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Am J Physiol Heart Circ Physiol 293: H3175-H3179, 2007. First published September 28, 2007; doi:10.1152/ajpheart.00795.2007
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Atherogenic vascular and lipid phenotypes in young patients with Type 1 diabetes are associated with diabetes high-risk HLA genotype

Michal Odermarsky,1 Anita Nilsson,2 Åke Lernmark,2 Sture Sjöblad,3 and Petru Liuba1

Pediatric 1Cardiology and 3Endocrinology, Lund University Hospital, Lund, Sweden; and 2Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden

Submitted 10 July 2007 ; accepted in final form 21 September 2007


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Expression of human leukocyte antigen (HLA) class II molecules on islet endothelial cells is a central vascular event in the pathogenesis of Type 1 diabetes. Previous studies demonstrated the ability of other vascular endothelial cells to express HLA and thereby to process islet autoantigens on their surface. We investigated whether the HLA-DQ2/8 genotype, which confers the highest risk for Type 1 diabetes, is associated with early atherosclerosis in youths with this disease. Brachial artery endothelium-dependent, flow-mediated dilation (BA-FMD) and carotid artery intima-media thickness (CA-IMT), as well as markers of systemic inflammation [C-reactive protein (CRP), fibrinogen, and orosomucoid], HbA1C, LDL, HDL, and total cholesterol, were assessed in 86 children and adolescents with Type 1 diabetes (mean age and diabetes duration, 15 and 7 yr, respectively) between 2004 and 2006. HLA genotypes were determined in dried blood spots by an oligoblot hybridization method. As a result, HLA-DQ2/8 was detected in 34 patients (DQ2/8). When this group was compared with the remaining patients (non-DQ2/8, n = 52), there were no differences in age, diabetes duration, HbA1C, body mass index, inflammatory markers, and IMT (P ≥ 0.4). In the DQ2/8 group, LDL-to-HDL ratio was elevated compared with that in the non-DQ2/8 group (1.8 vs. 1.3, respectively; P = 0.001), whereas FMD did not significantly differ between the groups (5.3% vs. 6.7%, respectively; P = 0.08). When patients were further categorized in relation to CRP (cut-off value, 1 mg/l), BA-FMD was significantly lower (3%, P < 0.01), whereas LDL-to-HDL ratio increased further (2.2, P < 0.001) in the subgroup of DQ2/8 and CRP ≥ 1 patients compared with the remaining three subgroups. These associations remained significant after adjustment for age, diabetes duration, and HbA1C by analysis of covariance. The brachial artery responses to nitroglycerine were similar in all subgroups. In conclusion, the diabetes-predisposing HLA-DQ2/8 genotype in children and adolescents with Type 1 diabetes interferes with endothelial and lipid-related mechanisms of early atherosclerosis, possibly in part through inflammatory pathways.

genetics; lipids; vascular function

TYPE 1 DIABETES mellitus occurs most frequently in children and adolescents and is of growing concern particularly in industrialized countries, including Sweden and the United States, as its incidence continues to rise (3).

A genetic susceptibility involving class II human leukocyte antigen (HLA) genes is recognized in more than 80% of young patients with Type 1 diabetes (13). The primary loci of genetic susceptibility to Type 1 diabetes have been mapped to the HLA-DQ region, which is located on chromosome 6 (23). Two HLA haplotypes, DQB1*0302-A1*0301 (DQ8) and DQB1*0201-A1*0501 (DQ2), appear to confer the highest risk for developing Type 1 diabetes (27), especially when both are present in the genotype (i.e., HLA-DQ2/8).

Previous studies suggested that the expression of HLA-DQ molecules on the surface of pancreatic microvascular endothelial cells could be an important vascular pathway in the autoimmune lymphocyte-mediated reaction that leads to beta-cell destruction, the underlying pathology of Type 1 diabetes (17, 26). This process is seemingly not confined to the pancreas since other organs such as gut and thyroid may be affected as well (1). A recent observation that aortic vascular endothelial cells also owe the ability to express HLA (6) lends support to this hypothesis.

An important question is whether the HLA-mediated endotheliopathy could also occur at the site of the conductance arteries, where atherosclerosis develops. Patients with Type 1 diabetes are at significant risk for cardiovascular disease in adult life (2). Early and accelerated atherosclerosis appears to play an important role in the excess cardiovascular morbidity (2, 5).

In light of the aforementioned findings and given the importance of vascular endothelial cells throughout the course of atherosclerosis (4) including in diabetes (22), we investigated whether the diabetes-predisposing HLA genotype DQ2/8 could interfere with lipid and vascular phenotypes of early atherosclerosis in children and adolescents with Type 1 diabetes.


   METHODS
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 METHODS
RESULTS
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Study population. Eighty-six children and adolescents aged between 7–22 yr (mean age, 15 yr; 49 males and 37 females) with Type 1 diabetes for at least 6 mo (mean duration 7 yr) were randomly recruited from the diabetes outpatient clinic at Children's Hospital Lund. All patients were on insulin treatment (Levemir or Lantus, and Novorapid). Four patients were on thyroid hormone replacement therapy (Levaxin). Exclusion criteria were familiar hypercholesterolemia, active smoking, history of premature coronary or cerebrovascular disease among first-degree relatives, and systemic hypertension. Body weight, height, arterial blood pressure (systolic and diastolic), and blood glucose were measured on the ultrasound visit. Data on demographic information, parental education and current occupation, and family and personal history for major cardiovascular risk factors (primary hypercholesterolemia, hypertension, premature coronary, and cerebrovascular disease) were assessed by a questionnaire. Data regarding diabetes duration were obtained from the registry of the outpatient diabetes clinic.

The study was approved by the ethical committee for human research at the Lund University. Written consent was obtained from all participants aged 18 yr and older or, if under 18, from their guardians. All participants gave oral consent.

HLA typing, inflammatory, and lipid analyses. HLA typing was performed from dried blood spots by the DELFIA method. Briefly, DNA in the blood was amplified, and the presence of the particular alleles was determined by a hybridization reaction using allele-specific, short oligonucleotides labeled with lanthanide chelates (14).

High-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol were analyzed by an enzymatic method (Roche/Hitachi 912, Roche Diagnostics). Plasma high-sensitivity C-reactive protein (CRP) was measured by enzyme-linked immunoassay using polyclonal antibodies (DACO Diagnostics, Glostrup, Denmark). Plasma orosomucoid and fibrinogen were assessed by specific immunoassays.

Assessment of endothelium-dependent dilation of the brachial artery. The dilatory responses to hyperaemia (endothelium-dependent agonist) and glycerol trinitrate (GTN, endothelium independent) were obtained in 70 patients. Briefly, longitudinal scans of the brachial artery (nondominant arm) were imaged several centimeters above the antecubital fossa via a 15-MHz linear ultrasound transducer of an Acuson Sequoia C256 (Siemens). The ultrasound beam frequency was set at 8 MHz. Once the image was obtained, the transducer was positioned throughout the ultrasound study with the aid of a transducer holder (Great Ormond Street Hospital, London, UK). ECG-gated end-diastolic scans of the artery were recorded at baseline, and a pressure cuff tourniquet placed around the forearm was thereafter inflated to 200 mmHg (minimum 50 mmHg over the systolic blood pressure) for 5 min. A new series of frames were taken for 15 s before and 120 s after cuff deflation. Arterial flow velocity was obtained before and during the first 15 s after cuff release by pulsed-Doppler signal at 70° to the vessel with the range gate in the center of the artery. Blood flow volume was calculated by multiplying the velocity-time integral of the Doppler signal by heart rate and the vessel cross-sectional area. Reactive hyperemia was calculated as the percent increase in flow after cuff release compared with baseline flow. Following a 10-min recovery period, additional frames were taken before and over a 4-min period after sublingual administration of 400 µg GTN spray. Flow-mediated and GTN-induced dilation of the brachial artery was expressed as maximum percent dilatation following cuff deflation and GTN administration, respectively. All scans were taken in a blind fashion, with the sonographer being unaware of the patients’ inflammatory and HLA characteristics.

Carotid artery ultrasound protocol. The ultrasound system used is described in Assessment of endothelium-dependent dilation of the brachial artery. The imaging protocol was previously described in detail (16). In short, longitudinal scans in bidimensional mode of the 1-cm-long distal end of the left common carotid artery were imaged so that the lumen-intima and intima-media interfaces were clearly distinguishable. All scans corresponded to the R-wave on the ECG. Four to six scans from each individual were recorded on videotape for off-line analysis of the carotid artery compliance, stiffness index, and intima-media thickness (IMT). The mean carotid IMT of four measurements along a 1-cm segment was calculated from each scan. Mean IMT values obtained from all scans from the same subject were averaged, and the resulted mean IMT was used for statistical analyses.

Statistics. ANOVA was used to assess the differences between the DQ2/8 and non-DQ2/8 groups in age, body mass index (BMI), diabetes duration, HbA1C, and lipid, inflammatory, and vascular indexes [brachial artery endothelium-dependent, flow-mediated dilation (BA-FMD) and carotid artery intima-media thickness (CA-IMT)]. Analysis of covariance (ANCOVA) was used to control the associations of the HLA-DQ2/8 genotype with the lipid and vascular indexes for the possible confounding effects of age, diabetes duration, BMI, and HbA1C. Simple and multiple regression was used for determining the association between inflammatory, lipid, and vascular indexes. CRP was log transformed given its skewed distribution. Statistical significance was set at P < 0.05. Data are given as means ± SE unless otherwise specified. StatView for Windows (SAS Institute) was employed as statistical software.


   RESULTS
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DISCUSSION
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Thirty-four patients (39%, 18 male and 16 female) were positive for the HLA-DQ2/8 genotype. Among the remaining 52 patients (31 male and 21 female), 15 had one of the two haplotypes (HLA-DQ2 or DQ8). No differences in age, BMI, diabetes duration, and HbA1C were noted between the DQ2/8 and non-DQ2/8 groups (P ≥ 0.4, Fig. 1). Blood glucose was similar in both groups (8.8 mmol/l in non-DQ2/8 group vs. 8.4 mmol/l in DQ2/8 group, P = 0.7).


Figure 1
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  		Fig. 1. Box plot distribution of age (in yr), diabetes duration (in yr), body mass index (BMI, in kg/m2), and glycosylated hemoglobin levels (in %) of patients with diabetes with (DQ2/8; n = 34 patients) and without (DQ2/8; n = 52 patients) human leukocyte antigen (HLA)-DQ2/8 genotype. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box. *P value.

 
Lipid and inflammatory profiles. No significant differences in CRP (P > 0.4), fibrinogen (P > 0.8), and orosomucoid (P > 0.7) were observed between the DQ2/8 and non-DQ2/8 groups.

Lipid data were available in 83 patients. Two patients (one from each group) had HDL cholesterol below the acceptable level (0.9 mmol/l). LDL cholesterol (acceptable upper limit, 3.3 mmol/l) was abnormally elevated in five patients (3 in the non-DQ2/8 group and 2 in the DQ2/8 group).

When the groups were compared, LDL cholesterol was higher in the DQ2/8 group (2.5 ± 0.1 mmol/l) than in the non-DQ2/8 group (2.1 ± 0.2 mmol/l, P < 0.05), whereas HDL cholesterol did not significantly differ between the DQ2/8 group (1.5 ± 0.07 mmol/l) and the non-DQ2/8 group (1.7 ± 0.05 mmol/l, P = 0.1). Total cholesterol showed a trend toward increased levels in the DQ2/8 group compared with the non-DQ2/8 group (4.4 ± 0.2 vs. 4.1 ± 0.1 mmol/l, P = 0.08). LDL-to-HDL ratio, an important atherogenic lipid index, was significantly higher in the DQ2/8 group (1.8 ± 0.2) than in the non-DQ2/8 group (1.3 ± 0.2, P < 0.01; Fig. 2A). The difference remained significant after adjustment for age, BMI, diabetes duration, HbA1C, and CRP (P = 0.02 by ANCOVA).


Figure 2
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  		Fig. 2. A: box plot illustrating the differences in LDL-to-HDL ratio between the DQ2/8 and non-DQ2/8 groups. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box. B: association of LDL-to-HDL ratio with C-reactive protein (CRP) in DQ2/8 and non-DQ2/8 patients. *P value; r, correlation coefficient; n, number of patients.

 
Overall, the LDL-to-HDL ratio showed a modest correlation with CRP (r = 0.4, P < 0.001) and BMI (r = 0.4, P < 0.01). When the patients were grouped based on the genotype, the correlation between CRP and LDL-to-HDL ratio became significant among the DQ2/8 patients (r = 0.6, P < 0.001; Fig. 2B). In this group, the association between LDL-to-HDL ratio and CRP remained significant after adjustment for age, BMI, diabetes duration, and HbA1C (P < 0.01).

Flow-mediated and GTN-induced dilations of the brachial artery and intima-media thickness of the carotid artery. The groups were similar in baseline brachial artery diameter, reactive hyperemia, GTN-induced dilation and carotid IMT (Table 1).


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  		Table 1. Profile of measurements in patients with and without HLA-DQ2/8 genotype

 
No significant difference was noted between the groups with regard to BA-FMD (5.3 ± 0.7% in the DQ2/8 group vs. 6.7 ± 0.5% in the non-DQ2/8 group, P = 0.08; Fig. 3A). However, in the DQ2/8 group, FMD inversely correlated with CRP (r = 0.5, P = 0.01), but no such association was observed in the non-DQ2/8 group (r = 0.1, P = 0.8; Fig. 3B). FMD did not correlate with LDL-to-HDL ratio in either groups (P > 0.5).


Figure 3
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  		Fig. 3. A: box plot illustrating the differences in flow-mediated dilation of brachial artery between the DQ2/8 and non-DQ2/8 groups. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box. B: association of flow-mediated dilation of brachial artery with CRP in DQ2/8 and non-DQ2/8 patients. *P value; r, correlation coefficient; n, number of patients.

 
Low-grade inflammation, lipid, and vascular indexes in DQ2/8+ patients. When the patients were further categorized according to their CRP levels (cut-off value, 1 mg/l), both LDL-to-HDL ratio (Fig. 4A) and FMD (Fig. 4B) showed a shift toward a more atherogenic profile in the DQ2/8 and CRP ≥ 1 subgroup (2.2 ± 0.2% and 3 ± 1.1%, respectively) compared with the remaining subgroups. The GTN-induced dilatory responses of the brachial artery and carotid IMT were similar in all subgroups (P > 0.3).


Figure 4
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  		Fig. 4. Box plot distribution of LDL-to-HDL ratio (A) and flow-mediated dilation of brachial artery (B) in relation to the HLA-DQ2/8 genotype and CRP (cut-point, 1 mg/l). The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box. *P value; n, number of patients.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
To the best of our knowledge, this study is the first to suggest that children and adolescents with Type 1 diabetes with genotype conferring the highest risk for this disease could be more susceptible to atherogenic endothelial and lipid phenotypes. Our findings also suggest a possible relationship between this genetic susceptibility and systemic inflammation.

It is nowadays agreed that Type 1 diabetes increases the risk of cardiovascular disease through inflammatory, oxidative, and glucose-related events that lead to vascular endothelial damage (11), which is a key mechanism in atherosclerosis through all of its stages (4). Mounting evidence points out that a close-to-normal glycemic control in patients with Type 1 diabetes is not sufficient to fully prevent the widespread vasculopathy (7), thus supporting the view that other intrinsic and extrinsic factors are important as well. Although the concept of heritability of cardiovascular disease has gained increasing attention during the past decade (19), no study has so far investigated whether genetic factors predisposing for Type 1 diabetes could interfere with atherogenic events in young patients with Type 1 diabetes.

Approximately 60% of the familial genetic risk for Type 1 diabetes is attributable to the HLA region (4). HLA-DQA1*0301-B1*0302 and DQA1*0501-B1*0201 haplotypes, especially when both are present in the genotype, have been found to be most strongly associated with the onset of Type 1 diabetes, whereas other haplotypes, e.g., HLA-DQA1*0102-B1*0602, confer an age-dependent negative association (27). The precise mechanisms whereby certain HLA increases diabetes susceptibility are not yet thoroughly clarified, but there is a general consensus that the HLA-DQ molecules exert their effects in part via the presentation of peptides from islet antigens to T cells, which contribute to the destruction of insulin-producing cells (28). Previous studies (17, 26) have shown that the expression of HLA molecules on the endothelial cells of islet microcirculation goes hand in hand with lymphocyte infiltration, thereby suggesting a possible pathogenic role of HLA-mediated endothelial vasculopathy in the development of Type 1 diabetes. Greening and colleagues (6) demonstrated that both pancreatic and aorta endothelial cells expressing HLA class II molecules have the ability to process and present the islet autoantigen GAD65. It is therefore conceivable to assume that endothelial cells of other peripheral arterial beds might also owe HLA-mediated antigen-presenting capacity in Type 1 diabetes (6). Particular HLA-DQ phenotypes, including DQ2/8, appear to facilitate the presence of potentially pathogenic T cells in the peripheral circulation via thymic selection (10).

Lymphocyte accumulation within the arterial wall is an important mechanistic component of atherosclerosis development (8) and contributes to endothelial injury (18). Endothelial injury promotes, in turn, additional immune events, including release of chemokines and cytokines, with further endothelial transmigration of immune cells and CRP synthesis via liver activation by interleukin-6 (15). The increased inflammatory activity leads to an alteration of lipoprotein metabolism characterized, in part, by an increase in LDL and a decrease in HDL cholesterol. Dyslipidemia prevails in Type 1 diabetes (12) and has an important role in endothelial injury and plaque development (24, 25). CRP is slightly, yet significantly, elevated in diabetic children (21). Nevertheless, a slight rise in CRP, i.e., over 1 mg/l, appears to be predictive of the relative risk of future cardiovascular events in apparently healthy adults (20). Järvisalo and colleagues (9) found that even less plasma concentrations of CRP (i.e., 0.7 mg/l) were associated with decreased endothelial vasodilatory function of the brachial artery. How exactly the putative association of CRP with the endothelial and lipidemic disturbances is amplified in patients with HLA-DQ2/8 diabetes is difficult to speculate, being in our opinion a tantalizing task for future studies addressing this topic.

In diabetic children and adolescents, measures of both functional and structural changes precursive to atherosclerosis seem to be influenced by age and diabetes duration. It is therefore possible that the observed associations with diabetes-risk HLA might be more pronounced in older patients or in those with longer disease duration. Also, further studies are needed to investigate whether a better diabetes control would translate into a lesser impact of the genotype on atherogenic endothelial and lipid phenotypes. In our study, these associations remained significant after adjustment for age, diabetes duration, and HbA1C, but a possible additive effect of these factors on the reported links cannot be ruled out. Whether the genotyping might be used to identify individuals for whom early lipid management may be warranted is perhaps an additional important task for future trials given the impact of diabetes dyslipidemia on cardiovascular risk.

Several limitations need to be considered. The size of the study group is rather small, although an invitation to participate was submitted to all patients with diabetes registered at our hospital. Our intention is to recruit additional patients aged 6 to 18 yr across the entire part of southernmost Sweden (Skåne county). Other HLA genotypes known to predispose to diabetes will be studied as well. We also intend to include siblings who are nondiabetic HLA matched to assess whether the HLA predisposition to diabetes could influence per se the vascular status and lipid profile in otherwise healthy children. Another limitation resides in the cross-sectional nature of this study. Follow-up studies over a 2-yr period are underway. Finally, even though flow-mediated dilation of the brachial artery is generally accepted as a surrogate of early atherosclerosis, it remains uncertain whether it could in time become a clinically useful measure of cardiovascular risk. Therefore, the precise clinical significance of the observed endothelial disturbances in relation to the HLA-DQ2/8 genotype remains uncertain.

In conclusion, the present study suggests independent associations of HLA-DQ2/8 genotype, which is known to confer the highest risk for Type 1 diabetes, with atherogenic lipid and vascular endothelial phenotypes in children and adolescents with Type 1 diabetes. The findings warrant large-scale, prospective studies to verify these findings and to assess whether this and other diabetes-susceptible HLA genotypes could accelerate atherosclerosis already during the preclinical phase of Type 1 diabetes.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The study was supported by the Flight Attendant Medical Research Institute, USA. Additional grants were received from Lund University, the Swedish Research Council, and the National Institutes of Health.


   ACKNOWLEDGMENTS
 
We thank Annica Maxedius, registered nurse, for excellent technical assistance in ultrasound scanning and blood sampling throughout the study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. Liuba, Div. of Cardiology, Dept. of Paediatrics, Lund Univ. Hospital, SE-22185 Lund, Sweden (e-mail: petru.liuba{at}med.lu.se)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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