Characterisation of the Novel HLA-B*40:01:02:68Q Allele by Sequencing-Based Typing.
HLA-B*40:01:02:68Q differs from HLA-B*40:01:02:01 by one nucleotide substitution in intron 2 at the splice site with exon 3.
Humans↗
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Identification of the HLA-A*11:01:01:97 Allele in an Individual From a Western India Kshatriya Family From Maharashtra.
HLA-A*11:01:01:97 differs from HLA-A*11:01:01:01 by a single nucleotide position gDNA 1247 T > A within Intron 3.
Humans↗
Characterisation of the Novel HLA-DPA1*02:164 Allele Identified by Next Generation Sequencing.
HLA-DPA1*02:164 differs from HLA-DPA1*02:02:02:01 by a non-synonymous nucleotide substitution in exon 3 and an intronic nucleotide substitution in intron 1.
Humans↗
A New Allele HLA-DQB1*06:02:01:42 Identified by HLA-Targeted Third-Generation Sequencing in a Chinese Individual.
HLA-DQB1*06:02:01:42 differs from HLA-DQB1*06:02:01:01 by one nucleotide change in intron 1.
Humans↗
Characterisation of 41 Novel HLA Alleles Identified in UK Haematopoietic Cell Transplant Donors.
PacBio's single molecule real-time sequencing identifies 41 novel classical and non-classical HLA alleles.
Humans↗
Biological role of interleukin 1 receptor antagonist isoforms.
The interleukin 1 receptor antagonist (IL1Ra) family of molecules now includes one secreted isoform (sIL1Ra) and three intracellular isoforms (icIL1Ra1, 2, and 3). Extensive evidence indicates that the sole biological function of sIL1Ra seems to be to competitively inhibit IL1 binding to cell-surface receptors. Although intracellular IL1Ra1 may be released from keratinocytes under some conditions, the intracellular isoforms of IL1Ra may carry out additional as yet poorly defined roles inside cells. Maintenance of a balance between IL1 and IL1Ra is important in preventing the development or progression of inflammatory disease in certain organs. Both the secreted and intracellular isoforms of IL1Ra contribute to maintenance of this balance. An allelic polymorphism in intron 2 of the IL1Ra gene (IL1RN*2) predisposes to the development or severity of a variety of human diseases largely of epithelial cell origin. Both the impaired production of IL1Ra and the overproduction of IL1beta are related to the presence of this allele. Restoration of the balance between IL1Ra and IL1 through a variety of approaches is a therapeutic goal in specific chronic inflammatory diseases.
Animals↗
An association between arterial pulse pressure and variation in the fibrillin-1 gene.
OBJECTIVE: To investigate whether variation in the fibrillin-1 gene was associated with blood pressure in healthy middle aged men, as had been observed in patients with abdominal aortic aneurysm. DESIGN, SETTING, AND PATIENTS: Middle aged men (n = 245), aged 50 to 61 years, were recruited from one of the nine general practices participating in the second Northwick Park heart study. Blood samples were obtained for the preparation of genomic DNA and analysis of plasma variables. MAIN OUTCOME MEASURES: Systolic, diastolic, and pulse pressures; fibrillin-1 genotype characterised with a four allele variable tandem nucleotide repeat polymorphism in intron 28. RESULTS: In healthy middle aged men only three common genotypes were observed: 2-2 (frequency 54.1%), 2-3 (16%) and 2-4 (15%). The mean arterial systolic (and pulse) pressure varied according to fibrillin-1 genotype: 2-4 genotype, 126-3 (47.6) mm Hg; 2-2 genotype, 131.0 (51.3) mm Hg; and 2-3 genotype, 135.5 (54.2) mm Hg. The median pulse pressure was 50 mm Hg. Distribution of men around the median pulse pressure, according to genotype, showed a significant trend for patients of 2-4 genotype to have the lowest pulse pressures, those of 2-2 genotype to have intermediate pressures, and those of 2-3 genotype to have the highest pulse pressures (p = 0.003 for healthy men). CONCLUSIONS: There appears to be a significant association between fibrillin-1 genotype and arterial pulse pressure in men aged 50 to 61 years.
Alleles↗
Alternative splicing, genomic structure, and fine chromosome localization of REV3L.
We have localized a human homolog, REV3L, of the Saccharomyces cerevisiae REV3 gene on chromosome region 6q21. The full-length cDNA consists of 10,919 nucleotides, with a putative open reading frame of 9,159 bp for a predicted protein of 3,053 amino acids. The gene contains 33 exons in about 200 kb of genomic DNA. In contrast to the previously reported sequence, an additional exon and an alternative splicing site are demonstrated.
Alternative Splicing↗
Interleukin-1 receptor antagonist expression in human endothelial cells and atherosclerosis.
The proinflammatory cytokine interleukin (IL)-1 is expressed mainly within the endothelium of atherosclerotic plaques and may be linked with inflammatory mechanisms of atherogenesis. IL-1 action is complex and regulated in part by its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1ra). Therefore, we studied differential and specific isoform expression of IL-1ra in the endothelium of diseased coronary arteries and in endothelial cells (ECs) stimulated under defined conditions. In view of an association with IL-1ra gene (IL-1RN) polymorphism, the influence of endothelial cell genotype at IL-1RN on IL-1ra protein production was also examined. Secreted IL-1ra and intracellular IL-1ra mRNAs were detected by semiquantitative reverse transcription-polymerase chain reaction in human atherosclerotic and dilated cardiomyopathic coronary arteries; protein expression appeared increased in atherosclerotic compared with dilated cardiomyopathic arteries, where IL-1ra appeared to be confined to the endothelium. Only intracellular IL-1ra type I mRNA was detected in human umbilical vein ECs (HUVECs) and human coronary artery ECs (HCAECs) when they were stimulated with bacterial lipopolysaccharide/phorbol myristate acetate and transforming growth factor-beta. IL-1beta and IL-1alpha were without effect. IL-1ra protein was detected in HUVECs (intracellular IL-1ra), HCAECs (intracellular IL-1ra), and human coronary artery smooth muscle cells (intracellular IL-1ra) by immunoprecipitation and Western blot. IL-1ra was detected in HUVEC cell lysates by ELISA and appeared to be influenced by the genotype of the IL-1RN variable number tandem repeat, an 86-bp repeat polymorphism in intron 2 of the IL-1ra gene, with lower levels of IL-1ra produced by IL-1RN allele 2-containing cells (ratio of IL-1ra to total protein: for 1,1 homozygotes, 1.38+/-0.28x10(-9) [n=15]; for 1,2 heterozygotes, 0.81+/-0.17x10(-9) [n=8]; and for 2,2 homozygotes, 0.63+/-0.19x10(-9) [n=5]; P<0.05 compared with 1,1 homozygotes). This is the first demonstration of IL-1ra in human diseased arteries, stimulated HUVECs, and HCAECs and indicates the endothelial cell as an important source. Endothelial IL-1ra production may be controlled by the endothelial IL-1RN genotype. These data further support the role of the IL-1 system of cytokines in the pathogenesis of atherosclerosis.
Arteriosclerosis↗
Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis.
To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n = 103) and control subjects (n = 103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-TT genotype (T indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (P < .05). The ACE-DD genotype (D indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (P < .0001). The odds ratio estimated by the combined analysis of the angiotensinogen-TT and ACE-DD genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-TT (1.75) or ACE-DD (4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-TT genotype did not enhance the predictability of myocardial infarction from the ACE-DD genotype. In conclusion, the angiotensinogen-TT genotype is a predictor for myocardial infarction, as well as the ACE-DD genotype, and the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.
Angioplasty, Balloon, Coronary↗
Association and linkage analyses of glucocorticoid receptor gene markers in essential hypertension.
Suggestive evidence has been obtained in a "4-corners" study for involvement of the glucocorticoid receptor gene (GRL) in genetic variation in blood pressure. Therefore, we tested markers at the GRL locus for association and linkage with essential hypertension (HT). For the association study, we used a well-characterized group of 129 white Australians of Anglo-Celtic extraction who had HT, a strong family history of HT (2 parents with the disease), and early-onset moderate-to-severe disease. Controls were 195 normotensive white subjects whose parents were normotensive past the age of 50 years. For the linkage study, we used 175 sibling pairs of similar ancestry. The case-control groups were genotyped for an Asn363Ser variant in exon 2, a G/T variant in intron 4, and a microsatellite marker (D5S207) tightly linked (<200 kb) to GRL. For the groups as a whole, no association or linkage was observed after analysis of data by a variety of statistical tests. Analysis of sibling-pair data gave an exclusion score of -3.8 for the logarithm of the odds for linkage, indicating significant nonlinkage. However, in females, weak association of the intron 4 polymorphism with HT (P=0.03), as well as with systolic and diastolic blood pressure in all subjects (P=0. 04 and 0.03), was observed, and in the case of the D5S207 marker, association with HT was apparent in males (P=0.0001). Thus, although our results provide no overall support for GRL in HT etiology, apparent gender-specific associations could exist in this genomic region, possibly reflecting correlated occurrence with (an)other metabolic syndrome disorder(s).
Age of Onset↗
Tumor necrosis factor-alpha -308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer's lung patients.
Hypersensitivity pneumonitis (HP) represents an immunologic reaction of the pulmonary parenchyma to an inhaled agent. Since tumor necrosis factor (TNF)-alpha is thought to be involved in the pathogenesis of HP, and polymorphisms in the TNF genes have been associated with variations in the production of TNF-alpha, we investigated the serum bioactivity and genotype of TNF in HP. TNF bioactivity was measured after hay dust challenge in eight patients with farmer's lung (Group A) and in 12 healthy, sensitized (antibody-positive) controls (Group B). Genotyping for the -308 TNF-alpha promoter polymorphism and the TNF-beta intron 1 gene polymorphism was performed in 20 patients with farmer's lung, 25 patients with pigeon breeder's lung, and 216 controls. TNF bioactivity increased in Group A at 4 to 10 h after hay dust challenge, but not in Group B (p < 0.05). The frequency for the TNFA2 allele, a genotype associated with high TNF-alpha production in vitro, was significantly higher in farmer's lung patients (frequency [f] = 0.43, p = 0.0012) than in controls (f = 0.19) or patients with pigeon breeder's lung (f = 0.16). Genotyping for TNF-beta revealed no significant abnormalities. Thus, increased production of TNF-alpha after hay contact, and a genetic predisposition to TNF-alpha production, are implicated in the pathogenesis of alveolitis in farmer's lung.
Adult↗
Effects of sex and of gene variants in constitutive nitric oxide synthases on exhaled nitric oxide.
Genetic factors may contribute to the variability of exhaled nitric oxide in healthy individuals. We studied exhaled nitric oxide and genetic variants in both neuronal and endothelial nitric oxide synthases in 105 healthy nonsmoking and smoking subjects. Genomic DNA was screened for a repeat polymorphism in intron 20 of the neuronal nitric oxide synthase gene and for the 894G/T mutation of the endothelial nitric oxide synthase gene. Exhaled nitric oxide was significantly higher in males than females among both nonsmokers (p < 0.0001) and smokers (p = 0.003). No association was found between exhaled nitric oxide and the endothelial nitric oxide synthase gene variant. However, healthy nonsmoking females with greater numbers of repeats (i.e., both alleles with 12 or more repeats) in neuronal nitric oxide synthase had significantly lower nitric oxide levels than did females with fewer numbers of repeats (i.e., at least one allele with fewer than 12 repeats) (13.6 +/- 1.6 versus 19.4 +/- 1.6 ppb, p = 0.02). No association was found between exhaled nitric oxide and neuronal nitric oxide synthase genotype in males. These data suggest that variants in the neuronal nitric oxide synthase gene contribute to the variability of airway nitric oxide concentrations in healthy females.
Adolescent↗
Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes.
BACKGROUND: Elevated white blood cell counts (WBC) in acute coronary syndromes (ACS) increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP) in an ACS population. METHODS: WBC and genotype of interleukin 6 (IL-6 G-174C) and of interleukin-1 receptor antagonist (IL1RN intronic repeat polymorphism) were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event. RESULTS: An increased white blood cell count (WBC) was associated with an increased C-reactive protein (r = 0.23, p < 0.001) and there was also a positive correlation between levels of beta-fibrinogen and C-reactive protein (r = 0.42, p < 0.0001). IL1RN and IL6 genotypes had no significant impact upon WBC. The difference in median WBC between the two homozygote IL6 genotypes was 0.21/mm3 (95% CI = -0.41, 0.77), and -0.03/mm3 (95% CI = -0.55, 0.86) for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p = 0.61) or IL6 (p = 0.48) genotype. CONCLUSIONS: Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients.
Acute Disease↗
Molecular study of the 3 beta-hydroxysteroid dehydrogenase gene type II in patients with hypospadias.
To determine whether some patients with idiopathic hypospadias have HSD3B2 mutations, we genotyped this locus in 90 patients with hypospadias (age, 6.0 +/- 0.4 yr) and 101 healthy fertile male controls. We measured basal plasma renin activity and performed an ACTH test for determination of 17-OH-pregnenolone, 17-OH-progesterone, cortisol, dehydroepiandrosterone sulfate, and androstenedione and an human chorionic gonadotropin test for determination of androstenedione, testosterone, and dihydrotestosterone. We did not observe a clear steroidogenic pattern suggestive of 3 beta-HSD deficiency in any patient. DNA was extracted from peripheral lymphocytes; and exons 1, 2, 3, and 4 were amplified by PCR and analyzed by denaturing gradient gel electrophoresis. An abnormal electrophoretic migration pattern of exon 4 was observed in five patients. Two patients had missense heterozygous mutations (S213T and S284R). In another three patients, we observed heterozygous nucleotide variants in exon 4 that did not produce a change in amino acids (A238, T259, T320). In vitro enzymatic activity was diminished by 40% and 32% in the S213T and S284R heterozygous mutations, respectively. One control exhibited a heterozygous mutation in exon 3 (V78I), which did not alter in vitro enzyme activity. In addition, we observed possible polymorphisms in intron 1 in four patients and one control. We conclude that subtle molecular abnormalities in the HSD3B2 gene may be observed in some patients with apparent idiopathic hypospadias but that this finding is uncommon.
3-Hydroxysteroid Dehydrogenases↗
Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene.
CONTEXT: Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown. OBJECTIVE: Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism. DESIGN: We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus. PARTICIPANTS: Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband. MAIN OUTCOME MEASURES: We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype. RESULTS: The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001). CONCLUSIONS: Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.
Aldosterone↗
Association between dopamine receptor genes and migraine without aura in a Sardinian sample.
BACKGROUND: Migraine seems to be caused by a combination of environmental and genetic factors. Clinical and pharmacologic evidence supports the hypothesis that dopaminergic transmission is involved in the pathogenesis of migraine. OBJECTIVE: The current report concerns a genetic study to test the involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity. METHODS: For the first time, a family-based association method--the Transmission Disequilibrium Test (TDT)--was used to examine an isolated population, such as Sardinians. We studied 50 nuclear families of patients affected by migraine without aura. The subgroup of dopaminergic migraineurs was selected based on the presence of both nausea and yawning immediately before or during the pain phase of migraine. RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup. No difference was observed in DRD2 allelic distribution in the overall sample, although the allelic distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02). CONCLUSIONS: Our data suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients.
Adolescent↗
Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis.
In this report, we present an asymptomatic infant, seen for a second opinion, who was given the diagnosis of cystic fibrosis (CF) as a neonate based on the presence of two mutant alleles, DeltaF508 and R117H. The diagnosis of CF adversely affected the family's emotional, employment, and financial statuses. Our evaluation included sweat chloride, nasal transepithelial potential difference, and bronchoscopy with bronchoalveolar lavage measurements, all which were consistent with findings expected from an individual without CF. Genotype analysis for the sequence polymorphism in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene revealed the 7 thymidines and 9 thymidines alleles. We conclude that this patient probably expresses enough epithelial cell surface CFTR function such that she has a normal phenotype. Based on our evaluation, she does not meet the current diagnostic criteria for CF. Although genotype analysis can be an useful adjunct, it should not be the sole diagnostic criterion for CF.
Chlorides↗