HLA-DR antigens and HLA-DQ beta chain polymorphism in susceptibility to rheumatoid arthritis.

Forty four patients with rheumatoid arthritis (RA) were studied for HLA-DR antigens and for HLA-DQ beta chain gene restriction fragment length polymorphism using DNA hybridisation. A significant increase in the prevalence of the DR4 antigen and a tendency towards an increase of DR1 was found in patients with RA. No allelic form of HLA-DQ restriction fragment length polymorphism patterns was increased, but the prevalence of an allele characterised by a combination of 7.5 and 3 kb fragments was decreased among patients with RA. The DQw8 subtype represented by a 12 kb fragment was the most common DR4 associated allele, and a 3.7 kb fragment related to DQw7 was found in only 5/25 (20%) DR4 positive patients and 2/12 (17%) controls. The results support the hypothesis that RA susceptibility factors are primarily located within HLA-DR genes but HLA-DQ genes may have a role in protection from the disease.     

Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes

Background The adipokine chemerin modulates the function of innate immune cells and may link obesity and inflammation, and therefore, a possible relation of chemerin to inflammatory proteins in obesity and type 2 diabetes (T2D) was analysed. As visceral fat contributes to systemic inflammation, chemerin was measured in portal venous (PVS), hepatic venous (HVS) and systemic venous (SVS) blood of patients with liver cirrhosis. Patients and methods Systemic chemerin was determined by ELISA in the serum of normal‐weight, overweight and T2D males, in the serum of T2D patients of both sexes, and in PVS, HVS and SVS of patients with liver cirrhosis. Results Circulating chemerin was similar in T2D and obese individuals but was significantly elevated in both cohorts compared to normal‐weight individuals. Chemerin positively correlated with leptin, resistin and C‐reactive protein (CRP). In T2D, chemerin was similar in male and female patients and increased in patients with elevated CRP. Chemerin was similar in PVS and SVS, indicating that visceral fat is not a major site of chemerin synthesis. Higher levels of chemerin in HVS demonstrate that chemerin is also released by the liver. Conclusions Visceral fat is not a major site of chemerin release, and elevated systemic levels of chemerin in obesity and T2D seem to be associated with inflammation rather than body mass index.     

HLA-D region RFLPs indicate that susceptibility to insulin-dependent diabetes in South India is located in the HLA-DQ region

Recently close markers for insulin-dependent diabetes mellitus in Western 'Caucasoid' subjects have been defined from DQ region (both alpha and beta genes) restriction fragment length polymorphisms. In order to define the genetic contribution to insulin-dependent diabetes mellitus in an Indian population we have analysed 58 unrelated Dravidian (South Indian) insulin-dependent diabetic patients and 43 controls. In insulin-dependent diabetes an increased frequency of the Taq 1 DQ beta restriction fragment length polymorphisms designated T2 omega/T6 (relative risk = 10.6), and of homozygotes for Taq 1 DQ alpha 4.6 kb (relative risk = 11), was found in the patients. The highest relative risk for insulin-dependent diabetes mellitus was obtained by comparing patients and control subjects who either (a) co-inherited DQT2 omega/T6 with certain DQ alpha restriction fragment length polymorphisms or (b) were DQ alpha 4.6 kb homozygotes, the combination of (a) and (b) accounting for 55.5% of insulin-dependent diabetes mellitus subjects and none of the controls (relative risk = 101; 95% confidence limits 93-109).     

Androgen receptor GGC repeat might be more involved than CAG repeat in the regulation of the metabolic profile in men

The influence of androgen receptor (AR) GGC repeat polymorphism on the metabolic profile of men has been much less studied than the one of CAG tract polymorphism. Therefore, in this study, we looked for the association of GGC and CAG tract with cardiovascular risk factors in men. Ninety-eight men followed by our andrological unit were retrospectively reviewed. Clinical and biochemical parameters on cardiovascular risk were considered. AR CAG and GGC polymorphisms were studied. GGC triplets were found to be positively and significantly correlated with several cardiovascular risk factors. On the other hand, inverse and significant correlations of CAG triplets were found with insulin and HOMA. As expected, age was positively correlated with cardiovascular risk, whereas total testosterone was inversely correlated with metabolic profile. Estradiol was not found to be correlated with any of the metabolic parameters. In the total sample, multivariate linear regression analysis confirms the positive and independent association of GGC triplets with glycemia, glycated hemoglobin, total cholesterol, triglycerides and homeostasis model assessment of insulin resistance (HOMA), whereas CAG repeat length is negatively associated with insulin and HOMA. Such associations are also substantially confirmed in non-diabetic subjects, whereas in diabetic patients only the GGC tract seems to be involved in the metabolic profile regulation. Our work shows a relevant role for GGC repeat tract in conditioning male cardiovascular risk, thus rendering necessary a deeper analysis on the role of GGC polymorphism both from the molecular and the clinical point of view.     

HLA-DR, HLA-DQ, and TAP genes in familial Hodgkin disease.

The HLA region has long been implicated in sporadic and familial Hodgkin disease (HD), with recent case-control studies suggesting that HLA class II loci predispose to sporadic nodular sclerosis HD (NSHD). To determine whether this predisposition extends to familial HD, HLA class II loci (DRB1, DQA1, DQB1, DRB3, DRB4, and DRB5) and transporter associated with antigen processing (TAP) loci (TAP1, TAP2) were investigated in 100 members of 16 families with at least 2 confirmed cases of HD. With the use of the transmission disequilibrium test, evidence for linkage disequilibrium with familial HD and, in particular, familial NSHD was obtained for the DRB1*1501-DQA1*0102-DQB1*0602 haplotype, the TAP1 allele encoding Ile at residue 333, and the DRB5-0101 allele. These 3 markers were in linkage disequilibrium and may not represent independent susceptibility regions. Use of a family-based approach excludes population stratification as an explanation for these findings.     

Hypothyroidism might be related to breast cancer in post-menopausal women.

An association between breast cancer and thyroid (autoimmune) diseases or the presence of thyroid peroxidase antibodies (TPOAb; a marker of thyroid autoimmune disease) has been suggested. However, little is known about whether women with thyroid (autoimmune) diseases are at increased risk for developing breast cancer. This cross-sectional and prospective cohort study investigated whether the presence of TPOAb or thyroid dysfunction is related to the presence or development of breast cancer. An unselected cohort of 2,775 women around menopause was screened for the thyroid parameters thyrotropin (TSH), free thyroxine (FT(4)), and TPOAb during 1994. Detailed information on previous or actual thyroid disorders and breast cancer, and on putative factors related to breast cancer and thyroid disorders, was obtained. Clinical thyroid dysfunction was defined by both abnormal FT4 and TSH, and subclinical thyroid dysfunction by abnormal TSH (with normal FT4). A TPOAb concentration >or= 100 U/ml was defined as positive (TPOAb(+)). The study group was linked with the Eindhoven Cancer Registry to detect all women with (in situ) breast cancer (ICD-O code 174) diagnosed between 1958 and 1994. Subsequently, in the prospective study, all women who did not have breast cancer in 1994 (n = 2,738) were followed up to July, 2003, and all new cases of (in situ) breast cancer and all cancer-related deaths were registered. Of the 2,775 women, 278 (10.0%) were TPOAb(+). At the 1994 screening, 37 women (1.3%) had breast cancer. TPOAbs were (independently) related to a current diagnosis of breast cancer (OR = 3.3; 95% CI 1.3-8.5). Of the remaining women, 61 (2.2%) developed breast cancer. New breast cancer was related to: (1) an earlier diagnosis of hypothyroidism (OR = 3.8; 95% CI 1.3-10.9); (2) the use of thyroid medication (OR = 3.2; 95% CI 1.0-10.7); and (3) low FT4 (lowest tenth percentile: OR = 2.3; 95% CI 1.2-4.6). In the first 3 years follow up, the relationship between FT4 and log-TSH was disturbed in women with a new breast cancer diagnosis. The presence of TPOAb was not related to breast cancer during follow-up. A direct relationship between thyroid autoimmunity and breast cancer is unlikely. Hypothyroidism and low-normal FT4 are related with an increased risk of breast cancer in post-menopausal women. Studies are needed to clarify the origins of this possible association.     

Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to Type 1 (insulin-dependent) diabetes mellitus

Summary Genes in the HLA complex are by far the most important in determining genetic predisposition or resistance to Type 1 (insulin-dependent) diabetes mellitus. In this review evidence is presented that the HLA genes mainly involved are those encoding some particular HLA-DQ molecules. Both among Black, Caucasian and Japanese subjects particular cis or trans encoded DQ molecules are significantly associated with susceptibility, while others are associated with resistance. A varying degree of susceptibility or resistance seems to be conferred by these DQ molecules, where those determining resistance are dominant over those determining susceptibility. The degree of genetic predisposition to develop Type 1 diabetes carried by an individual would therefore be the result of his or her particular combination of DQ molecules. A primary association to particular DQ molecules explains previously found associations to other HLA complex genes by linkage disequilibrium. Some mechanisms by which particular DQ molecules may determine susceptibility or resistance are also discussed. Potential islet beta-cell reactive CD4⁺ T-cells may escape negative selection (deletion) in the thymus, but normally become anergized or remain ignorant extra-thymically. However, under particular circumstances they may be triggered. The DQ molecules associated with Type 1 diabetes susceptibility may preferentially bind and present triggering and/or beta-cell derived peptides to such T cells, causing beta-cell destruction. The finding that particular DQ molecules determine susceptibility may lead to new methods of preventing development of Type 1 diabetes in susceptible individuals.     

Impaired non-esterified fatty acid suppression to intravenous glucose during late pregnancy persists postpartum in gestational diabetes: a dominant role for decreased insulin secretion rather than insulin resistance

Aims/hypothesis Non-esterified fatty acids are implicated in the pathogenesis of gestational (GDM) and type 2 diabetes. We examined the relationship between NEFA dynamics, insulin resistance and beta cell dysfunction in women with GDM in late pregnancy and postpartum.Methods A total of 19 Caucasian women with GDM and 19 healthy pregnant women matched for BMI and age underwent an IVGTT in the third trimester and 4 months postpartum, deriving values for insulin sensitivity (SI), insulin secretion (AIRg) and disposition index (DI). NEFA levels were measured serially.Results In pregnancy, the GDM women had similar SI but reduced AIRg and DI compared with control subjects. The GDM group demonstrated significantly slower NEFA suppression, which was attributable to the GDM women who required insulin during pregnancy (n=7) and who had markedly reduced AIRg and K_NEFA (NEFA disappearance constant) compared with their matched controls. In contrast, GDM subjects not requiring insulin (n=12) had similar NEFA suppression curves and AIRg to control subjects. Postpartum, GDM subjects demonstrated reduced SI and DI. The impaired suppression of NEFA persisted postpartum, but again only in the subgroup of GDM subjects who had required insulin during pregnancy. Furthermore, K_NEFA correlated with AIRg and DI in both states, but not with SI.Conclusions/interpretation Impaired NEFA suppression occurs in GDM subjects both in late pregnancy and postpartum in response to IVGTT-induced endogenous insulin secretion. The impaired NEFA suppression is present in GDM women with the most severe beta cell dysfunction (who had required insulin during pregnancy) and is related to their insulin secretory dysfunction rather than their reduced SI.     

Treatment of hypercholesterolemia in patients with primary biliary cirrhosis might be more beneficial than indicated

Cholesterol circulating levels are elevated in most of the patients with primary biliary cirrhosis. This review questions whether hypercholesterolaemia represents a cardiovascular risk in primary biliary cirrhosis and whether it should be treated. The published evidence indicates that hypercholesterolaemia in patients with primary biliary cirrhosis should be considered a cardiovascular risk factor only when other factors are present. Ursodeoxycholic acid the standard treatment of primary biliary cirrhosis improves the cholestasis and hereby lowers circulating levels of cholesterol. Primary biliary cirrhosis is not a contraindication to prescribe statins or fibrates to these patients. Interestingly, these two classes of drugs have been shown to improve not only the lipid profile but also the liver tests. In particular fibrates have been found to normalize liver tests in patients responding incompletely to ursodeoxycholic acid. Statins as well as fibrates possess specific anti-inflammatory properties which may be beneficial in primary biliary cirrhosis. In conclusion, hypercholesterolaemia in the absence of other cardiovascular risk factors does not require specific therapeutic intervention in patients with primary biliary cirrhosis. However, statins as well as fibrates seem to have beneficial effects on the primary biliary cirrhosis itself and deserve formal testing within clinical trials.     

Ideal rather than actual body weight should be used to calculate cell dose in allogeneic hematopoietic stem cell transplantation

Whether the CD34+ and CD3+ cell doses in allogeneic HSCT should be estimated using actual (ABW) or ideal (IBW) body weight has never been definitively determined. We have shown that CD34+ cell doses based upon IBW are better predictive of engraftment after autologous and allogeneic HSCT. Sixty-three patients undergoing reduced-intensity HSCT after a uniform preparative regimen were evaluated to determine the effect of cell dose. ABW and IBW were 45-147 kg (median 79) and 52-85 kg (median 67) respectively. The ABW-IBW difference was -24% to +133% (median +16%); nine patients were >5% underweight and 41 were >5% overweight. The CD34+ cell dose (10(6)/kg) was 1.4-11.8 (median 5) by IBW and 1.2-9.3 (median 4.5) by ABW. The CD3+ cell dose (10(8)/kg) was 0.9-14.9 (median 3) by IBW and 0.7-19.7 (median 2.7) by ABW. While CD34+ and CD3+ cell doses based upon IBW were found to affect transplant-related mortality, and disease-free and overall survival significantly, those based on ABW were either not predictive of outcome or the differences were of borderline significance. We suggest using IBW rather than ABW to calculate cell doses for HSCT; for statistical analyses and for clinical practice if a specific cell dose is being targeted.     

Central rather than generalized obesity is related to hyperglycaemia in Asian Indian subjects.

The relationship of body mass index and waist-hip ratio with plasma glucose concentrations during an oral glucose tolerance test (OGTT) was studied in native Indian (Asian) subjects. A total of 389 subjects (131 non-diabetic, 74 impaired glucose tolerant (IGT) and 184 Type 2 diabetic (newly diagnosed and untreated] were studied. Prevalence of obesity (BMI greater than or equal to 27.0 kg m-2 in men and greater than or equal to 25.0 kg m-2 in women, 21% and 47%, respectively) was lower in people with Type 2 diabetes than that reported in white Caucasian and migrant Asian populations. Body mass index was highest in IGT subjects (26.1 (19.7-34.3) kg m-2, median (5-95th centile] and was higher in diabetic subjects (24.2 (19.3-32.2) kg m-2) than in non-diabetic control subjects (23.5 (17.1-30.0) kg m-2). However, waist-hip ratio was higher in both IGT (0.88 (0.75-0.98)) and diabetic subjects (0.88 (0.75-1.00)) than in non-diabetic control subjects (0.83 (0.70-0.97)), with no difference between the hyperglycaemic groups. On multivariate analysis, fasting as well as 2-h plasma glucose concentrations during OGTT were found to be related to waist-hip ratio (p less than 0.01) and subscapular fat thickness (p less than 0.01) but not to body mass index (or triceps fat thickness). Thus, in native Indians central obesity seems to be a more important association of hyperglycaemia than generalized obesity.     

Measuring units for elastic stockings: priority to mmHg rather than classes.

Seven incontrovertible arguments show that the only valid measurement unit for elastic stockings is the millimetre of mercury and not a grading system. The mmHg is an international measurement unit; a new European grading system will make prescribing much more difficult; the degree of arterial insufficiency is calculated by taking systolic pressures by Doppler and is expressed in mmHg; in case of superimposition of elastic stocking, pressure add together but not grades; the unit used for pressure instruments is the mmHg; a clinical situation may require a compression force straddled between two grades; finally, new materials will certainly provide increasingly precise forces.     

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

Aims/hypothesis  

It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose.