Nonimmune chronic idiopathic neutropenia of adults (NI-CINA) is a frequently seen granulocytic disorder characterized by the “unexplained” persistent decrease of the number of circulating neutrophils below the lower limit of the normal distribution in a given ethnic population.1,2 The diagnostic criteria allowing the identification of the condition among other types of chronic neutropenia are presented elsewhere.3-5 The cause of the disorder and the underlying mechanisms leading to neutropenia in the affected subjects are unknown, but recent studies in our laboratory provided strong evidence for the existence of an unrecognized low-grade chronic inflammatory process in these patients, which may be involved in the pathogenesis of NI-CINA by increasing the production of a variety of proinflammatory cytokines and chemokines3 and therefore affecting both neutrophil production in bone marrow4 and neutrophil extravasation in the periphery.5 Here, we describe a predisposition of HLA-DRB1*1302 haplotype–carrying individuals to develop NI-CINA.

The study was carried out on 56 NI-CINA patients and 39 healthy volunteers, all residents of the island of Crete. Venous blood was collected into vacutainer tubes containing ethylenediaminetetraacetic acid (EDTA) as anticoagulant and used as a DNA source. DNA extraction was carried out by salting-out technique. For the typing of HLA alleles, polymerase chain reaction (PCR) was utilized. HLA-A, -B, and -C alleles were typed using PCR-sequence specific primers (PCR-SSP) with primer sets provided by PelFreez Clinical systems (Brown Deer, WI). HLA-DRB1 alleles were typed using the ELPHA high resolution hybridization system provided by Biotest AG (Dreieich, Germany). HLA-DQB1 and DPB1 alleles were typed using the InnoLiPa reverse slot blot hybridization system provided by Murex (Immunogenetics, Zwijndzecht, Belgium). Results were analyzed with the Yates continuity-corrected chi-square test using the GraphPad program.

We found that the frequency of the HLA-DRB1*1302 haplotype was 21.43% in the group of patients compared to 2.56% in the controls (P = .0199) (Table 1). The relative risk for the carriers was 8.36. The frequencies of all other HLA haplotypes did not differ significantly between patients and control subjects.

Table 1.

Frequency of selected HLA-DRB1 haplotypes in the NI-CINA patients

Haplotype Patients (%) (n = 56) Healthy controls (%) (n = 39) χ2-value Pvalue  
HLA-DRB1*0101 4  (7.14) 2  (5.13) 0.9748 ns  
HLA-DRB1*0301 3  (5.36) 1  (2.56) 0.8827 ns  
HLA-DRB1*0701 12  (21.43) 6  (15.38) 0.6359 ns  
HLA-DRB1*1001 2  (3.57) 3  (7.69) 0.6761 ns  
HLA-DRB1*1101 10  (17.86) 12  (30.77) 0.2223 ns  
HLA-DRB1*1104 21  (37.5) 15  (38.46) 0.9045 ns  
HLA-DRB1*1201 2  (3.57) 2  (5.13) 0.8827 ns  
HLA-DRB1*1301 3  (5.36) 5  (12.82) 0.3612 ns  
HLA-DRB1*1302 12  (21.43) 1  (2.56) 5.4210 P = .0199  
HLA-DRB1*1401 5  (8.93) 6  (15.38) 0.5212 ns  
HLA-DRB1*1501 3  (5.36) 4  (10.26) 0.6171 ns  
HLA-DRB1*1502 4  (7.14) 3  (7.69) 0.7655 ns  
HLA-DRB1*1601 10  (17.86) 3  (7.69) 0.2650 ns 
Haplotype Patients (%) (n = 56) Healthy controls (%) (n = 39) χ2-value Pvalue  
HLA-DRB1*0101 4  (7.14) 2  (5.13) 0.9748 ns  
HLA-DRB1*0301 3  (5.36) 1  (2.56) 0.8827 ns  
HLA-DRB1*0701 12  (21.43) 6  (15.38) 0.6359 ns  
HLA-DRB1*1001 2  (3.57) 3  (7.69) 0.6761 ns  
HLA-DRB1*1101 10  (17.86) 12  (30.77) 0.2223 ns  
HLA-DRB1*1104 21  (37.5) 15  (38.46) 0.9045 ns  
HLA-DRB1*1201 2  (3.57) 2  (5.13) 0.8827 ns  
HLA-DRB1*1301 3  (5.36) 5  (12.82) 0.3612 ns  
HLA-DRB1*1302 12  (21.43) 1  (2.56) 5.4210 P = .0199  
HLA-DRB1*1401 5  (8.93) 6  (15.38) 0.5212 ns  
HLA-DRB1*1501 3  (5.36) 4  (10.26) 0.6171 ns  
HLA-DRB1*1502 4  (7.14) 3  (7.69) 0.7655 ns  
HLA-DRB1*1601 10  (17.86) 3  (7.69) 0.2650 ns 

Yates continuity-corrected chi-square test. Statistically significant at P ≤ .05. ns, nonsignificant difference.

Proportions of haplotype-carrying subjects are in parentheses.

The clinical and biologic significance of our finding is unknown, but it seems possible that the frequency of the HLA-DRB1*1302 haplotype may have a role in the development of the aforementioned unrecognized low-grade chronic inflammation. Associations of HLA haplotypes with chronic inflammatory processes have already been well documented in a variety of clinical disorders.8 We believe that the increased frequency of the HLA-DRB1*1302 haplotype in NI-CINA patients may indicate the possible genetic basis in the development of such an inflammation, and thus it may predispose the haplotype-carrying subjects to develop the disorder.

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