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PubMed1998

The genetics of vitiligo in Korean patients.

BACKGROUND: Vitiligo is a common disorder whose exact cause is unknown, but genetic factors are thought to be involved. We analyzed 120 Korean proband families to clarify which genetic factors are involved in the pathogenesis of vitiligo in Korean patients. METHODS: The genetics of vitiligo were analyzed in 120 Korean proband families out of 1030 vitiligo patients. Each family was analyzed through a proband afflicted with vitiligo. RESULTS: In 51 (42.5%) of 120 proband families, at least one first-degree relative of the proband had vitiligo. The incidence of those affected among 1755 relatives (first-, second-, and third-degree) was found to be 8.0+/-0.6%. There was a statistically significant departure for segregation analysis which was inconsistent with inheritance as an autosomal or X-linked locus model. On the basis of our results, the inheritance pattern of vitiligo is more likely to tend toward the model of multifactorial inheritance. The threshold trait among first-degree relatives (7.2%) appeared to tend more toward the square root of the frequency in the general population (10%) than towards those of dominant (50%) or recessive (25%) models. CONCLUSIONS: These results indicate that there are certain genetic factors involved in the etiology of vitiligo, and that vitiligo seems to have a polygenic nature.

Female↗

PubMedDate not supplied

Genetic analysis of the construction of the AEJ.A congenic strain indicates that nonsyndromic CL(P) in the mouse is caused by two loci with epistatic interaction.

The A/WySn mouse strain has a high frequency (20%) of the craniofacial defect, cleft lip with or without cleft palate, CL(P), in fetuses or newborns. Previous genetic studies have indicated that the genetic control of the risk of CL(P) is complex, but the cause of the liability of the embryo involves only one or two loci. The genes that cause the liability to CL(P) in A/WySn have been transferred by 12 generations of selective breeding to a normal strain background, AEJ/RkBc, to form a congenic strain pair. The new strain, AEJ.A/Jur, has been used to map a major CL(P) locus, clf1. Analysis of the genetic data from the process of constructing the AEJ.A/Jur strain indicates that the cause of CL(P) in A/WySn mice is the joint action of two recessive loci, clf1 and clf2 with unequal duplicate epistasis. That is, the normal allele at clf1 is a dominant suppressor of the recessive phenotype at clf2, and the normal allele at clf2 is a semidominant suppressor of the recessive phenotype at the clf1 locus. To be at risk for CL(P), embryos must be homozygous for clf1 mutations and at least heterozygous for clf2 mutations, and the risk is higher if they are homozygous for mutations at both loci. The delineation of this epistatic model involving a locus, clf1, that has linkage homology with a region implicated in human CL(P), and that has three paralogous regions in both species, supports the following arguments: and that has three paralogous regions in both species, supports the following arguments: that the CL(P) of the A/WySn mouse strain is a homologue of human CL(P); that the genetic complexity of CL(P) in both species originates in epistasis, not in polygenic modifiers; that human linkage analyses should specify epistatic models for CL(P); that the paralogous linkage groups should be considered candidate regions for other CL(P) loci.

Animals↗

PubMed2004

Multigenic control of hepatic iron loading in a murine model of hemochromatosis.

BACKGROUND & AIMS: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading. METHODS: To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers. RESULTS: We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism. CONCLUSIONS: Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.

Animals↗

PubMed1998

Dopamine uptake by platelet storage granules in first-degree relatives of Tourette's syndrome patients.

BACKGROUND: Considering that platelets have been established to be good peripheral markers for the study of catecholaminergic neurons, we have applied an assay to measure the uptake of (3H)-dopamine (DA) into platelet storage granules (PSG). Recently, we reported that Tourette's syndrome (TS) patients (pts) show decreased DA uptake into PSG. METHODS: In the present study, 28 first-degree relatives (3 with chronic motor tics, 3 with transient tics, 6 with obsessive-compulsive behavior, and 16 without symptomatology) belonging to the families of 13 patients, and 14 unrelated healthy controls were studied. RESULTS: Double reciprocal plots were constructed for each subject, and the apparent maximum velocity (Vmax) and Michaelis constant (K(m)) were determined by linear regression analysis (Lineaweaver-Burke plots). The uptake of DA (0.5-5 mumol/L) (mean +/- SEM) by PSG from relatives with symptomatology was similar to the TS patients (symptomatic relatives Vmax 181 +/- 22.2 fmol/mg protein, K(m) (mumol/L) 6.42 +/- 0.29; TS pts Vmax 108 +/- 6.9, K(m) 7.79 +/- 0.64). Relatives without symptomatology on the contrary showed DA affinity characteristics similar to the controls (t test, paired t test, multivariate analysis of variance, and log transformation). CONCLUSIONS: The data presented suggest that TS is hereditary, but they do not distinguish between an autosomal dominant inheritance and a mixed or polygenic model.

Blood Platelets↗

PubMed1999

Genotypic and phenotypic characterization of six new recombinant congenic strains derived from NOD/Shi and CBA/J genomes.

Recombinant Congenic Strains (RCS) are useful for dissecting complex polygenic traits. Here, we describe genetic and phenotypic characterization of six new RCS generated from outcrosses between NOD/Shi and CBA/LsLt, followed by sib mating of first backcross progeny (to CBA) for 20 generations, whereupon genetic and phenotypic analysis commenced. Four of the RCS were selected on the basis of residual heterozygosity present at F20 in one of the three original RCS. Contrary to expectations for RCS developed at first backcross, all derived at least 50% of the polymorphic markers typed from the NOD parental strain. Development of autoimmune insulin-dependent diabetes mellitus (IDDM) in NOD is a strain-specific characteristic. The major genetic component predisposing NOD mice to IDDM, their H2(g7) haplotype, was present in all RCS. Nevertheless, the presence of variable amounts of CBA genome at non-MHC loci conferred complete resistance in all RCS to spontaneous IDDM development, and rendered them strongly resistant to cyclophosphamide-induced IDDM. Although the RCS more resemble NOD in regard to certain strain-specific characteristics, such as prolificacy, an immunologic phenotype that was significantly reduced when compared to both parental strains was the number of peripheral CD8(+) T cells. Given the genetic characterization presented, these new RCS should prove valuable to investigators interested in studying genes controlling differential susceptibilities distinguishing the NOD and CBA inbred strain backgrounds.

Animals↗

PubMed2004

Exploring the genetic basis of disease using RNA interference.

Cancer and autoimmunity are polygenic diseases. In order to better understand the mechanisms of disease development and progression it is essential to uncover which genes are involved. Much has been learned from population studies in human patients by searching for polymorphic genetic loci associated with disease. In addition, animal models of tumor development, as well as models for various autoimmune conditions such as multiple sclerosis and Type I diabetes, have helped determine genetic loci that contribute to disease susceptibility. However, characterization of the exact genes involved is often difficult and requires lengthy and technically demanding genetic manipulations. The generation of knockout animals is the method of choice to probe single genes. However, this is not possible in all species or even in all inbred strains within a species. The recent discovery of a new post-transcriptional gene silencing pathway termed RNA interference, which is mediated by short fragments of double-stranded RNA (short-interfering RNA), has opened up new avenues for genetic manipulation of experimental animals. This review will consider how silencing genes by RNA interference within the context of experimental disease models promises to become a powerful new tool for the genetic analysis of cancer and autoimmunity. Advances in RNA interference technology now permit the relatively rapid generation of transgenic animals in a wide range of species with complex genetic backgrounds that were previously inaccessible to genetic manipulation. This novel approach should help refine the characterization of disease-associated genes, either by silencing specific candidates or even by screening a larger number of genes in vivo within a comparatively short time frame.

Animals↗

PubMed2006

Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison's disease in Portuguese Water Dogs.

Addison's disease, an immune-mediated disorder caused by destruction of the adrenal glands, is a rare disorder of Western European populations. Studies indicate that the disorder is polygenic in nature, involving specific alleles of the CTLA-4, DRB1*04 and DQ, Cyp27B1, VDR and MIC-A and -B loci. A similar immune form of Addison's disease occurs in several breeds of domestic dog, with frequencies ranging from 1.5 to 9.0%. The high frequency of the disease in domestic dog breeds likely reflects the small number of founders associated with many breeds, subsequent inbreeding, and the frequent use of popular sires. The Portuguese Water Dog (PWD) is a significantly affected breed. An analysis of 11,384 PWDs surveyed between 1985 and 1996 suggests a breed-specific disease incidence of 1.5%. As with humans, the disease is typically of late onset. This study involves a genetic comparison of Addison's disease in the PWD to the analogous disease in humans. The study is facilitated by the existence of complete pedigrees and a relatively high degree of inbreeding among PWDs. The breed originated from 31 founders, with 10 animals responsible for 90% of the current gene pool. We describe, specifically, the identification of two disease-associated loci, on Canis familiaris (CFA) chromosomes CFA12 and 37, which are syntenic with the human DRB1 histocompatibility locus alleles HLA-DRB1*04 and DRB1*0301, and to a locus for immunosuppression syntenic with CTLA-4. Strong similarities exist therefore in the complex genetic background of Addison's disease in humans and in the PWD. With the completion of the canine and human genome sequence, the purebred dog is set to become an important comparative model for Addison's as well as other human immune disorders.

Addison Disease↗

PubMedDate not supplied

Mode of inheritance of finger dermatoglyphic traits among Vaidyas of West Bengal, India.

BACKGROUND: It is well established that dermatoglyphics are genetically determined. But, to date, few studies have given attention to the inheritance pattern of dermatoglyphics. Furthermore, despite the existence of different advanced statistical packages, none of these previous studies implemented a model-fitting technique to reveal the mode of inheritance. Thus, the genetic nature of dermatoglyphics is still not clear. AIM: In the present communication, an attempt has been made to provide some information regarding the genetics of finger dermatoglyphics by estimating the magnitude and mode of inheritance of these traits. SUBJECTS AND METHODS: The fingerprints of 824 individuals from 200 families including two generations were collected from Barasat in North 24-Parganas, West Bengal. The study includes familial correlations between first-degree relatives and corresponding heritabilities. In the final stage, segregation analyses by the Pedigree Analysis Package (PAP) were conducted on these data to understand the mode of inheritance. RESULTS: The major findings indicated the following: (a) Familial correlations in all possible relationships (except spouse correlation) were statistically significant and of comparable magnitude. (b) The corresponding heritabilities were in the range between 59% for Pattern Intensity Index (PII) and 77% for Total Finger Ridge Count (TFRC). These estimates were in agreement with previously published data on this subject. (c) By segregation analysis, the 'Sporadic', 'Environmental', 'No major gene effect' as well as 'No polygenic component' models were strongly rejected (p < 0.05) and the hypothesis of a major gene's (MG) influence on all studied traits was accepted, though the proportion of MG variance was low. (d) The Most Parsimonious Mendelian model clearly indicated the contribution of a major gene with dominant (for PII) and additive (for two ridge counts) effects. CONCLUSION: The present report supports the evidence of the existence of a major gene on these dermatoglyphic traits and the transmission of this effect is consistent with Mendelian expectation.

Dermatoglyphics↗

PubMed1998

Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study.

BACKGROUND: Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families. METHODS: We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all "normal" offspring were examined by a paediatric cardiologist. FINDINGS: The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring--a recurrence risk of 4.1%. This result differed significantly from sibling risk (2.1%; p=0.021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0.047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0.032). We found an excess of miscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occurred in seven (3.1%) of 223 offspring, 12 (2.2%) of 539 siblings, five (0.3%) of 1575 second-degree relatives, and eight (0.3%) of 2728 third-degree relatives. INTERPRETATION: Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.

Adult↗

PubMed1996

Polymorphism in serotonin transporter gene associated with susceptibility to major depression.

UNLABELLED: BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder. METHODS: A comparison of a polymorphic region of the human serotonin transporter gene was carried out between two groups. The study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar disorder) with major affective disorder. The control group comprised 122 anonymous blood donors, and 71 volunteers who had been screened for psychiatric disorders. FINDINGS: We detected three novel alleles of the variable-number-tandem-repeat (VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies of the VNTR element, respectively. The frequencies of the different forms of the allele in the control group were compared with those in the affective disorder group. There was a significant difference between the control and affective disorder groups, largely explained by the excess of the STin2.9 allele in the unipolar group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele with nine copies of the repeat was significantly associated with risk of unipolar disorder (odds ratio=6.95 [95% CI 1.8-27.2]). INTERPRETATION: This association, for an obvious candidate gene, may provide a critical starting point for an understanding of the likely polygenic contributions towards susceptibility to affective disorder.

Alleles↗

PubMed2002

Kidney cancer in the Swedish Family Cancer Database: familial risks and second primary malignancies.

BACKGROUND: Familial risks in kidney cancer and association with second primary malignancies were studied using the nationwide Swedish Family Cancer Database. METHODS: Cancer data were retrieved from the Swedish Cancer Registry from years 1961 to 1998 and included 23,137 cases of kidney cancer. Standardized incidence ratios (SIRs) were used to measure the cancer risks. RESULTS: Seventy-one families were identified where both a parent and an offspring had kidney cancer, giving a familial risk for offspring of 1.56 (1.22 to 1.95) and population attributable proportion of 0.78%. A risk for kidney cancer from an affected sibling was considerably higher with a SIR of 4.72 (2.28 to 9.20), giving an attributable proportion of 0.77%. The discordant tumor site that was associated with kidney cancer between two generations was hemangioblastoma of central nervous system. Discordant cancer sites that were associated with kidney cancer in siblings were ovaries, endocrine glands and pancreas. There was an over threefold increase of second primary malignancies of the urinary bladder, nervous system and endocrine gland in kidney cancer patients. The risks for second primary hemangioblastoma following kidney cancer or familial kidney cancer was 21.19 (6.69 to 43.83) and 1206 (114 to 3456), respectively. CONCLUSIONS: The high ratio of sibling risk to offspring risk in kidney cancer may reflect a recessive susceptibility. The high risk for second primary cancers in the patients without family history is consistent with a polygenic model and variable degree of environmental modification.

Adolescent↗

PubMed1995

Crosses of NOD mice with the related NON strain. A polygenic model for IDDM.

Chromosome locations of non-major histocompatibility complex (MHC) genes contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD mice to other inbred strains congenic for the NOD MHC haplotype (H2g7). At least nine non-MHC IDDM susceptibility genes (Idd) were previously identified at first backcross (BC1) after outcross of NOD to C57BL/10.H2g7 congenic mice (B10.H2g7). We investigated whether the same set of Idd loci segregated with IDDM susceptibility after outcross of NOD to NON.H2g7 congenic mice. Since the outcrosses to NON.H2g7 and B10.H2g7 were performed in the same vivarium, direct comparisons were made of the chromosomal locations and relative strengths of Idd alleles in diabetic progeny from the two different outcrosses. In comparison with the NOD x B10.H2g7 outcross, the NOD x NON.H2g7 outcross produced significantly higher IDDM frequencies in F1, F2, and BC1 generations. The high F2 diabetes frequency allowed evaluation of the effects of homozygous expression of both the susceptibility and the resistance allele at Idd loci. This analysis demonstrated that no single non-MHC Idd locus was essential for the onset of diabetes in this cross. After outcross to NON.H2g7, Idd4 (chromosome [Chr] 11), Idd5 (Chr 1), and Idd8 (Chr 14) did not segregate with IDDM in either the BC1 or the F2 generation. Diabetogenic NOD-derived alleles at Idd2 (Chr 9), Idd3 (Chr 3), and Idd10 (Chr 3) were segregating in the BC1. An NON-derived allele contributing to susceptibility on Chr 7 (Idd7) was also detected. Dominant traits, detectable only in the F2 cross, were encoded by Chr 4 (Idd9) and two newly mapped loci on Chr 13 (Idd14) and 5 (Idd15). A third dominant trait was encoded by Chr 6 (possibly Idd6), but here, in contrast to Idd9, Idd14, and Idd15, the NON allele was diabetogenic. Stepwise logistic regression analysis of the BC1 and F2 data confirmed that the ability to identify certainty of the non-MHC Idd loci was contingent on the extent of homozygosity for NOD background genes. This study shows that the diabetogenic phenotype can be achieved through the actions of variable combinations of MHC-unlinked genes and a diabetogenic MHC haplotype.

Animals↗

PubMed2003

Genetic markers of disease susceptibility and severity in giant cell arteritis and polymyalgia rheumatica.

BACKGROUND AND OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are common and often overlapping diseases that generally occur in elderly patients. In this article, we examine the role of different genes as markers of disease susceptibility and severity in GCA and PMR. METHODS: The influence of human leukocyte antigen (HLA)-DRB1 and tumor necrosis factor alleles, as well as the different allelic polymorphisms, on the susceptibility and severity to GCA and PMR was examined. A review of the literature was conducted. RESULTS: Most studies have described an association of GCA with HLA-DRB1(*)04 alleles. However, HLA-DRB1 association in patients with PMR varies from one population to another. In Northwest Spain, patients with GCA and PMR exhibited different tumor necrosis factor microsatellite polymorphism associations. Studies of intercellular adhesion molecule-1 biallelic polymorphisms have yielded contradictory results. Interleukin 1 cluster and tumor necrosis factor alpha polymorphisms increased susceptibility to GCA and PMR slightly. In Northwest Spain, interleukin 6 promoter polymorphism at position -174 modulated the phenotypic expression of PMR in biopsy-proven GCA. In the same population, regulated upon activation, normal T cell expressed and presumably secreted gene promoter biallelic polymorphism at position -403 was a marker for PMR susceptibility but not for GCA, and corticotropin-releasing hormone polymorphism appeared to be implicated in the risk of severe ischemic complications in patients with GCA. CONCLUSIONS: The present analysis confirms that GCA and PMR are polygenic diseases. The search for additional genes is necessary to better understand the pathogenesis of these conditions.

Animals↗

PubMed2004

Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension.

BACKGROUND: The CYP4A11 arachidonic acid monooxygenase oxidizes endogenous arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite with renovascular and tubular functions. Mice with targeted disruption of Cyp4a14, a murine homologue of CYP4A11, have severe hypertension. We combined molecular and biochemical approaches to identify a functional variant of the CYP4A11 20-HETE synthase and determine its association with hypertensive status in 2 independent human populations. METHODS AND RESULTS: A thymidine-to-cytosine polymorphism at nucleotide 8590 resulted in a phenylalanine-to-serine substitution at amino acid 434. Expression of cDNA with serine 434 resulted in a protein with a significantly reduced AA and lauric acid metabolizing activity. In a population of 512 whites from Tennessee, the age, body mass index, and gender-adjusted OR of having hypertension attributable to the 8590C variant was 2.31 (95% CI 1.41 to 3.78) compared with the reference 8590TT genotype. In subjects from the Framingham Heart Study, the adjusted ORs of hypertension associated with the 8590C variant were 1.23 (CI 0.94 to 1.59; n=1538) in all subjects and 1.33 (CI 1.01 to 1.77; n=1331) when subjects with diabetes were excluded. No association of the variant with hypertension was detected in a population of 120 blacks. CONCLUSIONS: We identified a variant of the human CYP4A11 (T8590C) that encodes for a monooxygenase with reduced 20-HETE synthase activity. The association of the T8590C variant with hypertension supports its role as a polygenic determinant of blood pressure control in humans, and results obtained from the large population database suggest that the relevance of the variant may vary according to hypertension comorbidity.

Adult↗

PubMed2026

From gut to pancreas: Shared genetic susceptibility and biological convergence in acute pancreatitis and Crohn's disease.

BACKGROUND: Acute pancreatitis (AP) and Crohn's disease (CD) exhibit overlapping clinical presentations and an unexpectedly high rate of comorbidity. Whether this reflects shared genetic susceptibilities remains unclear. METHODS: We performed a cross-trait genome-wide association analysis leveraging European-ancestry summary statistics for AP (Ncases = 8446; Ncontrols = 437,418) and CD (Ncases = 12,194; Ncontrols = 28,072). Firstly, cross-trait genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Secondly, to pinpoint specific pleiotropic loci and prioritize candidate genes, we employed PLACO under a rigorous composite null hypothesis, integrated with Bayesian colocalization and SMR/HEIDI analyses. Finally, we dissected the underlying biological context by mapping tissue-specific regulatory enrichment and pathway convergence using FUMA, MAGMA, and Stratified LD Score Regression (S-LDSC). RESULTS: AP and CD showed significant positive genetic correlation (LDSC: rg = 0.178, SE = 0.079, P = 0.025; HDL: rg = 0.294, SE = 0.096, P = 0.0021). Pleiotropy analyses revealed 86 SNPs and 6 independent genome-wide significant pleiotropic loci (lead variants at 5q33.1, 6q22.33, 7q34, 10q24.2, 15q22.33 and 19q13.11, PPLACO < 5 × 10-8). Colocalization showed suggestive evidence of a shared causal signal at 6q22.33 (PP4 = 0.666). Gene-based tests of the AP-CD cross-trait statistics prioritized eight pleiotropic genes-RSPO3, ATG16L1, SMAD3, FADS1, ZPBP2, FADS2, PRKAA1 and IRGM. Gene-set analyses highlighted IL-23/Th17-related and broader inflammatory response pathways. CONCLUSIONS: AP and CD share polygenic susceptibility and converge on immune and inflammatory processes, with prioritized genes pointing to autophagy, lipid metabolism and TGF-β/SMAD-related biology.

Humans↗

PubMed2005

Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays.

BACKGROUND: The differential pathophysiologic mechanisms that trigger and maintain the two forms of inflammatory bowel disease (IBD), Crohn disease (CD), and ulcerative colitis (UC) are only partially understood. cDNA microarrays can be used to decipher gene regulation events at a genome-wide level and to identify novel unknown genes that might be involved in perpetuating inflammatory disease progression. METHODS AND FINDINGS: High-density cDNA microarrays representing 33,792 UniGene clusters were prepared. Biopsies were taken from the sigmoid colon of normal controls (n = 11), CD patients (n = 10) and UC patients (n = 10). 33P-radiolabeled cDNA from purified poly(A)+ RNA extracted from biopsies (unpooled) was hybridized to the arrays. We identified 500 and 272 transcripts differentially regulated in CD and UC, respectively. Interesting hits were independently verified by real-time PCR in a second sample of 100 individuals, and immunohistochemistry was used for exemplary localization. The main findings point to novel molecules important in abnormal immune regulation and the highly disturbed cell biology of colonic epithelial cells in IBD pathogenesis, e.g., CYLD (cylindromatosis, turban tumor syndrome) and CDH11 (cadherin 11, type 2). By the nature of the array setup, many of the genes identified were to our knowledge previously uncharacterized, and prediction of the putative function of a subsection of these genes indicate that some could be involved in early events in disease pathophysiology. CONCLUSION: A comprehensive set of candidate genes not previously associated with IBD was revealed, which underlines the polygenic and complex nature of the disease. It points out substantial differences in pathophysiology between CD and UC. The multiple unknown genes identified may stimulate new research in the fields of barrier mechanisms and cell signalling in the context of IBD, and ultimately new therapeutic approaches.

Adolescent↗

PubMedDate not supplied

Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients.

BACKGROUND: Many genetic diseases are caused by mutations in ion channel genes. Because type 2 diabetes is characterized by pancreatic beta-cell insensitivity to glucose, the genes responsible for glucose metabolism and calcium signaling in pancreatic beta-cells are candidate type 2 diabetes susceptibility genes. METHODS: We have examined genomic variations in two ion channel genes relevant to the molecular pathology of diabetes mellitus, the Kir6.2 subunit of the ATP-sensitive potassium channel gene and alpha(1D) subunit of the voltage-dependent calcium channel (VDCC) gene among Japanese type 2 diabetic patients. RESULTS: There are two alleles in the Kir6.2 gene: EI, glutamic acid at codon 23 and isoleucine at codon 337 and KV, lysine at codon 23 and valine at codon 337. The allelic frequencies of these polymorphisms are similar in type 2 diabetic patients and normal subjects. We also detected trinucleotide repeat polymorphisms in the amino terminus and the carboxyl terminal region of the alpha(1D) gene. Expansion of the ATG trinucleotide repeat from seven to eight was detected only in type 2 diabetic patients, but the frequency was low and was similar in type 2 diabetic patients and normal subjects. CONCLUSIONS: Although variations of the Kir6.2 and alpha(1D) genes are not associated with the development of common type 2 diabetes, further studies may determine the role of these genomic variations, especially those in the alpha(1D) VDCC gene, in the pathogenesis of certain subsets of type 2 diabetes, or as a co-factor in the polygenic disorder generally.

Alleles↗

PubMed2025

Genetic Landscape of Opsoclonus-Myoclonus-Ataxia Syndrome in Children.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder, with involuntary rapid saccadic conjugate eye movements as one of characteristics, primarily affecting the cerebellum. While the exact pathogenesis remains unclear, genetic and autoimmune factors have been suggested to contribute to its development. METHODS: We enrolled patients diagnosed with OMAS before the age of 18 years at a pediatric neuroimmunology clinic in Boston, United States, using the 2004 Genoa Criteria. Whole genome sequencing was conducted for the patients and their biological parents in all cases, with one case including an unaffected twin sibling. RESULTS: De novo germline variants (DNVs) in probands were identified and validated and analyses of structural variants, recessive variants in neuroimmune-associated genes, and high-resolution human leukocyte antigen (HLA) typing were performed. Our study included 42 patients, 23 of whom had neuroblastoma. We found 12 confirmed DNVs in protein-coding regions in nine patients (29.0% of 31 from 30 trios and 1 quartet). Ten patients (23.8% of 42) had rare homozygous or compound heterozygous variants known to alter protein function, affecting 11 genes. Notably, the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) ∗01 allele was observed in 27 out of 84 (32.1%) alleles in the patients, significantly higher than that in the general population (chi-square test, P < 0.0001). In one case, a potential genetic modifier of OMAS with severe cerebellar atrophy was identified, associated with a protein-truncating DNV in the CACNA2D2 gene. CONCLUSIONS: This first genome sequencing study reveals potential genetic contributors to OMAS, implicating polygenic predisposition-with HLA-DRB1∗01 as a possible factor-combined with nongenetic risk factors like neuroblastoma.

Humans↗