracellular matrix; expression levels are increased in the coeliac lesion where tissue damage is observed. Polymorphisms associated with elevated expression (MMP-3 -1171 allele 5A; MMP-1 -1607 2G), at 11q22.2, a region repeatedly showing evidence of linkage in coeliac disease, are associated with other chronic inflammatory disorders which may share a common molecular pathology. We tested for an association between these candidate gene polymorphisms and coeliac disease. METHODS: Two independent collections of 225 and 102 combined (Norwegian and Swedish) simplex families, and 160 independent healthy controls from the Norwegian Bone Marrow Donor Registry were used. Each individual was genotyped by PCR and fragment length analysis on an automated sequencer. The transmission/disequilibrium test was applied. Odds ratios were calculated employing probands or affected sibs where available, as cases versus independent controls. RESULTS: MMP-1 allele 2G did not show evidence of association in any tests undertaken. Neither did we find evidence for association of MMP-3 allele 5A, except among the combined family data: a non-significant tendency toward reduced risk was observed among males carrying MMP-3 allele 5A (40.2% transmission, Pc = 0.2). Further testing to clarify this observation did not reveal a significant association (odds ratio = 0.67 (95% confidence interval: 0.42-1.07), P = 0.08). CONCLUSIONS: We did not find significant evidence to support an association of MMP-3 allele 5A or MMP-1 allele 2G with coeliac disease in Norwegian and Swedish populations.

Celiac Disease↗

PubMed1997

Estimation of effects of quantitative trait loci in large complex pedigrees.

A method was derived to estimate effects of quantitative trait loci (QTL) using incomplete genotype information in large outbreeding populations with complex pedigrees. The method accounts for background genes by estimating polygenic effects. The basic equations used are very similar to the usual linear mixed model equations for polygenic models, and segregation analysis was used to estimate the probabilities of the QTL genotypes for each animal. Method R was used to estimate the polygenic heritability simultaneously with the QTL effects. Also, initial allele frequencies were estimated. The method was tested in a simulated data set of 10,000 animals evenly distributed over 10 generations, where 0, 400 or 10,000 animals were genotyped for a candidate gene. In the absence of selection, the bias of the QTL estimates was < 2%. Selection biased the estimate of the Aa genotype slightly, when zero animals were genotyped. Estimates of the polygenic heritability were 0.251 and 0.257, in absence and presence of selection, respectively, while the simulated value was 0.25. Although not tested in this study, marker information could be accommodated by adjusting the transmission probabilities of the genotypes from parent to offspring according to the marker information. This renders a QTL mapping study in large multi-generation pedigrees possible.

Animals↗

PubMed2005

Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility.

BACKGROUND: Migraine is a polygenic multifactorial disease, possessing environmental and genetic causative factors with multiple involved genes. Mutations in various ion channel genes are responsible for a number of neurological disorders. KCNN3 is a neuronal small conductance calcium-activated potassium channel gene that contains two polyglutamine tracts, encoded by polymorphic CAG repeats in the gene. This gene plays a critical role in determining the firing pattern of neurons and acts to regulate intracellular calcium channels. METHODS: The present association study tested whether length variations in the second (more 3') polymorphic CAG repeat in exon 1 of the KCNN3 gene, are involved in susceptibility to migraine with and without aura (MA and MO). In total 423 DNA samples from unrelated individuals, of which 202 consisted of migraine patients and 221 non-migraine controls, were genotyped and analysed using a fluorescence labelled primer set on an ABI310 Genetic Analyzer. Allele frequencies were calculated from observed genotype counts for the KCNN3 polymorphism. Analysis was performed using standard contingency table analysis, incorporating the chi-squared test of independence and CLUMP analysis. RESULTS: Overall, there was no convincing evidence that KCNN3 CAG lengths differ between Caucasian migraineurs and controls, with no significant difference in the allelic length distribution of CAG repeats between the population groups (P = 0.090). Also the MA and MO subtypes did not differ significantly between control allelic distributions (P > 0.05). The prevalence of the long CAG repeat (>19 repeats) did not reach statistical significance in migraineurs (P = 0.15), nor was there a significant difference between the MA and MO subgroups observed compared to controls (P = 0.46 and P = 0.09, respectively), or between MA vs MO (P = 0.40). CONCLUSION: This association study provides no evidence that length variations of the second polyglutamine array in the N-terminus of the KCNN3 channel exert an effect in the pathogenesis of migraine.

Gene Frequency↗

PubMed2002

The role of PC-1 and ACE genes in diabetic nephropathy in type 1 diabetic patients: evidence for a polygenic control of kidney disease progression.

BACKGROUND: The DD genotype of the ACE gene predisposes to faster diabetic nephropathy (DN) progression but its role in DN development is more controversial. We reported previously, in type 1 diabetic patients, an association between faster DN progression and the PC-1 gene Q121 variant, which associates with insulin resistance in non-diabetic subjects. We investigated here whether the combination of the ACE DD genotype and the PC-1 Q121 variant predicts the development and/or progression of DN in type 1 diabetic patients. METHODS: Type 1 diabetic patients either with (n=159) or without (n=122) nephropathy were evaluated in a cross-sectional study. DN was defined as the presence of microalbuminuria or persistent proteinuria in a subject with more than 10-year duration of disease and concomitant diabetic retinopathy, and with no evidence of heart failure or other renal disease. Seventy-five (47 male/28 female) type 1 diabetic patients with nephropathy in whom retrospective information with repeated measurements of serum creatinine was available, were analysed in a longitudinal study. RESULTS: No association of the PC-1 Q121 variant and the ACE D/D genotype with DN development was observed. However, the ACE DD genotype and the PC-1 Q121 variant were associated, both independently (P=0.02 and P=0.025, respectively) or in combination (P=0.02), with a faster rate of glomerular filtration rate decline. An interaction (P=0.03) was observed between the two genes in increasing the individual patient's risk of being a fast progressor. CONCLUSION: Our data suggest that, in type 1 diabetic patients, the ACE and the PC-1 genes interact in increasing the individual risk of having a faster DN progression.

Adult↗

PubMed1998

Juvenile chronic arthritis profile in Greek children.

BACKGROUND: Juvenile chronic arthritis (JCA) is the commonest autoimmune rheumatic disease in childhood and presents different clinical subtypes. Juvenile chronic arthritis is considered to be of a polygenic nature and its genetic background is still under investigation. The clinical profile of JCA in the Greek population has not been studied completely. This study retrospectively analyzed the clinical and immunological features of JCA in Greek children presented between 1989 and 1994. Human leukocyte antigen (HLA)-positive or -negative associations in the different clinical subtypes were also detected. The findings of this study were correlated with those reported from other populations. METHODS AND RESULTS: Antinuclear antibodies (ANA) anti-ds DNA and anti-extractable nuclear antigen antibodies were estimated by immunofluorescent and ELISA assays. Human leukocyte antigen typing was performed by microlymphocytotoxicity, using immunobeads. The peak ages of JCA onset were between 2 and 5 years and also between 9 and 12 years. There was a high female predominance in pauciarticular and polyarticular groups. The most common disease was pauciarticular (58.7%) followed by systemic (25%) arthritis. The incidence of eye involvement was 12.5% and presented only in the pauciarticular group. Overall, ANA positivity was 53.7%, increasing to 90% in pauciarticular cases associated with chronic uveitis. In the early onset (EOPA) pauciarticular subtype, positive-HLA associations with alleles DR11 and DR8 were shown. In the late onset pauciarticular (LOPA) group only B27 allele was increased. CONCLUSIONS: The results of this retrospective study did not reveal major differences between JCA in Greek children compared with other Caucasian series.

Adolescent↗

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2026

Harnessing Polygenic Risk Scores to Refine Venous Thromboembolism Risk Stratification.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity in patients of all ages. Despite growing interest in polygenic risk scores (PRS) for VTE, their utility remains understudied. Our objective was to evaluate the independent impact of a PRS on VTE susceptibility in adults and children. METHODS: We completed a retrospective, case-control study of two separate cohorts with evaluation of three VTE PRS models, with the primary analysis focused on a 293 single nucleotide polymorphism (SNP) PRS. The adult cohort included 597 VTE cases and 31 998 controls, and the pediatric cohort included 109 cases and 448 controls, both obtained from a de-identified databank with linked genetic data. Separate adult and pediatric multivariable logistic regressions were performed to measure the association of risk factors with VTE. RESULTS: Higher PRS in adults was significantly associated with increased odds of VTE, with each 1-standard deviation increase in PRS conferring an adjusted odds ratio of 1.25 (OR = 1.25, 95% CI 1.15-1.36, p < 0.001). Leading risk factors for adults were cancer (OR = 2.43, 95% CI: 2.04-2.89, p < 0.001) and recent surgery (OR = 2.16, 95% CI: 1.83-2.54, p < 0.001). The standardized PRS also exhibited increased risk for VTE in children (OR = 1.38, 95% CI 1.10-1.74, p = 0.003). Central venous catheterization (OR = 5.65, 95% CI 3.40-9.50, p < 0.001) was the foremost risk factor for pediatric VTE. CONCLUSION: VTE in adults and children is multifactorial, with clinical and genome-wide risk factors contributing. PRS may serve as a valuable adjunct to clinical risk factors for VTE risk stratification.

Humans↗

PubMed1998

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations.

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Adaptation, Physiological↗

PubMed1987

Epilepsy with primarily generalized myoclonic-astatic seizures: a genetically determined disease.

This paper presents case reports of patients suffering from myoclonic-astatic and stimulus-sensitive myoclonic seizures, respectively. It gives details of clinical and EEG data in the pertinent families. This is discussed in the context of controversial nosographic concepts of epilepsies with myoclonic seizures, and of the results of extensive family investigations. The findings demonstrate the decisive importance of hereditary factors in the pathogenesis of myoclonic and myoclonic-astatic epilepsy, the genetic background of which is probably polygenic.

Child, Preschool↗

PubMed2003

Musculoskeletal and other extrapulmonary disorders in sarcoidosis.

Sarcoidosis is a multisystemic inflammatory disease, still of unknown origin, characterized by epithelioid non-caseating granuloma in all affected organs. Granuloma formation is lead by a Th1-type response. The exact mechanism that leads to either progression or spontaneous resolution of the disease is not known. Familial aggregation, and the variations in presentation and severity of sarcoidosis according to ethnic background, are suggestive of a polygenic origin that is still to be determined. The contribution of environmental factors, as well as their interactions with genetic factors, remains to be demonstrated. The clinical presentation, musculoskeletal and other extrapulmonary disorders, as well as patients work-up, are reviewed. Sarcoidosis is often a benign disease. Corticosteroids, either alone or in association with other drugs, are still the mainstay of treatment. Defining clearly who will need treatment and what treatment to be used in a particular patient remains controversial.

Humans↗

PubMed2001

Disease model: hyperinsulinemia and insulin resistance. Part B--polygenic and other animal models.

Deficiency of leptin or its receptor produces hyperinsulinemia with marked obesity. Paradoxically, severe insulin resistance also accompanies lipodystrophy. Animal models of these contrasting conditions have enabled us to observe the profound and complicated aspects of the underlying pathologies. In addition, conventional polygenic rodents with known genetic backgrounds, such as the spontaneously hypertensive rat and the Goto-Kakisaki rat, have also been used to investigate these abnormalities.

Animals↗

PubMed2002

Gallstones: genetics versus environment.

OBJECTIVE: The aim of this study was to determine if a significant genetic component contributes to the pathogenesis of symptomatic gallstones. SUMMARY BACKGROUND DATA: Gallstones represent a polygenic disorder that affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Risk factors include age, gender, race, parity, obesity, and diabetes. A family history of gallstones also has been identified as a risk factor suggesting that genetics play a role in gallstone formation. However, the role of genetics in the pathogenesis of gallstone formation has not been determined. METHODS: A gallbladder disease-specific questionnaire was administered to 904 healthy unrelated adult volunteers (association study). The questionnaire ascertained a history of cholecystectomy and gallstone disease in first-degree relatives, as well as medical history, demographic, and anthropometric data. A logistic regression model was used to identify risk factors for symptomatic gallstone disease in a multivariate analysis. A maximum likelihood based variance decomposition approach was then used in 1,038 individuals from 358 families (family study) to estimate the additive genetic heritability of symptomatic gallstone disease. RESULTS: In the association study significant risk factors for symptomatic gallstone disease were female gender (relative risk 8.8, P <.003), obesity (BMI > 30, relative risk 3.7, P <.001), age > 50 (relative risk 2.5, P <.001), and a positive family history of previous cholecystectomy in a first-degree family member (relative risk 2.2, P <.01). In the family study the additive genetic heritability of symptomatic gallstones was 29% (P <.02), age and gender were significant covariates and explained 9.3% of the phenotypic variation in gallbladder disease. CONCLUSIONS: These data suggest that genetic factors are responsible for at least 30% of symptomatic gallstone disease. However, the true role of heredity in gallstone pathogenesis is probably higher because data based on symptomatic gallbladder disease underestimates the true prevalence in the population.

Adolescent↗

PubMed1972

Genetic determination of phenotypic variation in sickle cell trait.

Two genetic sources of variation influence the percentage of sickle cell hemoglobin found in heterozygotes. One factor is strongly related to the percentage of hemoglobin S in the carrier parent and appears to be determined by sickle hemoglobin isoalleles, whereas the other is related to racial background and may well be polygenic.

Adult↗