Human leukocyte antigens as genetic markers in Greek patients with sporadic pancreatic cancer.

PURPOSE: In this study we investigated the relationship between specific HLA antigens and sporadic pancreatic cancer in Greek population. METHODS: The allele frequencies of serologically and molecular defined class I and II HLA antigens were studied in 60 unrelated patients with pancreatic cancer histologically confirmed. The results obtained for HLA frequencies were compared with those of 105 healthy control subjects (control group). RESULTS: Increased frequencies of HLA-A30 (16.7 vs. 3.8%; P < 0.01; OR = 5.05), A31 (9.5 vs. 1.9%; P < 0.05; OR = 5.72), B18 (31.7 vs. 14.3%; P < 0.05; OR = 2.78) and Cw7 (53.3 vs. 21.9%; P < 0.01; OR = 4.07) were observed in patients with pancreatic cancer in comparison to the control subjects. CONCLUSIONS: This study demonstrates the association between specific HLA antigens and pancreatic cancer development in whites and suggests a genetic susceptibility factor for the disease.

HLA phenotypes as promoters of cardiovascular remodelling in subjects with arterial hypertension.

The objective of this study was to investigate the association between human leukocyte antigens (HLA) phenotypes and cardiovascular remodelling, as expressed by left ventricular mass (LVM) and carotid intima-media thickness (IMT), in hypertensives. We examined 153 subjects with arterial hypertension and 61 normotensive controls living in the greater Athens area. The population was classified into three groups and specifically group I (normotensives), group II with Grade 1 hypertension and group III with Grade 2 or 3 hypertension. HLA class I and class II antigens were studied by microlymphocytotoxic technique. Carotid IMT and LVM were determined by ultrasonography. The prevalence of HLA DQ7 in the hypertensive cohort was 27.4% that was significantly smaller than the 52.5% among the controls (P = 0.002). The HLA DR11 was found in 24.0% of the hypertensives and in 52.5% of the controls (P < 0.001). Group III hypertensives with HLA DR11 exhibited significantly higher LVM/h in comparison to the hypertensives without this HLA (199.0 +/- 28.8 vs 171.2+44.1g/m, P = 0.009). This association was not present in groups I and II. Similarly, group III hypertensives with HLA DQ7 were characterized by higher IMT in comparison to those without this HLA (0.94 +/- 0.19 vs 0.83 +/- 0.23 mm, P = 0.048). HLA DR17 was associated with higher IMT in both groups II and III (1.00 +/- 0.19 vs 0.82 +/- 0.19 mm, P = 0.046 and 1.01 +/- 0.23 vs 0.84 +/- 0.22 mm, P = 0.049, respectively) but not in group I. In conclusion, certain HLA phenotypes may be related to the levels of arterial blood pressure. Moreover, it seems that these HLA phenotypes may identify subjects with arterial hypertension that are more prone to develop cardiovascular hypertrophy.

Association of the HLA antigens with early atheromatosis in subjects with type 2 diabetes mellitus.

BACKGROUND: Inflammation plays an important role in the pathogenesis of atherosclerosis. The major histocompatibility complex, as expressed by the human leukocyte antigens (HLA) is considered to regulate the immune response. The aim of this study was to investigate the association of the HLA antigens with vascular remodeling estimated by the carotid intima-media thickness (IMT) in subjects with type 2 diabetes mellitus (DM). METHODS: We evaluated 197 patients with type 2 DM, 80 males and 117 females, mean age 61.8+/-7.8 years, with no history of cardiovascular events. The presence of other major cardiovascular risk factors was recorded. The currently identified HLA class I (-A, -B, -Cw) and class II (DR, -DQ) antigens were studied by a classical 2 step microlymphocytotoxic technique in peripheral blood T and B lymphocytes. Measurements of the IMT were performed in the right and left common carotid arteries, 15-20 mm proximal to the dilatation of the carotid bulb in an end-diastolic "frozen" and magnified B-mode ultrasonographic image. Glycosylated hemoglobin A1c (HbA1c) and C-reactive protein (CRP) were also measured. The results are presented as mean +/-1 standard deviation. RESULTS: Regarding the HLA phenotypes in the final analysis we tested a total of 24 HLA antigens that exhibited a frequency of at least 5% in our diabetic population. Only HLA A3 was found to be significantly associated with the carotid IMT. Forty-nine (24.9%) diabetics were HLA A3 positive (group A), while 148 (75.1%) were HLA A3 negative (group B) and had mean IMT of 0.89+/-0.16 mm and 0.98+/-0.21 mm, respectively (p<0.01). Also the two groups differed significantly in respect to CRP, with group A exhibiting lower serum levels (1.1+/-0.4 mg/dl vs 2.6+/-0.7 mg/dl for group A and B, respectively, p<0.05). However, no differences were observed between the two groups as far as blood glucose control, arterial hypertension and dyslipidaemia were concerned. CONCLUSIONS: Human leukocyte antigen A3 is associated with less vascular damage, as expressed by carotid wall thickness, in subjects with type 2 DM. These subjects may be characterized by a milder inflammatory response, as shown by the lower serum levels of CRP.

Association of specific HLA phenotypes with left ventricular mass and carotid intima-media thickness in hypertensives.

The aim of this study was to investigate the hypothesis that the expression of certain HLA antigens may constitute a risk marker for cardiovascular hypertrophy in subjects with arterial hypertension. We examined 158 subjects with newly diagnosed arterial hypertension. HLA class I (-A, -B, -Cw) and class II (-DR, -DQ) antigens were studied by two-step microlymphocytotoxic technique in peripheral T and B lymphocytes. Carotid intima-media thickness (IMT) was determined noninvasively by ultrasonography. The left ventricular mass was calculated according to the formula of Devereux and was normalized by the individual's height (LVM/h). The individuals with DR13 and DR17 were characterized by higher values of IMT compared to those without these HLA (0.096+/-0.018 cm v 0.085+/-0.021 cm, P = .011, 0.100+/-0.019 cm v 0.084+/-0.021 cm, P = .012, respectively). The presence of HLA DQ7 was characterized by markedly higher values of IMT that just failed to reach statistical significance (0.091+/-0.019 cm v 0.084+/-0.022 cm, P = .045). Furthermore, subjects with HLA DQ7 and DR11 exhibited higher values of LVM/h in comparison to those without these HLA (191.3+/-36.2 g/m v 166.9+/-41.0 g/m, P = .029 and 194.6+/-34.3 g/m v 166.6+/-40.9 g/m, P = .034, respectively). Hypertensive subjects with HLA B51 tended to have lower LVM/h (166.6+/-39.0 g/m with v 176.0+/-41.7 g/m without HLA B51, P = .045). In conclusion, it can be postulated that certain HLA phenotypes exhibit an association with increased carotid IMT and left ventricular mass in hypertensive subjects. The determination of these antigens may help to identify subjects at high risk for cardiovascular events.

Distribution of different HLA antigens in Greek hypertensives according to the angiotensin-converting enzyme genotype.

The angiotensin-converting enzyme (ACE) insertion/deletion polymorphism is an independent risk factor for cardiovascular disease. It has also been suggested that some HLA genes may contribute to the genetic susceptibility to essential hypertension. So far, an association between ACE polymorphism and HLA antigens in arterial hypertension has not been reported. We have studied 94 subjects with newly diagnosed essential hypertension, 49 men and 45 women (mean age, 52.3 +/- 11.3 years), as well as 104 randomly selected, age- and gender-matched normotensive individuals (54 men and 50 women, mean age 48.7 +/- 10.8 years). Both cohorts originated from the Greek population and lived in the greater Athens area. The ACE genotype was analyzed by polymerase chain reaction. HLA class I and II antigens were studied by serologic and molecular techniques. The prevalence of the ACE genotypes did not differ significantly between hypertensives and normal individuals. The casual blood pressure levels and the average ambulatory blood pressure levels were similar among the three ACE genotypes. Hypertensives with the ACE-DD genotype were characterized by an increased prevalence of the HLA-A2 antigen (50% v 31.4%, P < .005) and DR6 (16.7% v 11.4%, P < .01) in comparison to the normotensive subjects with the ACE-DD genotype. HLA-A24 was found more frequently among the hypertensives with the ACE-ID genotype than in the normal controls with the same genotype (35.5% v 26.4%, P < .05). ACE-DD genotype is associated with a high prevalence of specific HLA antigens. The coexistence of the ACE-DD genotype with certain HLA phenotypes could reveal a distinct hypertensive population with increased risk for cardiovascular events.

Human leukocyte antigens as genetic markers in colorectal carcinoma.

PURPOSE: Similar to findings obtained for most carcinomas, the pathogenesis of colorectal cancer is considered to be multifactorial. There is strong evidence for an inherited, genetic predisposition to disease in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. There is still debate, however, about the contribution of genetic factors to the pathogenesis of sporadic colorectal cancer. The present study was undertaken to search for human leukocyte antigen associations in a group of patients with colorectal cancer and to correlate the findings with both the histology of the disease and family history. SUBJECTS AND METHODS: The allele frequencies of serologically defined human leukocyte antigen class I and II antigens were studied in 101 patients with a recent, histologically confirmed diagnosis of colorectal cancer. All individuals in this study were unrelated to each other. After surgical treatment, all patients were grouped according to the stage (Dukes Stages A, B, C, and D), differentiation (Grades 1, 2, and 3), and the site of the tumor. Patients were also classified with regard to family history for colorectal cancer. The results obtained for human leukocyte antigen frequencies were compared with those of 105 healthy control subjects (control group). RESULTS: An increased frequency of human leukocyte antigen-B18 (27.72 vs. 14.28 percent; P < 0.025; odds ratio = 2.3) and of human leukocyte antigen-DQ5 (43.56 vs. 22.5 percent; P < 0.01; odds ratio = 2.65) was observed for patients with colorectal cancer vs. control subjects, respectively. In addition, human leukocyte antigen-B18 was present with increased frequency (30.76 percent; P < 0.05; odds ratio = 2.66; and 26.67 percent; P < 0.05; odds ratio = 2.18) among patients with rectal and colon carcinoma, respectively. A higher frequency of human leukocyte antigen-DQ5 (45.33 percent; P < 0.01; odds ratio = 2.84) was observed among patients with colon carcinoma. Remarkably, human leukocyte antigen-DQ5 (50 vs. 22.5 percent; P < 0.05; odds ratio = 3.43) and human leukocyte antigen-A1 (41.66 vs. 12.38 percent; P < 0.01; odds ratio = 5.05) were found to be strongly associated with a family history of colorectal cancer. CONCLUSION: The observation of specific human leukocyte antigen associations with particular subsets of colorectal cancer strongly suggests that genetic susceptibility for the development of colorectal cancer exists. Although the multifactorial pathogenesis of colorectal cancer must be considered, human leukocyte antigens may have useful predictive and diagnostic value.

D-penicillamine induced myasthenia gravis in rheumatoid arthritis: an unpredictable common occurrence?

Five patients out of 71 with rheumatoid arthritis (RA), who received D-penicillamine, developed myasthenia gravis (MG) within a two-year period. They all responded promptly to discontinuation of the drug and pyridostigmine administration. None of the patients had anti-Ro(SSA) antibodies or features of Sjögren's syndrome, whereas three of the five had the HLA-DR1 phenotype. The relatively high frequency of MG observed in our population, along with its unpredictability and potentially serious sequelae, necessitates its inclusion in the list of side effects of D-penicillamine routinely discussed with the patient, prior to initiation of the treatment. Full alertness of both the patient and the physician to even minor initial myasthenic symptoms, that dictate immediate discontinuation of the drug, is of obvious importance.

HLA alloantigens in Greek patients with systemic lupus erythematosus.

The frequency of the HLA-A, -B and -DR alloantigens was studied in 74 unselected, consecutive, unrelated Greek patients with systemic lupus erythematosus (SLE) and the results were compared with those of healthy controls (380 for the class I antigens and 154 for the class II antigens). No statistically significant differences were noted between patients and controls regarding the prevalence of any class II antigen. Furthermore, no such differences were observed between our 36 anti-Ro (SSA) positive and the rest of our SLE patients. However, the coexistence of anti-Ro (SSA) and anti-La (SSB) antibodies (9 patients) correlated significantly with HLA-B8, whereas the haplotype HLA-B8DR3 was more common in the anti-Ro (SSA) positive patients than in the rest-although the difference did not reach statistical significance. The combination of high anti-ds-DNA and low C4 serum levels correlated with absence of HLA-DR5. Our findings, while in agreement with those of certain previous studies, are somewhat different from those of others. The differences may at least partly be related to variations in the control populations employed. On the other hand some of the differences, in accordance with other peculiarities of Greeks with connective tissue disease, emphasize the role of racial and/or ethnic background in the HLA-association of various autoimmune diseases and the fact that the detectable HLA alloantigens in certain diseases modify disease and autoantibody expression rather than being responsible for the autoimmune process itself.

Soluble interleukin-2 receptors and autoantibodies in the serum of healthy elderly individuals.

Recently, we reported an increased incidence of various autoantibodies in a healthy elderly population (Group A, 64 subjects). Presently we examined whether there is variability in the expression of the age-associated immunological aberrations between different geriatric populations by extending our observations in another healthy elderly population (Group B, 119 subjects). We also determined the serum levels of soluble IL-2 receptors (sIL-2R) attempting to define the activation status of the immune system during senescence. Compared to non-elderly controls, healthy elderly individuals exhibited a significantly higher incidence of autoantibodies as well as significantly higher levels of sIL-2R in serum (p less than 0.001), the latter possibly suggesting the occurrence of lymphocytic activation during the ageing process. The overall prevalence of autoantibodies was statistically associated with the presence of raised sIL-2R levels in serum (p less than 0.005). These aberrant immunological phenomena were more frequent among the elderly of group A, compared to group B (p less than 0.005). In contrast to the uniform expression of various autoantibodies previously observed in group A, the autoantibody profile of group B consisted mainly of rheumatoid factor and antibodies to single-stranded DNA. Finally, no association could be demonstrated between the presence of autoantibodies and HLA antigens in 42 elderly studied.

HLA-alloantigen associations in Greek patients with Sjögren's syndrome.

The frequency of HLA-A, -B, and -DR alloantigens was studied in 46 patients with primary Sjögren's syndrome (pSS), 14 patients with secondary Sjögren's syndrome (sSS) and rheumatoid arthritis (RA), 26 classical RA patients without clinical or histologic evidence of Sjögren's syndrome (SS) and 172 normal controls. A statistically significant increase in the frequency of HLA-DR5 alloantigen was observed in the pSS patients, compared with the controls (P less than 0.007, corrected). No differences were detected between pSS patients with or without extraglandular manifestations, nor were any found between anti-Ro(SSA) positive and negative patients. The frequency of HLA-DR3 alloantigen (30%) was not significantly higher in our pSS population than in controls (25%), nor was that of -DR4 in the RA or the sSS patients. The results of the present study indicate that the 'SS susceptibility gene' in Greek patients is linked with the HLA-DR5 expression gene and they support the hypothesis that the fundamental pSS gene may belong to another locus.

[HLA antigens in patients with Sjögren's syndrome]. / HLA-antigeny u bol'nykh s sindromom Shegrena.

HLA-antigens were studied in 116 Greek patients: 22 with pSS, 14 with sSS and RA, 26 with classical RA and 420 healthy controls. A statistically significant increase in HLA-DR5 was observed mainly in pSS patients with anti-Ro (SSA). A significant increase in HLA-B8, HLA-DR3 and HLA-DR5 was observed in pSS patients with anti-La (SSB) antibodies as compared to the controls.

Lack of HLA-antigen association in Greek rheumatoid arthritis patients.

One hundred and eighteen unrelated Greek patients with classic rheumatoid arthritis (RA) were tissue-typed for HLA-A, -B, -DR antigens and the frequency was compared to that of healthy controls. Greek RA patients regardless of sex, anatomical severity, seropositivity and age at disease onset are not associated with any of the HLA alloantigens tested. Only an increased prevalence, not statistically significant, was observed of the HLA-DR5 antigen in the Ro (SSA) positive RA group.