Biomedical subjects

K I Welsh

Publications and source records attributed to K I Welsh.

At least 55 records · Page 3Linked to original sources

PubMed2000

Selective omission of the donor cross-match before renal transplantation: efficacy, safety and effects on cold storage time.

BACKGROUND: A donor lymphocyte cross-match (XM) test performed before renal transplantation is considered mandatory but may delay the transplant and increase the cold storage time. With careful documentation of sensitizing events and with knowledge of previous antibody screening results, it is often possible to predict the XM result for a given donor HLA mismatch. In this study, a policy was adopted of omitting the pretransplant XM in patients in whom a negative result was predicted with absolute confidence. METHODS: Recipients were selected for cadaveric donor kidney transplantation using a computer algorithm based on HLA match, sensitization status, time on the waiting list and donor and recipient age. The immediate pretransplant cross-match test was omitted in non-sensitized recipients and in sensitized recipients where antibody specificities were precisely defined and not against donor HLA. RESULTS: From October 1997 to May 1999, 53 of 96 (55%) consecutive cadaveric kidney donor transplants were performed without a pretransplant XM. In all cases, a negative donor HLA-specific antibody XM was confirmed after transplantation. Omission of the pre-transplant XM was associated with a significant reduction in cold ischemic time (15.0 hr vs. 18.2 hr, P=0.01) and a reduced incidence of delayed graft function (13% vs. 33%, P=0.03). However, there was no difference in transplant outcome at 1 year. CONCLUSION: Rigorous attention to priming events together with careful antibody screening allows the pre-transplant XM test to be safely omitted in approximately half the patients awaiting renal transplantation. This policy allows a modest reduction in cold ischemia time, but it remains to be seen whether this is of clinical benefit.

Adult↗

PubMed2000

p53 codon 72 polymorphism and susceptibility to skin cancer after renal transplantation.

BACKGROUND: Infection with human papillomavirus (HPV) is an important risk factor for the development of skin cancer after renal transplantation. It has recently been suggested that degradation of the tumor suppressor gene p53 is an important mechanism for human papillomavirus-induced carcinogenesis. A common genomic polymorphism occurs at codon 72 of the p53 gene, and in vitro the codon 72Arg variant appears to be particularly susceptible to degradation. METHODS: To test the hypothesis that this polymorphism predisposes to the development of human papillomavirus-associated tumors, we studied p53 codon 72 genotype in 222 long-term survivors of renal transplantation, of whom 55 had developed at least one skin tumor. RESULTS: No differences in allele or genotype frequency were detected between individuals who had or had not developed skin tumors after transplantation, or any subgroup thereof. CONCLUSIONS: The p53 codon 72Arginine allele does not confer susceptibility to the development of skin tumors after renal transplantation.

Alleles↗

PubMed2000

Identification of novel Tapasin polymorphisms and linkage disequilibrium to MHC class I alleles.

Tapasin is a Mr 48,000 glycoprotein and has a specialized role in MHC class I-restricted antigen presentation. It is encoded by a gene which maps centromeric to the MHC class II region of human Chromosome 6 within 200 kb of HLA-DP. There is variable dependence upon tapasin for MHC class I expression among different MHC class I alleles. HLA-B*4402 and to a lesser extent HLA-A1 and B8 are tapasin dependent, whereas HLA-B27, A2 and to a lesser extent B7 and A3 are tapasin independent. We investigated whether tapasin is polymorphic and whether these Tapasin alleles are in linkage with any MHC class I alleles. We identified three new mutations within intron 4, which are in a particular linkage with the previously described exon 4 (G16003C) dimorphism. The intronic mutations are G16146T, G16232A, and T16317A (numbering according to cosmid clone F0811; GenBank accession number Z97184). The allele frequency of Tapasin*01 (G16003) was 0.47 and Tapasin*02 (C16003) was 0.53 in this UK population. Four of the eight possible intronic haplotypes were identified and their cis linkage with the tapasin dimorphism ascertained. Tapasin*01 was associated with all the identified haplotypes, while Tapasin*02 was only associated with the wild-type intronic sequence (GGT). There was no significant linkage (P>0.01) of the Tapasin dimorphism or new Tapasin alleles to any of the MHC class I A, B, or C alleles studied or to the extended A1 B8 DR3 haplotype.

Adult↗

PubMed2000

Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.

BACKGROUND & AIMS: The detection of phenotype-determining genes as opposed to disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HLA-B*27-related spondyloarthropathies by the European Spondyloarthropathy Study Group. However, previous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classification that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spondyloarthropathies. METHODS: IBD patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were identified by case note review and questionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multiple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenteric reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS). RESULTS: Type 1 arthropathy was associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0. 001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger and an association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101. CONCLUSIONS: These data suggest that the clinical classification into type 1 and type 2 arthropathies describes immunogenetically distinct entities and establish that in polygenic disorders, genes may determine clinical phenotype without conferring overall disease susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and immunogenetically similar to the spondyloarthropathies, but different HLA associations may define phenotypically distinct groups. Type 2 arthropathy has different HLA associations and may have a different etiology. Further studies are now required to confirm these associations and to elucidate the different pathogenetic mechanisms.

Colitis, Ulcerative↗

PubMed2000

Identification of the null HLA-A2 allele, A*0232N.

We have identified a null HLA-A*02 allele, HLA-A*0232N, by using a combination of serology, flow cytometry, polymerase chain reaction using sequence-specific primers (PCR-SSP) and full-length sequencing. The null HLA-A2 allele was identified in an Asian individual originally typed by serology as an apparently homozygous HLA-A3, B51. Subsequent genotyping by PCR-SSP identified the genotype as HLA-A*0201, *0301, B*51, Cw*1402. The serological type and lack of detectable HLA-A2 was confirmed using monoclonal antibody typing reagents. Flow cytometry studies failed to identify any cell surface HLA-A2 expression on the patient's peripheral blood lymphocytes. Genotyping using a PCR-SSP set designed to detect null alleles revealed the mutation had not been previously described. Full-length sequencing of the allele identified an allele which was subsequently named HLA-A*0232N. This allele is identical to HLA-A*0201 except for a novel point mutation (T for C) at position 493 which creates a premature stop codon. The sequencing enabled the development of a monospecific A*0232N PCR-SSP reaction which was used to screen 973 DNA samples: no further examples of A*0232N were identified.

Alleles↗

PubMed2000

Identification of a new HLA-B39 allele: HLA-B3924.

We have identified a new HLA-B*39 allele through polymerase chain reaction (PCR) using sequence-specific primers (SSP) and sequence-based typing of exons 2 and 3. This novel allele was identified in three HLA-identical siblings of Turkish origin. This allele only differs from HLA-B*3903 at a unique single nucleotide substitution (T for C) at position 365 in exon 3 which results in an amino acid change in codon 98 of methionine (ATG) to threonine (ACG). The sequencing enabled the development of a monospecific PCR-SSP reaction which can be used to discriminate between HLA-B*3924 and other B*39 alleles.

Alleles↗

PubMed2000

Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies.

The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNF alpha), lymphotoxin-alpha (LT alpha) and interleukin-10 (IL-10) genes on stimulated TNF alpha and IL-10 production was studied in ulcerative colitis (UC) patients, Crohn's disease (CD) patients and in healthy controls. A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF alpha, LT alpha and IL-10 genes. Production of the TNF alpha and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNF alpha gene, three haplotypes of LT alpha and three haplotypes of IL-10 were identified. No significant differences in haplotype frequencies were found between patients and controls overall. On subgroup analysis however, haplotype TNF-2 was more frequent in women with extensive colitis compared to distal colitis (31% vs 12%; P = 0.028). This difference was even greater for the combined TNF-2-LT alpha-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LT alpha-2 haplotypes were associated with higher TNF alpha production in CD patients, and the TNF-4 haplotype was associated with lower TNF alpha production in UC patients. The A allele in the IL-10 promoter region at position -1082 was associated with decreased IL-10 production in CD patients and controls (P = 0.005, P = 0.015 respectively). These data provide evidence that the effect of TNF alpha, LT alpha and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls.

Adolescent↗

PubMed2000

Is interleukin-6 important in inflammatory bowel disease?

The IL-6 gene maps to an area of chromosome 7 known to be significant for susceptibility to inflammatory bowel disease. The functional effects of interleukin-6 (IL-6) polymorphisms in the 4th intron and in the 3' flanking region of IL-6 gene were studied in 192 inflammatory bowel disease patients and healthy subjects. A polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to determine a G to A polymorphism (* at position 4470 in intron 4 of IL-6 gene). Four alleles in the 3' flanking region were studied using a variable number of tandem repeats PCR (VNTR-PCR) amplification. Production of IL-6 was measured in lipopolysaccharide (LPS) stimulated whole blood samples by an enzyme-linked immunosorbent assay (ELISA). A modest increase in the frequency of the IL-6*G allele was noted in Crohn's disease (CD) patients (50%) and ulcerative colitis (UC) patients (46.1%) as compared to controls (39.8%, P = 0.025). We were unable to find any significant functional effect of the IL-6 polymorphisms tested on IL-6 protein production. We postulate that the IL-6 polymorphisms investigated here may be in linkage disequilibrium with a susceptibility gene and that they may be utilised as genetic markers.

Adolescent↗

PubMed2000

Interleukin-10 gene promoter polymorphism in English and Polish healthy controls. Polymerase chain reaction haplotyping using 3' mismatches in forward and reverse primers.

A polymerase chain reaction with sequence-specific primers (PCR-SSP) system using primers with mismatches at the 3' ends was developed to determine polymorphisms in IL-10 promoter region. Three previously described biallelic polymorphisms in IL-10 were linked in a 12 reaction PCR-SSP system and the method used to provide genotype data on 233 UK and 166 Polish controls. There are eight possible polymorphic combinations in IL-10 promoter gene but only three were observed in both control groups. Population frequencies of IL-10 genotypes show, in contrast to HLA, that UK and Polish frequencies are remarkably similar.

Alleles↗

PubMed2000

Identification of four novel interleukin-13 gene polymorphisms.

The development of allergic asthma is thought to involve environmental and inherited genetic components and has pathophysiological features reflecting in part the activity of T cell cytokines. Interleukin-13, a product primarily of activated lymphocytes, is considered to be a critical effector molecule in allergic airway response and has been found to be overexpressed in the airways of patients with asthma. The IL-13 gene is located on chromosome 5q31, one of the major loci to be linked to asthma susceptibility, and amongst a cluster of genes which dominate the immunopathology of allergic disease. Recently, an IL-13 promoter polymorphism was found to be associated with allergic asthma. In the present study we report the identification of four novel biallelic polymorphisms in the IL-13 gene, two intronic and two exonic, one of which results in a basic to hydrophilic amino acid change. We characterised the frequencies of these four biallelic polymorphisms and the frequencies of the haplotypes, resulting from the combination of these four biallelic polymorphisms, in a population of 196 UK Caucasoid healthy individuals.

Alleles↗

PubMed2000

Mannose-binding lectin promoter and structural gene variants in sarcoidosis.

BACKGROUND: Sarcoidosis is a chronic granulomatous disease of unknown aetiology. Studies have suggested that the causative agent may be an infectious micro-organism. The mannose binding lectin (MBL) is involved in innate immunity to a wide range of micro-organisms. Mutations in the promoter region and exon 1 of the MBL gene occur with high frequency and are associated with reduced serum levels of MBL and increased susceptibility to microbial diseases. This study investigated whether MBL variants predispose to sarcoidosis by increasing their susceptibility to micro-organisms. METHODS: MBL gene promoter and exon 1 variants were detected by sequence specific primer polymerase chain reaction (SSP-PCR) in 167 UK Caucasian sarcoidosis patients and 164 control subjects. Severity of pulmonary disease outcome among patients was assessed by radiography after a minimum of 4 years from disease onset and classified as mild, moderate, and severe disease categories, accordingly. RESULTS: MBL variant frequencies were similar in patients and controls studied. Among sarcoidosis patients, the frequencies of variants were similar regardless of severity of disease outcome. The average patient ages at time of diagnosis were similar for all MBL genotypes. CONCLUSIONS: MBL gene variants do not appear to influence susceptibility to sarcoidosis, age of disease onset, or severity of disease.

Adolescent↗

PubMed2000

Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency.

Mannose binding lectin (MBL) is an important component of the innate immune response. Low producing MBL alleles are associated with an increased risk of infection, especially when adaptive immunity is already compromized. We investigated the role of MBL polymorphism in common variable immunodeficiency (CVID), a disease of unknown aetiology characterized by defective humoral immunity, recurrent infections and highly variable clinical phenotype. Six biallelic single nucleotide polymorphisms in the MBL promoter and coding region (- 550, - 221, + 4, codons 52, 54 and 57) were haplotyped using a novel PCR-SSP method in 163 CVID patients and 100 controls. Low producing coding alleles and promoter haplotypes were associated with early age of disease onset. The mean age of disease onset was 14.5 years in patients with low producing MBL coding alleles, compared with 25 years in patients with wild type coding regions (t-test P = 0.002). Mean age of onset in patients with the low producing LXPA haplotype was 6.8 years, compared with 29.3 years for the HYPA haplotype (P = 0.003). The MBL + 4 Q allele was associated with autoimmune disease (P = 0.003, OR 4.4). These results suggest that MBL deficiency compounds the antibody deficiency in CVID, and reinforces the ostensible role of MBL in innate immunity. MBL deficiency may also facilitate the development of autoimmune disease in CVID.

Adolescent↗

PubMed2000

Chronic allograft failure in human renal transplantation: a multivariate risk factor analysis.

OBJECTIVE: To identify potential risk factors for the development of chronic renal allograft failure. SUMMARY BACKGROUND DATA: Chronic allograft failure (CAF) is the leading cause of late graft loss in renal transplantation. The authors studied the risk factors for the development of CAF in a single center during a period in which a consistent baseline immunosuppression regimen (cyclosporine, azathioprine, and prednisolone) was used. METHODS: Data from the Oxford Transplant Center Database were assessed on 862 renal allografts during a 10-year period. Risk factors were identified using multivariate logistic regression analysis. RESULTS: Biopsy-proven CAF occurred in 77 patients (9.2%) in the entire group. Multivariate risk factor analysis revealed that early and late acute rejection episodes, proteinuria, and serum triglycerides were significant factors. Acute rejection after 3 months was more important than early acute rejection. Serum triglyceride level and proteinuria at 1 year were both elevated in the CAF group. Male sex provided a protective effect. Serum creatinine levels at 6 months after the transplant were not predictive of the risk of developing CAF. CONCLUSIONS: These results from the largest single-center review to date suggest that both antigen-dependent and -independent factors are involved in the pathogenesis of CAF. Acute rejection at all time points has a significant impact on the development of CAF.

Adult↗

PubMed2000

Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers.

Central dopaminergic reward pathways give rise to dependence and are activated by nicotine. Allelic variants in genes involved in dopamine metabolism may therefore influence the amount of tobacco consumed by smokers. We developed assays for polymorphisms in dopamine beta-hydroxylase (DBH), monoamine oxidase (MAO) and catechol O-methyl transferase (COMT) using the polymerase chain reaction with sequence specific primers (PCR-SSP). We then typed 225 cigarette smokers to assess whether genotype was related to the number of cigarettes smoked a day. Smokers with DBH 1368 GG genotype smoked fewer cigarettes than those with GA/AA [mean difference -2.9 cigarettes, 95% confidence interval (CI) -5.5, -0.4; P = 0.022]. The effect reached statistical significance in women (-3.8, 95% CI -6.4, -1.0, P = 0.007) but not in men (-1.5, 95% CI -6.0, 3.0, P = 0.498). Overall, the effect was greater when analysis was confined to Caucasians (-3.8, 95% CI -6.6, -1.1, P = 0.007). Smokers with MAO-A 1460 TT/TO smoked more cigarettes than those with CC/CT/CO (2.9, 95% CI 0.6, 5.1, P = 0.013). Within each sex group, the trend was similar but not statistically significant (difference for men 2.9, 95% CI -1.0, 6.7; for women 2.0, 95% CI -0.7, 4.8). The effect of the allele was greater in smokers with a high body mass index (> 26) (difference 5.1, 95% CI 1.4, 8.8, P = 0.008). More heavy smokers (> 20 a day) had the DBH 1368A allele when compared to light smokers (< 10 a day). (Relative risk 2.3, 95% CI 1.1, 5.0, P = 0.024.) The trend for increasing prevalence of the DBH A allele in heavy smokers was greater when analysis was restricted to Caucasians (relative risk 3.2, 95% CI 1.3, 8.2, P = 0.004). Conversely, heavy smokers were less likely to have the MAO-A 1460C allele (relative risk 0.3, 95% CI 0.1, 0.7, P = 0.012). Variations in DBH and MAO predict whether a person is a heavy smoker and how many cigarettes they consume. Our results support the view that these enzymes help to determine a smoker's requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some find it very difficult to stop smoking. This finding has important implications for smoking prevention and offers potential for developing patient-specific therapy for smoking cessation.

Adult↗

PubMed2000

Glutathione S-transferase polymorphisms and skin cancer after renal transplantation.

BACKGROUND: Susceptibility to skin cancer after transplantation is multifactorial, and risk factors include skin type, sun exposure, and level of immunosuppression. A major mechanism of carcinogenesis is ultraviolet radiation-induced free radical damage, and genetically determined ability to metabolize free radicals may also predispose to skin cancer. The glutathione S-transferase enzymes play a major role in limiting the toxic effects of reactive oxygen species, and this study was designed to determine whether polymorphisms in these enzymes are associated with skin cancers in renal transplant recipients. METHODS: Two hundred twenty-two long-term survivors of renal transplantation were examined for polymorphisms in the GSTM1, GSTT1, and GSTP1 genes, using a unified polymerase chain reaction with sequence specific primers (PCR-SSP) genotyping method. RESULTS: The GSTP1*C allele was associated with the development of squamous cell carcinomas (SCCs; P = 0.01). No associations of the GSTM1 null genotype or the GSTT1 null genotype were identified, and the development of basal cell carcinomas was not associated with any GST polymorphism studied. CONCLUSIONS: These results indicate that genetic variation in enzymes involved in free radical metabolism in the skin are associated with the development of skin cancer. While all renal transplant recipients should be advised to protect themselves from the sun, the identification of transplant patients with a genetic predisposition to skin tumors may permit the targeting of preventative and early intervention strategies to high-risk individuals.

Alleles↗

PubMed2000

Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility.

BACKGROUND: The vitamin D receptor (VDR) gene represents a strong positional candidate susceptibility gene for inflammatory bowel disease (IBD). The VDR gene maps to a region on chromosome 12 that has been shown to be linked to IBD by genome screening techniques. It is the cellular receptor for 1,25(OH)(2) vitamin D(3) (calcitriol) which has a wide range of different regulatory effects on the immune system. IBD is characterised by activation of the mucosal immune system. AIM: To determine if polymorphisms in the VDR gene are associated with susceptibility to IBD SUBJECTS: European Caucasoids: 158 patients with ulcerative colitis, 245 with Crohn's disease, and 164 cadaveric renal allograft donor controls. METHOD: Single nucleotide polymorphisms (TaqI, ApaI, and FokI) in VDR were typed in patients with Crohn's disease, ulcerative colitis, and controls by polymerase chain reaction with sequence specific primers. RESULTS: There were significantly more homozygotes for the TaqI polymorphism at codon 352 of exon 8 (genotype "tt") among patients with Crohn's disease (frequency 0.22) than patients with ulcerative colitis (0.12) or controls (0.12) (odds ratio 1.99; 95% confidence interval 1.14-3.47; p=0.017). CONCLUSION: This study provides preliminary evidence for a genetic association between Crohn's disease susceptibility and a gene that lies within one of the candidate regions determined by linkage analysis.

Adolescent↗

PubMed2000

CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis.

Genes for the chemokine receptors CCR5 and CCR2 are characterized by polymorphisms resulting in a nonfunctional receptor expression. Ligands for CCR2 and CCR5 (chemokines monocyte chemotactic protein-1 [MCP-1] and RANTES) are implicated in the pathogenesis of sarcoidosis. We have, therefore, analyzed polymorphisms of CCR5 (32-bp deletion in CCR5 gene [Delta32]) and of CCR2 (replacement of valine by isoleucine in CCR2 gene [64I]) in 66 Czech patients with sarcoidosis in comparison with a representative sample of Czech normal population. The frequencies of CCR5Delta32 and CCR2-64I polymorphisms in patients with sarcoidosis were different from that in control subjects. CCR5Delta32 allelic frequency was significantly increased in patients. By contrast, the CCR2-64I allele was more frequent in control subjects; however, the difference did not attain significance. Interestingly, the CCR5Delta32 allele was associated with clinically more apparent disease: it was present in 39.1% of patients requiring corticosteroids but only in 16.7% patients who did not need therapeutic intervention (odds ratio [OR] = 2.9). When patients requiring corticosteroids were compared with control subjects, the differences in the CCR5Delta32 frequencies were enhanced (p < 0.01). In conclusion, the observed association of CCR5Delta32 and CCR2-64I with sarcoidosis implicates a role for these polymorphisms in disease susceptibility and protection.

Adolescent↗

PubMed2000

Cytokine gene polymorphisms in autoimmune thyroid disease.

Susceptibility to the autoimmune thyroid diseases, Graves' disease (GD) and autoimmune hypothyroidism (AIH), depends on a complex interaction between environmental and genetic factors. The human leukocyte antigen and cytotoxic T lymphocyte-associated-4 regions appear to influence susceptibility to disease, but the effect is not major, and the other genes remain unknown. Cytokines are crucial in the regulation of immune and inflammatory responses and therefore are potential candidate genes for autoimmune thyroid disease. In a case-control study, using a unified method of genotyping, we have examined 15 polymorphisms in 9 cytokine genes in 215 patients with autoimmune thyroid disease (GD, 138; AIH, 77) and 101 normal controls. Polymorphisms in the genes for interleukin-1alpha (IL-1alpha), IL-1beta, IL-1 receptor antagonist, IL-1 receptor 1, IL-4, IL-4 receptor, IL-6, IL-10, and transforming growth factor-beta were investigated. Genotyping was performed using the PCR and sequence-specific primers. Analysis showed a reduced frequency of the variant t allele in the IL-4 promoter polymorphism (position 590) in patients with GD and in the entire patient group (GD and AIH) compared with the control group [corrected P (Pc) = 0.00004 and Pc < 0.00001 for GD and all patients, respectively]. This was reflected in a reduction in the heterozygote genotype in the patient groups compared to the controls [c/t heterozygotes GD, 12%; Pc = 0.06, odds ratio, 0.4 (95% confidence interval, 0.2-0.7); all patients, 11%; Pc = 0.008; odds ratio, 0.4 (95% confidence interval, 0.2-0.7); control subjects, 23%]. There were no significant differences between the study groups for the other polymorphisms examined, and subgroup analysis revealed no association with clinical parameters of disease. These results suggest that an IL-4 variant or a closely linked gene has a modest protective effect against the development of autoimmune thyroid disease, particularly GD. This variation in the IL-4 gene may provide further clues to the pathogenesis of autoimmune thyroid disease and other organ-specific autoimmune diseases. Furthermore, these results suggest that subtle variation in immunoregulatory genes may be associated with autoimmune disease states.

Cohort Studies↗