0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Associations of HLA-C Alleles With Multinodular Goiters:  Study in a Population From Southeastern Spain FREE

Antonio Ríos, PhD; Jose M. Rodríguez, PhD; María R. Moya, PhD; Pedro J. Galindo, MD; Manuel Canteras, PhD; María R. Alvarez, PhD; Pascual Parrilla, PhD
[+] Author Affiliations

Author Affiliations: Departments of Surgery (Drs R[[iacute]]os, Rodr[[iacute]]guez, Galindo, and Parrilla), Immunology (Drs Moya and Alvarez), and Biostatistics (Dr Canteras), Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.


Arch Surg. 2006;141(2):123-128. doi:10.1001/archsurg.141.2.123.
Text Size: A A A
Published online

Hypothesis  Several immunological alterations have been found in patients with multinodular goiter (MG). These alterations, together with the association described between certain autoimmune thyroid diseases and alleles of the major histocompatibility complex (HLA alleles), justify the need for studies of the HLA alleles and MG in an attempt to identify associations.

Design  Case-control study.

Setting  Tertiary referral center.

Patients  Ninety consecutive patients underwent surgical procedures for MG. The control group comprised 100 unrelated, healthy, white subjects.

Intervention  Genotyping for HLA-C alleles was done using the molecular biological technique of polymerase chain reaction using sequence-specific primers and was carried out for all of the patients.

Main Outcome Measures  The analyzed variables included age, sex, family history of thyroid pathological abnormalities, clinical features of the patient, clinical grading of the goiter, intrathoracic thyroid component, goiter weight, associated carcinoma, and the HLA-C gene.

Results  A significant association was observed between the lower incidence of the HLA-Cw4 allele and the appearance of MG (15.5% vs 8.3%, respectively; P = .001; relative risk [RR] = 0.49). These results suggest that the HLA-Cw4 allele can exert a protective effect against MG. Analysis of the different clinical variables shows the most significant association to be the absence of the HLA-Cw4 allele in patients with goiters with an intrathoracic component (P = .001; RR = 0.19) and in patients with goiters weighing more than 200 g (P = .02; RR = 0.17). Associations between the HLA-C alleles and MG were also observed, such as the presence of the HLA-Cw7 allele and a family history of thyroid pathological abnormalities (P = .03; RR = 3.91) as well as the HLA-Cw1 allele and the presence of goiter-associated thyroid carcinoma (P = .02; RR = 8.60).

Conclusions  The HLA-Cw4 allele can act as a protector against the development of MG, as it occurs less frequently in the population with MG, and those with this allele develop smaller goiters with no intrathoracic component.

Multinodular goiter (MG) is the most prevalent thyroid pathological abnormality worldwide, although its geographical incidence varies greatly according to environmental iodization.1 Most countries in central and southern Europe have endemic goiter areas with a prevalence of MG of 3% to 6%, the most affected regions being Germany, Italy, Portugal, Greece, Turkey, and Spain. In the United States, the annual incidence of nodular thyroid disease is 0.1% to 1.5%, and the prevalence is 4% to 7%.

Multinodular goiter is considered a nonautoimmune thyroid disease, and there have been findings to support this hypothesis.2 However, several immunological alterations have been found in these patients, such as HLA-DR antigen expression in thyrocytes,3 the presence of growth-stimulating immunoglobulins,4 and an increase in dendritic cells and lymphocytes,5 which suggest the possibility of autoimmune problems.6 Although many of these findings may be an epiphenomenon of other primary defects in immunoregulation, the alteration of lymphocyte populations indicates a primary defect.7,8 Corrales et al7 demonstrated the existence of an increase of CD8+CD57+ T lymphocytes and CD16 natural killer cells in peripheral blood. This cell increase is related to the increase in the suppressor and/or cytotoxic immune mechanisms,9 which may represent an immunoregulation mechanism in the progression of goiter. This occurrence, together with the association described between certain autoimmune thyroid diseases and alleles of the major histocompatibility complex (HLA alleles) justifies the need for studies of HLA and MG in an attempt to identify associations and possible risk factors.

In the past, serological techniques were used to detect HLA antigens, as this is a useful method for detecting class A and B alleles. However, the results are very poor when serological techniques are used for detecting HLA-C alleles. This explains why there are few studies of HLA-C alleles in thyroid pathology.10,11 Currently, the development of molecular biological techniques allows for a more reliable detection of these antigens.12 However, probably owing to cost and the fact that these techniques have only existed for a short time, there have been only a few studies1215 using these techniques and none to our knowledge using them to study MG.

The aim of this study is to determine whether there are any associations between MG and HLA-C alleles to detect which may be risk factors and which may provide protection from disease.

PATIENTS

The study group comprised 90 patients who underwent surgery in our department between January 1997 and December 2000. The mean ± SD patient age was 49 ± 13 years, and most patients (83 patients [92%]) were women, of whom 13 (12%) had a family history of thyroid pathological abnormalities and 21 (23%) lived in goitrogenic areas. The mean evolution time was more than 6 years (mean ± SD evolution time, 82 ± 90 months); 34 cases (38%) were clinically asymptomatic, 24 (27%) had compressive features, and 23 (26%) had hyperthyroidism. On examination, the goiter was grade I (can be touched but not seen) in 6 cases (7%), grade II (can be seen and touched) in 60 (67%), and grade III (affects neighboring structures) in the remaining 24 (27%). On palpation, 79 (88%) of the goiters had an elastic consistency, and 42 (47%) were intrathoracic. Neck and chest radiographic examination showed tracheal deviation or compression in 40 cases (44%), all of them corresponding to intrathoracic goiters. Ultrasonographic examination confirmed the presence of MG, and scintigraphic examination was performed for the 23 patients with hyperthyroidism. Thyroid antibodies were negative in all of the cases.

The indications for surgery were the presence of compression symptoms (24 cases [27%]), suggestion of malignancy (23 cases [26%]), asymptomatic intrathoracic goiter (14 cases [16%]), hyperthyroidism (12 cases [13%]), a progressive increase in size (7 cases [8%]), the patient's own request (5 cases [5%]), and radiological tracheal compression (5 cases [5%]). Eighty-six patients (96%) received a total thyroidectomy, and the other 4 (4%) received a hemithyroidectomy for a unilateral MG. The mean ± SD weight of the excised specimen was 83 ± 67 g, with 16 cases (18%) having specimens weighing more than 200 g. The histological study confirmed the presence of multinodular hyperplasia in all of the cases, and 11 cases (12%) were associated with thyroid carcinoma.

HLA-C TYPING

The molecular biological technique of polymerase chain reaction using sequence-specific primers was used for typing the HLA-C genes.1214 For this, a peripheral blood extraction was taken in a tube containing EDTA. The steps for this technique include the Higuchi method of rapid nucleic acid extraction and DNA quantification with a spectrophotometer (Amersham Pharmacia Biotech, Piscataway, NJ). Subsequently, the FastypeTM SSP System (Bio-Synthesis, Inc, Lewisville, Tex; supplied by Diagnostica Longwood SA, Zaragoza, Spain) was used for typing following the manufacturer's recommendations. When the amplification reaction was finished, the tubes were left to cool at room temperature and the amplification was viewed in agarose gel using a UV-light transilluminator. The presence of amplification was recorded using a Polaroid 440 camera (Polaroid [France] SA, Montigny le Bretonneux, France). The entire HLA-typing process was carried out by 1 of us (M.R.M.).

CONTROL GROUP

The method described earlier was also used to study HLA-C alleles in a control sample of 100 unrelated, healthy, white subjects. This control group corresponded to subjects representative of the healthy population randomly selected from unrelated, healthy, Spanish, white blood donors. We previously ruled out thyroid pathological abnormalities in these subjects by clinical examination.

STATISTICAL ANALYSIS

The variables analyzed for detecting associations between certain alleles and certain subgroups of patients with goiter included age, sex, family history of thyroid pathological abnormalities, residence in goitrogenic areas, being clinically asymptomatic, presence of hyperthyroidism, compression symptoms, goiter grading based on physical examination, presence of an intrathoracic component according to the criterion of Dahan et al16 (goiter that, in an operative position, has its lower edge at least 3 cm below the sternal manubrium), excised goiter weight of 200 g or more, and presence of goiter-associated thyroid carcinoma.

The HLA-C allele frequencies were estimated by direct counts, and they represent the percentage of individuals who are positive for a particular allele. To compare the differences between the frequencies in the control and MG groups, a 2 × 2 contingency table analysis was done using the Pearson χ2 test and the Mantel-Haenszel test, with the Fisher exact test when the expected value for an HLA marker was less than 5. All of the analyses were performed using the Epi Info version 5.01 software package (Centers for Disease Control and Prevention, Atlanta, Ga). The relative risk (RR) was calculated according to the Woolf method. The P values were corrected by multiplying them by the number of alleles tested (Bonferroni correction).17 The association between the clinical variables and HLA-C alleles was made using the Pearson χ2 test, with the Fisher exact test when the expected value for an HLA marker was less than 5. Only P values of less than .05 were considered statistically significant.

GENERAL ANALYSIS

The most common alleles in MG were HLA-Cw7 (37 alleles [20.6%]), followed by HLA-Cw16 (24 alleles [13.3%]), and HLA-Cw5 (19 alleles [10.6%]). Table 1 shows that the distribution of the HLA-Cw4 allele in MG is significantly less than in the control group (15 alleles [8.3%]; P = .001; Bonferroni-corrected P = .02; RR = 0.49). Thus, the HLA-Cw4 allele has an incidence of 15.5% in the control group whereas it occurs in just 8.3% in the MG group. These results suggest that the HLA-Cw4 allele can provide a protective effect against MG.

Table Graphic Jump LocationTable 1. Distribution of the HLA-C Alleles in the Control and Multinodular Goiter Groups

The HLA-Cw16 allele has a lower frequency in the control group (15 alleles [7.5%]) than in the MG group (24 alleles [13.3%]). However, these initially significant differences (P = .0496; RR = 1.92) are lost when we apply the Bonferroni correction (Bonferroni-corrected P = .89).

CLINICAL VARIABLES ANALYSIS

On analyzing the associations between the different clinical variables of the patients with MG and HLA-C alleles, we see that there is no significant association with regard to age, sex, residence in potentially goitrogenic areas, patients' symptoms (asymptomatic status, compression symptoms, or hyperthyroidism), or goiter grading (all P>.05) (Table 2).

Table Graphic Jump LocationTable 2. Correlation Between the Clinical Variables of Multinodular Goiter and the Distribution of HLA-C Alleles

By contrast, 4 statistically significant associations were revealed between HLA-C alleles and clinical variables (Table 2). There were 3 alleles, HLA-Cw1, HLA-Cw4, and HLA-Cw7, with different distributions. As shown in Table 2, the most important association was the low representation of the HLA-Cw4 allele in patients with goiters with an intrathoracic component (P = .001; RR = 0.19) and in patients with goiters weighing more than 200 g (P = .02; RR = 0.17). A relationship between HLA-C alleles and MG was also observed for 2 other variables. One is between the presence of the HLA-Cw7 allele and a family history of thyroid pathological abnormalities (P = .03; RR = 3.91), and the other is between the HLA-Cw1 allele and the presence of goiter-associated thyroid carcinoma (P = .02; RR = 8.60).

On application of the Bonferroni correction, the association between the presence of an intrathoracic component and the low frequency of the HLA-Cw4 allele persisted (Bonferroni-corrected P = .02; RR = 0.19), indicating that this allele could protect against the development of goiter with an intrathoracic component.

Molecules of HLA antigens are membrane glycoproteins with the biological role of presenting peptides to Tαβ lymphocytes,18 and they are characterized by their extraordinary polymorphism.19 Both class I and class II HLA alleles continually provide an updated sample of potential antigens from cytosolic and extracellular compartments to T lymphocytes.20,21 A relationship has been found between autoimmune benign thyroid pathological abnormalities and certain HLA alleles. Susceptibility to developing these autoimmune diseases is primarily related to certain specific peptides presented by HLA molecules,22,23 as has been shown previously in type I diabetes mellitus.24 These types of associations have been described principally in Graves disease and Hashimoto thyroiditis.22,25,26 The HLA-DR3 allele has been associated with both of these diseases, and HLA-DR5 has been associated with Hashimoto thyroiditis and postpartum and nongoitrous autoimmune thyroiditis (Table 3). In contrast, it was also found that HLA-DR6 and HLA-DQw1 can act as protective factors against Hashimoto thyroiditis,29,30 and HLA-A11, HLA-A2, and HLA-B35 can act as protective factors against MG.36 For the first time to our knowledge, we describe a similar association between HLA-Cw4 and MG.

Table Graphic Jump LocationTable 3. Reported HLA Alleles Associated With Benign Thyroid Pathological Abnormalities

There are few studies on the association between HLA and MG, as they have been limited so far to thyroid pathological abnormalities of a clear autoimmune origin. In the available articles that we consulted, we only found the Russian study by Rasovskii et al36 in which 101 nodular goiters were reviewed and associations with the HLA-Aw19, HLA-A28, and HLA-B18 alleles were found. Papasteriades et al37 studied HLA alleles in hyperthyroidism, especially in Graves disease, and observed that no HLA-A or HLA-B alleles were associated with cases of toxic MG in their series.

With regard to benign thyroid disease, there are still few studies on HLA-C alleles, and only Ozaki et al38 have described the relationship between 1 HLA-C allele and a thyroid pathological abnormality (HLA-Cw7 allele and differentiated thyroid carcinoma). Our study shows that there is a significant association between the lower incidence of the HLA-Cw4 allele and the appearance of MG. In fact, on analyzing the different clinical variables in the MG subgroup, we observed an association between the absence of the HLA-Cw4 allele and the presence of goiters with an intrathoracic component. The HLA-Cw4 allele has been associated with susceptibility to diseases such as Meniere disease,39 schizophrenia,40 osteoarthritis,41 and others, among which are tumoral diseases such as leukemia.42 However, it has not been described as a protector allele in any disease. In our series, it appears to act as a protective factor against the development of MG, as not only does it occur less frequently in the population with MG, but those who carry this allele develop smaller goiters with no intrathoracic component.

When analyzing the risk of developing a goiter among individuals bearing the HLA-Cw4 allele, we observed that it drops to half of the risk that the rest of the population has (RR = 0.49). In other words, the degree of protection against goiters in these patients is 2 times higher than in the control population. In patients with MG and the HLA-Cw4 allele, the degree of protection against the development of an intrathoracic component is more than 5 times higher (RR = 0.19) than in patients with MG without the HLA-Cw4 allele. Additionally, the degree of protection by the HLA-Cw4 allele against the development of a large goiter weighing more than 200 g was higher still (RR = 0.17), ie, the incidence of these large goiters was 6 times higher in cases in which the HLA-Cw4 allele was absent. Lastly, despite the high degree of protection, the relationship between the HLA-Cw4 allele and goiters weighing more than 200 g is not statistically significant on application of the Bonferroni correction, possibly owing to the small size of this subgroup of patients in our series.

As for the general distribution of the HLA-C alleles, we also observed a tendency at the limit of statistical significance between goiters and the HLA-Cw16 allele. This allele can only be detected by molecular biological techniques, and some of its subtypes have been described in recent years.43 This justifies the few articles in which it has been described, but among the few associations described for this allele are those that link it with Behçet disease,44 acquired immunodeficiency syndrome,45 and melanoma.46,47 Therefore, further studies of goiter could be of wider interest.

On the other hand, our study shows that the HLA-Cw1 allele is associated with MGs that have thyroid carcinoma, although statistical significance is lost when the Bonferroni correction is applied. This allele seems to constitute a risk factor for the development of goiters at high risk of becoming malignant, and therefore, it could be useful for defining a poor prognosis of this disease. The HLA-Cw1 allele has also been considered in some studies48 as a regulator of the immune response in neoplastic processes. Although the HLA-Cw1 allele might be regarded as a risk factor for the development of thyroid carcinoma when associated with MG, considering the small number of cases of cancer in our series, this association must be regarded with some reservation.

Lastly, we found that the HLA-Cw7 allele could be associated with a family history of thyroid pathological abnormalities, although owing to the small number of case studies, this observation should be considered with some caution. Nonetheless, this finding is supported by previous studies showing that the HLA-Cw7 allele can condition a poor immune response in patients with neoplasms48,49 and that this HLA-C allele is associated with differentiated thyroid carcinoma.38 Therefore, in people with a family history of thyroid pathological abnormalities, there is greater risk of developing thyroid carcinoma.50,51 Our finding of an association between the HLA-Cw7 allele and such family history indicates that patients with both characteristics could be at major risk of malignization. Our previous results52 in patients with differentiated thyroid carcinoma revealed a relationship between the HLA-Cw7 allele and this carcinoma.

To summarize, we describe for the first time, to our knowledge, an association between HLA-C alleles and goiter. The HLA-Cw4 could have a protective effect against this disease, and it especially prevents the development of an intrathoracic component. By contrast, the HLA-Cw1 allele could be related to a major risk of developing cancer, and the HLA-Cw7 allele could be related to a family history of goiters. These observations lead to a new way of detecting those patients in which surgical intervention could be justified, but further and wider series must be carried out to substantiate these results.

Correspondence: Antonio Ríos, PhD, Avenida de la Libertad 208, Casillas 30007, Murcia, Spain (arzrios@teleline.es).

Accepted for Publication: April 12, 2005.

Hurley  DLGharib  H Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29527- 540
PubMed
Aguayo  JSakatsume  YJamieson  CRow  VVVolpe  R Nontoxic nodular goiter and papillary thyroid carcinoma are not associated with peripheral blood lymphocyte sensitization to thyroid cells. J Clin Endocrinol Metab 1989;68145- 149
PubMed Link to Article
Jansson  RKarlsson  AForsum  V Intrathyroidal HLA-DR expression and T lymphocyte phenotypes in Graves' thyrotoxicosis, Hashimoto's thyroiditis and nodular colloid goiter. Clin Exp Immunol 1984;58264- 272
PubMed
Van der Gaag  RDDrexhage  HAWiersinga  WM  et al.  Further studies on thyroid growth stimulating immunoglobulins in euthyroid nonendemic goiter. J Clin Endocrinol Metab 1985;60972- 979
PubMed Link to Article
Kabel  PJVoorbij  HADe Haan  Mvan der Gaag  RDDrexhage  HA Intrathyroidal dendritic cells. J Clin Endocrinol Metab 1988;66199- 207
PubMed Link to Article
Kraiem  ZGlaser  BYigla  MPauker  JSadeh  OSheinfeld  M Toxic multinodular goiter: a variant of autoimmune hyperthyroidism. J Clin Endocrinol Metab 1987;65659- 664
PubMed Link to Article
Corrales  JJOrfao  AMiralles  JM  et al.  Immunological features of sporadic multinodular goiter. Clin Investig 1993;71552- 558
PubMed Link to Article
Grubeck-Loebenstein  BDerfler  KKassal  H  et al.  Immunological features of nonimmunogenic hyperthyroidism. J Clin Endocrinol Metab 1985;60150- 155
PubMed Link to Article
Wall  JRBaur  RSchleusener  HBandy  P Peripheral blood and intrathyroidal mononuclear cell populations in patients with autoimmune thyroid disorders enumerated using monoclonal antibodies. J Clin Endocrinol Metab 1983;56164- 169
PubMed Link to Article
Rigopoulou  DMartínez  JMartínez  F  et al.  Both class I and class II HLA antigens are thyroid cancer susceptibility factors. Tissue Antigens 1994;43281- 285
PubMed Link to Article
Ahuja  SHoppe  Ivon Keyserlingk  HErnst  H HLA and thyroid carcinoma. Exp Clin Endocrinol 1992;99134- 136
PubMed Link to Article
Bunce  MWelsh  KI Rapid DNA typing for HLA-C using sequence specific primers (PCR-SSP): identification of serological and non-serologically defined HLA-C alleles including several new alleles. Tissue Antigens 1994;437- 17
PubMed Link to Article
Bunce  MBarnardo  MCNMWelsh  KI Improvements in HLA-C typing using sequence-specific primers (PCR-SSP) including definition of HLA-Cw9 and Cw10 and a new allele HLA-“Cw7/8v.” Tissue Antigens 1994;44200- 203
PubMed Link to Article
Levine  JEYang  SY SSOP typing of the Tenth International Histocompatibility Workshop reference cell lines for HLA-C alleles. Tissue Antigens 1994;44174- 183
PubMed Link to Article
Ando  HMizuki  NAndo  R  et al.  HLA-C genotyping in the Japanese population by the PCR-SSP method. Tissue Antigens 1996;4855- 58
PubMed Link to Article
Dahan  MGaillard  JEschapase  H Surgical treatment of goiters with intrathoracic development. Delarue  NCEschapase  HThoracic Surgery: Frontiers and Uncommon Neoplasms: International Trends in General Thoracic Surgery St Louis, Mo Mosby1989;5- 10
Svejgaard  ARyder  LP HLA and disease associations: detecting the strongest association. Tissue Antigens 1994;4318- 27
PubMed Link to Article
Geelhoed  GW Tracheomalacia from compressing goiter: management after thyroidectomy. Surgery 1988;1041100- 1108
PubMed
Takahata  N MHC diversity and selection. Immunol Rev 1995;143225- 247
PubMed Link to Article
DeGroot  LJQuintans  J The causes of autoimmune thyroid disease. Endocr Rev 1989;10537- 562
PubMed Link to Article
Duquesnoy  RJ Immunogenetics of the human major histocompatibility complex. Clin Lab Med 1991;11509- 536
PubMed
Heward  JGough  SC Genetic susceptibility to the development of autoimmune disease. Clin Sci (Lond) 1997;93479- 491
PubMed
Weetman  AP New aspects of thyroid immunity. Horm Res 1997;48 ((suppl 4)) 51- 54
PubMed Link to Article
Thorsby  E Invited anniversary review: HLA associated disease. Hum Immunol 1997;531- 11
PubMed Link to Article
McLachlan  SM The genetic basis of autoimmune thyroid disease: time to focus on chromosomal loci other than the major histocompatibility complex (HLA in man). J Clin Endocrinol Metab 1993;77605A- 605C
PubMed Link to Article
Dalton  TABennett  JC Autoimmune disease and the major histocompatibility complex: therapeutic implications. Am J Med 1992;92183- 188
PubMed Link to Article
Kotsa  KWatson  FWeetman  APA CTLA-4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidism. Clin Endocrinol (Oxf) 1997;46551- 554
PubMed Link to Article
Farid  NR Are the immune responses to endocrine autoantigens genetically restricted? Autoimmunity 1989;347- 55
PubMed Link to Article
Tamai  HKimura  ADong  RP  et al.  Resistance to autoimmune thyroid disease is associated with HLA-DQ. J Clin Endocrinol Metab 1994;7894- 97
PubMed
Yanagawa  TMangklabruks  ADeGroot  LJ Strong association between HLA-DQA1*0501 and Graves' disease in a male Caucasian population. J Clin Endocrinol Metab 1994;79227- 229
PubMed
Cho  BYChung  JHShong  YK  et al.  A strong association between thyrothopin receptor-blocking antibody-positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1*0302 in Koreans. J Clin Endocrinol Metab 1993;77611- 615
PubMed
Honda  KTamai  HMorita  TKuma  KNishimura  YSasazuki  T Hashimoto's thyroiditis and HLA in Japanese. J Clin Endocrinol Metab 1989;691268- 1273
PubMed Link to Article
Maenpaa  JLautenschlager  INyberg  MKoskimies  SKontiaimen  S Thyroid infiltrating lymphocytes, thyroid function, and HLA-DR in juvenile autoimmune thyroiditis. Acta Endocrinol (Copenh) 1989;121573- 577
PubMed
Parkes  ABDarke  COthman  S  et al.  Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis. Eur J Endocrinol 1996;134449- 453
PubMed Link to Article
Bogner  UBadenhoop  KPeters  H  et al.  HLA-DR/DQ gene variation in nongoitrous autoimmune thyroiditis at the serological and molecular level. Autoimmunity 1992;14155- 158
PubMed Link to Article
Rasovskii  BLDimova  MNKiseleva  TPAkhmed’ianova  LGMinina  VM Antigens of the HLA system in nodular formations of the thyroid gland [in Russian]. Probl Endokrinol (Mosk) 1993;3928- 30
PubMed
Papasteriades  CAlevizaki  MNEconomidou  JIkkos  DG HLA antigens in Greek patients with thyrotoxicosis (Graves' disease and toxic nodular goiter). J Endocrinol Invest 1984;7283- 286
PubMed Link to Article
Ozaki  OIto  KKobayashi  KSuzuku  AManabe  YHosoda  Y Familial occurrence of differentiated, nonmedullary thyroid carcinoma. World J Surg 1988;12565- 571
PubMed Link to Article
Koyama  SMitsuishi  YBibee  KWatanabe  ITerasaki  PI HLA associations with Meniere's disease. Acta Otolaryngol 1993;113575- 578
PubMed Link to Article
Ivanyi  PIvanyi  DZemek  P HLA Cw4 in paranoid schizophrenia. Tissue Antigens 1977;941- 44
PubMed Link to Article
Wakitani  SImoto  KMazuka  TKim  SMurata  NYoneda  M Japanese generalised osteoarthritis was associated with HLA class I: a study of HLA-A, B, Cw, DR in 72 patients. Clin Rheumatol 2001;20417- 419
PubMed Link to Article
Bortin  MMD’Amaro  JBach  FHRimm  AAvan Rood  JJ HLA associations with leukemia. Blood 1987;70227- 232
PubMed
Grundschober  CLabonne  MPJavaux  FSteiner  QGGebuhrer  LTiercy  JM Sequence of four new HLA-Cw alleles: a possible role of interallelic recombination. Tissue Antigens 1998;5172- 79
PubMed Link to Article
Sanz  LGonzález  Fde Pablo  RNuñez Roldan  AKreisler  MVilches  C HLA-Cw*1602: a new susceptibility marker of Behçet's disease in southern Spain. Tissue Antigens 1998;51111- 114
PubMed Link to Article
Hendel  HCaillat-Zucman  SLebuanec  H  et al.  New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol 1999;1626942- 6946
PubMed
Carrel  SSchreyer  MSpagnoli  GCerottini  JCRimoldi  D Monoclonal antibodies against recombinant-MAGE-1 protein identify a cross-reacting 72-kDa antigen which is co-expressed with MAGE-1 protein in melanoma cells. Int J Cancer 1996;67417- 422
PubMed Link to Article
van der Bruggen  PSzikora  JPBoel  P  et al.  Autologous cytolytic T lymphocytes recognize a MAGE-1 nonapeptide on melanomas expressing HLA-Cw*1601. Eur J Immunol 1994;242134- 2140
PubMed Link to Article
Araki  KNoguchi  YHirouchi  T  et al.  Cancer regression induced by modified CTL therapy is regulated by HLA class II and class I antigens in Japanese patients with advanced cancer. Int J Oncol 2000;171107- 1118
PubMed
Heidecker  LBrasseur  FProbst-Kepper  MGueguen  MBoon  TVan den Eynde  BJ Cytolytic T lymphocytes raised against a human bladder carcinoma recognize an antigen encoded by gene MAGE-A12. J Immunol 2000;1646041- 6045
PubMed Link to Article
Ríos  ARodríguez  JMIllana  JTorregrosa  NMParrilla  P Familial papillary carcinoma of the thyroid: report of 3 families. Eur J Surg 2001;167339- 343
PubMed Link to Article
From  GMellemgaard  AKnudsen  NJorgensen  TPerrild  H Review of thyroid cancer cases among patients with previous benign thyroid disorders. Thyroid 2000;10697- 700
PubMed Link to Article
Ríos  ARodríguez  JMMoya  MR  et al.  Frequency of HLA-C alleles in differentiated thyroid carcinoma in southeastern Spain: HLA-Cw7 as a poor prognosis factor. Cancer 2004;100264- 269
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Distribution of the HLA-C Alleles in the Control and Multinodular Goiter Groups
Table Graphic Jump LocationTable 2. Correlation Between the Clinical Variables of Multinodular Goiter and the Distribution of HLA-C Alleles
Table Graphic Jump LocationTable 3. Reported HLA Alleles Associated With Benign Thyroid Pathological Abnormalities

References

Hurley  DLGharib  H Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29527- 540
PubMed
Aguayo  JSakatsume  YJamieson  CRow  VVVolpe  R Nontoxic nodular goiter and papillary thyroid carcinoma are not associated with peripheral blood lymphocyte sensitization to thyroid cells. J Clin Endocrinol Metab 1989;68145- 149
PubMed Link to Article
Jansson  RKarlsson  AForsum  V Intrathyroidal HLA-DR expression and T lymphocyte phenotypes in Graves' thyrotoxicosis, Hashimoto's thyroiditis and nodular colloid goiter. Clin Exp Immunol 1984;58264- 272
PubMed
Van der Gaag  RDDrexhage  HAWiersinga  WM  et al.  Further studies on thyroid growth stimulating immunoglobulins in euthyroid nonendemic goiter. J Clin Endocrinol Metab 1985;60972- 979
PubMed Link to Article
Kabel  PJVoorbij  HADe Haan  Mvan der Gaag  RDDrexhage  HA Intrathyroidal dendritic cells. J Clin Endocrinol Metab 1988;66199- 207
PubMed Link to Article
Kraiem  ZGlaser  BYigla  MPauker  JSadeh  OSheinfeld  M Toxic multinodular goiter: a variant of autoimmune hyperthyroidism. J Clin Endocrinol Metab 1987;65659- 664
PubMed Link to Article
Corrales  JJOrfao  AMiralles  JM  et al.  Immunological features of sporadic multinodular goiter. Clin Investig 1993;71552- 558
PubMed Link to Article
Grubeck-Loebenstein  BDerfler  KKassal  H  et al.  Immunological features of nonimmunogenic hyperthyroidism. J Clin Endocrinol Metab 1985;60150- 155
PubMed Link to Article
Wall  JRBaur  RSchleusener  HBandy  P Peripheral blood and intrathyroidal mononuclear cell populations in patients with autoimmune thyroid disorders enumerated using monoclonal antibodies. J Clin Endocrinol Metab 1983;56164- 169
PubMed Link to Article
Rigopoulou  DMartínez  JMartínez  F  et al.  Both class I and class II HLA antigens are thyroid cancer susceptibility factors. Tissue Antigens 1994;43281- 285
PubMed Link to Article
Ahuja  SHoppe  Ivon Keyserlingk  HErnst  H HLA and thyroid carcinoma. Exp Clin Endocrinol 1992;99134- 136
PubMed Link to Article
Bunce  MWelsh  KI Rapid DNA typing for HLA-C using sequence specific primers (PCR-SSP): identification of serological and non-serologically defined HLA-C alleles including several new alleles. Tissue Antigens 1994;437- 17
PubMed Link to Article
Bunce  MBarnardo  MCNMWelsh  KI Improvements in HLA-C typing using sequence-specific primers (PCR-SSP) including definition of HLA-Cw9 and Cw10 and a new allele HLA-“Cw7/8v.” Tissue Antigens 1994;44200- 203
PubMed Link to Article
Levine  JEYang  SY SSOP typing of the Tenth International Histocompatibility Workshop reference cell lines for HLA-C alleles. Tissue Antigens 1994;44174- 183
PubMed Link to Article
Ando  HMizuki  NAndo  R  et al.  HLA-C genotyping in the Japanese population by the PCR-SSP method. Tissue Antigens 1996;4855- 58
PubMed Link to Article
Dahan  MGaillard  JEschapase  H Surgical treatment of goiters with intrathoracic development. Delarue  NCEschapase  HThoracic Surgery: Frontiers and Uncommon Neoplasms: International Trends in General Thoracic Surgery St Louis, Mo Mosby1989;5- 10
Svejgaard  ARyder  LP HLA and disease associations: detecting the strongest association. Tissue Antigens 1994;4318- 27
PubMed Link to Article
Geelhoed  GW Tracheomalacia from compressing goiter: management after thyroidectomy. Surgery 1988;1041100- 1108
PubMed
Takahata  N MHC diversity and selection. Immunol Rev 1995;143225- 247
PubMed Link to Article
DeGroot  LJQuintans  J The causes of autoimmune thyroid disease. Endocr Rev 1989;10537- 562
PubMed Link to Article
Duquesnoy  RJ Immunogenetics of the human major histocompatibility complex. Clin Lab Med 1991;11509- 536
PubMed
Heward  JGough  SC Genetic susceptibility to the development of autoimmune disease. Clin Sci (Lond) 1997;93479- 491
PubMed
Weetman  AP New aspects of thyroid immunity. Horm Res 1997;48 ((suppl 4)) 51- 54
PubMed Link to Article
Thorsby  E Invited anniversary review: HLA associated disease. Hum Immunol 1997;531- 11
PubMed Link to Article
McLachlan  SM The genetic basis of autoimmune thyroid disease: time to focus on chromosomal loci other than the major histocompatibility complex (HLA in man). J Clin Endocrinol Metab 1993;77605A- 605C
PubMed Link to Article
Dalton  TABennett  JC Autoimmune disease and the major histocompatibility complex: therapeutic implications. Am J Med 1992;92183- 188
PubMed Link to Article
Kotsa  KWatson  FWeetman  APA CTLA-4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidism. Clin Endocrinol (Oxf) 1997;46551- 554
PubMed Link to Article
Farid  NR Are the immune responses to endocrine autoantigens genetically restricted? Autoimmunity 1989;347- 55
PubMed Link to Article
Tamai  HKimura  ADong  RP  et al.  Resistance to autoimmune thyroid disease is associated with HLA-DQ. J Clin Endocrinol Metab 1994;7894- 97
PubMed
Yanagawa  TMangklabruks  ADeGroot  LJ Strong association between HLA-DQA1*0501 and Graves' disease in a male Caucasian population. J Clin Endocrinol Metab 1994;79227- 229
PubMed
Cho  BYChung  JHShong  YK  et al.  A strong association between thyrothopin receptor-blocking antibody-positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1*0302 in Koreans. J Clin Endocrinol Metab 1993;77611- 615
PubMed
Honda  KTamai  HMorita  TKuma  KNishimura  YSasazuki  T Hashimoto's thyroiditis and HLA in Japanese. J Clin Endocrinol Metab 1989;691268- 1273
PubMed Link to Article
Maenpaa  JLautenschlager  INyberg  MKoskimies  SKontiaimen  S Thyroid infiltrating lymphocytes, thyroid function, and HLA-DR in juvenile autoimmune thyroiditis. Acta Endocrinol (Copenh) 1989;121573- 577
PubMed
Parkes  ABDarke  COthman  S  et al.  Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis. Eur J Endocrinol 1996;134449- 453
PubMed Link to Article
Bogner  UBadenhoop  KPeters  H  et al.  HLA-DR/DQ gene variation in nongoitrous autoimmune thyroiditis at the serological and molecular level. Autoimmunity 1992;14155- 158
PubMed Link to Article
Rasovskii  BLDimova  MNKiseleva  TPAkhmed’ianova  LGMinina  VM Antigens of the HLA system in nodular formations of the thyroid gland [in Russian]. Probl Endokrinol (Mosk) 1993;3928- 30
PubMed
Papasteriades  CAlevizaki  MNEconomidou  JIkkos  DG HLA antigens in Greek patients with thyrotoxicosis (Graves' disease and toxic nodular goiter). J Endocrinol Invest 1984;7283- 286
PubMed Link to Article
Ozaki  OIto  KKobayashi  KSuzuku  AManabe  YHosoda  Y Familial occurrence of differentiated, nonmedullary thyroid carcinoma. World J Surg 1988;12565- 571
PubMed Link to Article
Koyama  SMitsuishi  YBibee  KWatanabe  ITerasaki  PI HLA associations with Meniere's disease. Acta Otolaryngol 1993;113575- 578
PubMed Link to Article
Ivanyi  PIvanyi  DZemek  P HLA Cw4 in paranoid schizophrenia. Tissue Antigens 1977;941- 44
PubMed Link to Article
Wakitani  SImoto  KMazuka  TKim  SMurata  NYoneda  M Japanese generalised osteoarthritis was associated with HLA class I: a study of HLA-A, B, Cw, DR in 72 patients. Clin Rheumatol 2001;20417- 419
PubMed Link to Article
Bortin  MMD’Amaro  JBach  FHRimm  AAvan Rood  JJ HLA associations with leukemia. Blood 1987;70227- 232
PubMed
Grundschober  CLabonne  MPJavaux  FSteiner  QGGebuhrer  LTiercy  JM Sequence of four new HLA-Cw alleles: a possible role of interallelic recombination. Tissue Antigens 1998;5172- 79
PubMed Link to Article
Sanz  LGonzález  Fde Pablo  RNuñez Roldan  AKreisler  MVilches  C HLA-Cw*1602: a new susceptibility marker of Behçet's disease in southern Spain. Tissue Antigens 1998;51111- 114
PubMed Link to Article
Hendel  HCaillat-Zucman  SLebuanec  H  et al.  New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol 1999;1626942- 6946
PubMed
Carrel  SSchreyer  MSpagnoli  GCerottini  JCRimoldi  D Monoclonal antibodies against recombinant-MAGE-1 protein identify a cross-reacting 72-kDa antigen which is co-expressed with MAGE-1 protein in melanoma cells. Int J Cancer 1996;67417- 422
PubMed Link to Article
van der Bruggen  PSzikora  JPBoel  P  et al.  Autologous cytolytic T lymphocytes recognize a MAGE-1 nonapeptide on melanomas expressing HLA-Cw*1601. Eur J Immunol 1994;242134- 2140
PubMed Link to Article
Araki  KNoguchi  YHirouchi  T  et al.  Cancer regression induced by modified CTL therapy is regulated by HLA class II and class I antigens in Japanese patients with advanced cancer. Int J Oncol 2000;171107- 1118
PubMed
Heidecker  LBrasseur  FProbst-Kepper  MGueguen  MBoon  TVan den Eynde  BJ Cytolytic T lymphocytes raised against a human bladder carcinoma recognize an antigen encoded by gene MAGE-A12. J Immunol 2000;1646041- 6045
PubMed Link to Article
Ríos  ARodríguez  JMIllana  JTorregrosa  NMParrilla  P Familial papillary carcinoma of the thyroid: report of 3 families. Eur J Surg 2001;167339- 343
PubMed Link to Article
From  GMellemgaard  AKnudsen  NJorgensen  TPerrild  H Review of thyroid cancer cases among patients with previous benign thyroid disorders. Thyroid 2000;10697- 700
PubMed Link to Article
Ríos  ARodríguez  JMMoya  MR  et al.  Frequency of HLA-C alleles in differentiated thyroid carcinoma in southeastern Spain: HLA-Cw7 as a poor prognosis factor. Cancer 2004;100264- 269
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 3

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com


Allele