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Association of Meniere disease with human leukocyte antigen in Taiwanese population.


The etiology of Meniere disease (MD) is multifactorial; genetic factors seem to play an important role. The associations between MD and human leukocyte antigen (HLA) status have been studied previously in several populations and have shown that the HLA alleles imparting susceptibility varied. In the present study, we explored HLA status in Taiwanese patients with definitive MD. HLA was typed via polymerase chain reaction, sequence-specific oligonucleotide genotyping in 35 patients with MD diagnosed using the criteria of the American Academy of Otolaryngology-Head and Neck Surgery and 70 unrelated healthy controls. HLA allele association tests were used to evaluate differences in allelic frequencies between the patients and controls. The allelic frequency of HLA-A*11 was significantly greater in MD patients than in controls (52.9 vs. 31.4%, odds ratio: 2.45, 95% confidence interval: 1.4 to 4.4, p = 0.004, p corrected = 0.03). Thus, A*ll may be a useful HLA biomarkerin Taiwanese patients with MD. Further larger-scale studies are required.


Prosper Meniere first described Meniere disease (MD) in 1861. (1) MD is characterized by intermittent episodes of vertigo, fluctuating hearing loss, tinnitus, and aural pressure. (1) MD is the second most common cause of vertigo in the United States, with the prevalence being approximately 200 per 100,000 (0.2% of the population). (2) The pathogenesis may feature disturbance of cochlear fluid homeostasis and/or endolymphatic hydrops of the membranous labyrinth. (3)

MD may have a multifactorial etiology featuring both a genetic predisposition and environmental factors. (4,5) Various etiologies have been suggested, including infection, allergy, an endocrine disturbance, a sympathetic vasomotor disturbance, psychosomatic factors, and disorders of the immune system. (6) Most cases of MD are sporadic; a minority of patients have a relevant family history featuring autosomal-dominant MD inheritance. (7) In 1979, McCabe introduced the concept of autoimmune inner ear disease, (8) as MD was thought to be associated with such autoimmunity as evidenced by the response to steroid therapy of some MD patients with elevated levels of circulating immune complexes, especially during the active phase. (8-10)

Relationships between the human leukocyte antigen (HLA) complex and MD have been extensively investigated; however, the candidate HLA genes have varied worldwide (table 1). For example, HLA-Cw7 was more common in British patients, (11) DRB1*1602 in Japanese patients, (12) and DRB1*09 served as a protective genetic marker in a Beijing Han population. (13) Mediterranean patients with bilateral MD are often of HLA DRB1*1101 status. (14) In Korean patients with MD, the frequencies of Cw*0303 and Cw*0602 were significantly greater and those of B44 and Cw*0102 were significantly less compared with controls. (15)

Recently, Dabiri et al found that the HLA-Cw*04 and HLA-Cw*16allelesweresignificantly elevated in Iranian patients with both definitive and probable MD. (16) However, any such association in Taiwanese patients with MD has not yet been investigated. Therefore, we explored whether an HL A marker was associated with MD in such a population.

Patients and methods

Ethical considerations. All patients gave written informed consent as mandated by the Declaration of Helsinki. The Institutional Review Board of Chang Gung Memorial Hospital and National Taiwan University Hospital approved the study.

Patients. For this case-control study performed between December 2009 and December 2013, DNA samples were obtained from 35 unrelated patients with definitive MD (experimental group) while 70 healthy controls were enrolled at Chang Gung Memorial Hospital, Linkou. All patients with MD were diagnosed using the MD criteria of the American Academy of Otolaryngology-Head and Neck Surgery (A AO-HNS). (17) These criteria were two or more definitive spontaneous episodes of vertigo [greater than or equal to] 20 m inutes in duration; audiometrically documented hearing loss on at least one occasion; tinnitus or aural fullness in the treated ear; and exclusion of other causes such as otosyphilis or acoustic neuroma.

DNA extraction and genotyping. Peripheral blood samples (10 ml) from all patients and controls were collected into tubes containing ethylenediamine tetraacetic acid. The buffy coats were lysed and genomic DNA isolated using proteinase K and a QI Aamp blood kit (Qiagen; Hilden, Germany) according to the manufacturer's instructions. The H LA-A, B, Cw, DRB1, and DQ loci were typed by polymerase chain reaction amplification fol lowed by sequence-specific oligonucleotide probing. The amplified sequences were hybridized to arrays of immobilized probes.

Statistical analysis. Allele frequency (AF) was calculated using the following formula:

AF (%) = (n/2 N) x 100, where n = the number of subjects with a particular allele and N = the total number of individuals.

Differences in HLA allele frequencies between MD patients and controls were compared using the chi-square or Fisher exact test, as appropriate. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were also calculated. The Bonferroni method was used to derive corrected p values (p corrected: pc); a difference was considered significant when thepc value was <0.05.

All statistical analysis was performed with the aid of the Statistical Package for the Social Sciences software v. 17.0.


The clinical features of the study group are shown in table 2. We studied 35 adult Taiwanese patients (21 women and 14 men) with a mean age of 53.9 [+ or -] 13.6 years and a definitive MD diagnosis. The age at onset was 49.4 [+ or -] 12.7 years. Unilateral lesions were present in 33 patients and bilateral lesions in 2 patients. Most lesions (62.9%) were left sided. In terms of hearing status, 19 patients (54.3%) had a hearing loss of 25 to 40 dB, 12 (34.3%) had a loss of >40 to 70 dB, and 4 (11.4%) had a loss >70 dB. The hearing losses of the less affected ears of the 2 patients with bilateral MD were both <25 dB.

The caloric test was run on 32 patients, of whom 22 had evidence of canal paralysis (R/L = 8/14) and 10 did not. Furthermore, the extent of functional disability as reported by the self-administered AAO-HNS instrument was level I in 2 patients, level II in 5, level III in 10, level IV in 10, level V in 3, and level VI in 1. Four patients could not select sentences defining their conditions.

A total of 8 HLA-A, 13 HLA-B, 9 HLA-Cw, 12 HLADRB1, and 6 HLA-DQ alleles were typed. The prevalence of HLA-A*11 was significantly greater in MD patients compared with controls (37/70 [52.9%] vs. 44/140 [31.4%], OR: 2.45, 95% CI: 1.4 to 4.4, p = 0.004, pc = 0.03). No other allele frequency differed significantly between the groups (data available in table form upon request from the corresponding author).


In this case-control study, we found that All was strongly associated with definitive MD in ethnic Chinese living in Taiwan. This HLA marker has never been reported in other MD populations. Various autoimmune diseases, including MD, are associated with particular HLA class I and/or class II alleles. British, (11) Korean, (14) Iranian, (16) and (now) Taiwanese studies have revealed that HLA class I antigens are associated with MD. However, HLA class II antigens were associated with MD in Japanese, (12) Northern Chinese (13) (a Beijing Han population), and Mediterranean MD patients. (15) Therefore, ethnic differences in such associations are in play. The differential distributions of relevant HLA class I or II loci may yield insights into the immune reaction or inflammatory response associated with MD.

A*11, an HLA class I molecule, is encoded between the HLA-A and HLA-B loci on chromosome 6p21.3 and has long been known to exert specific biologic functions, being the natural ligand for the inhibitory KIR3DL2 receptor. (18) Several epitopes recognized by cytotoxic T lymphocytes are HLA-All-restricted.

Infections and immune conditions associated with HLA-A11 expression havebeen investigated; these include familial otosclerosis, pulmonary tuberculosis, leprosy, cytomegalovirus infection with epilepsy, osteosarcoma, antidepressant-induced hepatitis, steroid-responsive nephrotic syndrome, and diffuse panbronchiolitis. (19-26) It has been proposed that immunologic responses are initiated under certain conditions by general or unique HLA determinants in susceptible All carriers. (27)

The presence of certain HLA antigens renders patients susceptible to MD; ethnic differences in HLA-associated genes may partially explain the variations in MD incidence among populations. However, HLA genetic differences are not the only relevant factors. Contributions made by unidentified genetic, multigenetic, environmental, and infectious factors also must be considered. In addition, patients of the same ethnicity living in different regions may vary in terms of the MD- associated HLA gene. For example, HLA-B54 and HLA-A11 were positively associated with diffuse panbronchiolitis in Northern and Southern Chinese, respectively. (26) Therefore, it is reasonable that DRB1*09 should be protective in a Beijing Han population (Northern Chinese) with MD but that A*11 should increase MD susceptibility in a Taiwanese population (East-Southern Chinese).

The effects of genetic predisposition and geographic background on MD development in various ethnic Chinese groups require further study. We found a positive association between HLA-A*11 and MD in ethnic Chinese of Taiwan, which is unlike what has been noted in other populations. We suggest that the HLA class I antigen may play an immunologic role in M D pathogenesis in Taiwanese patients. Our sample size was relatively small and our study, thus, underpowered. Further larger scale population studies are required to confirm our findings.

From the Division ofOtology, Department ofOtolaryngology (Dr. Chan and Dr. Wu), the Graduate institute ofClinical Medical Science (Dr. Chan), and the Department of Nephrology, Kidney Institute (Dr. Lai), Chang Gung Memorial Hospital, Linkou, Taiwan; the College of Medicine, Chang Gung University, Taoyuan, Taiwan (Dr. Chan, Dr. Wu, and Dr. Lai); the Department ofPediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (Dr. Ho); the Fu Jen School of Medicine, Catholic University, New Taipei City, Taiwan (Dr. Ho); and the China Medical University Hospital, Kidney Institute, Taichung, Taiwan (Dr. Lai).

Corresponding author: Ping-Chin Lai, MD, PhD, Department of Nephrology, Kidneylnstitute.ChangGungMemorialHospital, College of Medicine, Chang Gung University, No. 5, Fuxing St., Guishan Dist., Taoyuan City 333, Taiwan. Email: Funding/support: This work was fundedby Research GrantCMRPG381101 from Chang Gung Memorial Hospital, Linkou, Taiwan.

Kai-Chieh Chan, MD; Che-Ming Wu, MD; Wan-Ling Ho, MD, PhD; Ping-Chin Lai, MD, PhD.


This study was supported by grants from CMRPG381101 from Chang Gung Memorial Hospital, Linkou, Taiwan.


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Table 1. Population studies on HLA alleles associated
with Meniere disease (p < 0.05) in English literature

Reference                   Population         HLA class I

Xenellis et al (11)         British            CW*7

Koyama et al (12)           Japanese

Meng et al (13)             Northern Chinese

Lopez-Egcamez et al (14)    Mediterranean

Yeo et al (15)              Southern Korean    CW*0303




Dabiri et al (16)           Iranian            CW*04


Present study               Taiwanese          A*11

Reference                   HLA class II

Xenellis et al (11)

Koyama et al (12)           DRB1*1602

Meng et al (13)             DRB1*09

Lopez-Egcamez et al (14)    DRB1*1101

Yeo et al (15)

Dabiri et al (16)

Present study

Key: HLA = human leukocyte antigen.

Table 2. Clinical characteristics of study population
(N = 35)

Age (yrs [+ or -] SD)           53.9 [+ or -] 13.6
Sex, n (%)
  Women                         21 (60.0)
  Men                           14 (40.0)
Onset age (yrs [+ or -] SD)     49.4 [+ or -] 12.7
Lesion side, n (%)
  Unilateral                    33 (94.3)
    Left                        22 (62.9)
    Right                       11 (31.4)
  Bilateral                     2 (5.7)
Hearing staging
<25 dB                          2 * (5.7)
25-40 dB                        19 (54.3)
40-70 dB                        12 (34.3)
>70dB                           4 (11.4)
Caloric test (n = 32)
  Negative                      10 (31.3)
  Right canal paralysis         8 (25.0)
  Left canal paralysis          14 (43.8)
Glycerol test (n = 19)
  Negative                      10 (52.6)
  Positive                      9 (47.4)

* Refers to better ear's hearing level
in bilateral Meniere disease.

Key: SD = standard deviation.
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Author:Chan, Kai-Chieh; Wu, Che-Ming; Ho, Wan-Ling; Lai, Ping-Chin
Publication:Ear, Nose and Throat Journal
Geographic Code:9TAIW
Date:Dec 1, 2018
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