Relationship of hypovitaminosis D and secondary hyperparathyroidism with bone mineral density among UK resident Indo-Asians

BACKGROUND: There is a high prevalence of vitamin D deficiency in UK resident Indo-Asians and this may be complicated by secondary hyperparathyroidism. OBJECTIVE: To investigate the relationship between these conditions and bone mineral density (BMD) in Indo-Asian rheumatology patients. METHODS: 110 Indo-Asian patients presenting to a general rheumatology clinic were selected for the study, of whom 77 were vitamin D deficient (HD), and 33 also had associated secondary hyperparathyroidism (HD-SHPT). BMD measurements at the femoral neck (FN), lumbar spine (LS), distal radius (DR), and radius 33% were obtained. T and Z scores were used in the evaluation of the dual energy x ray absorptiometry findings. The Mann-Whitney U test and chi(2) tests were used in the statistical analysis. RESULTS: The patients with HD-SHPT had significantly lower serum 25-OH-vitamin D, higher serum alkaline phosphatase, and lower calcium levels than the HD group. Both T and Z scores failed to show any significant difference between the groups in the LS, but patients with HD-SHPT compared with those with HD had significantly lower FN T scores (-1.05 (1.47) v 0.28 (1.22), p=0.003), FN Z scores (-0.45 (1.27) v 0.26 (0.96), p=0.001), DR T scores (-1.83 (1.82) v -0.44 (1.77), p<0.001), DR Z scores (-1.25 (1.44) v -0.08 (1.6), p=0.001), radius 33% T scores (-1.65 (1.66) v -0.79 (1.21), p=0.008), and radius 33% Z scores (-1.07 (1.28) v -0.44 (1.1), p=0.017). CONCLUSION: Hypovitaminosis D complicated by secondary hyperparathyroidism is associated with significantly decreased bone mineral density.     

Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians

OBJECTIVE: To investigate whether genetic variation at the loci encoding the corticotropin-releasing factor receptors-1 and -2 (CRF-R1 and CRF-R2) contributes to human obesity. DESIGN: The coding region of the CRF-R1 and CRF-R2 genes was screened in 51 severely obese children (body mass index (BMI)>4 kg/m(2) standard deviations above the age-related mean) using denaturing high-performance liquid chromatography and direct nucleotide sequencing. Common polymorphisms that were identified were typed from a UK Caucasian population-based cohort by a PCR-based forced restriction digestion. A repeated measures analysis was used to determine associations between the C861T and G1047A genotypes and anthropometric and biochemical indices relevant to obesity. RESULTS: In subjects with extreme early-onset obesity, four missense mutations were found, each in a single individual: CRF-R1 (Val161Met) and CRF-R2 (Glu220Asp, Val240Ile and Val411Met). However, none of these missense mutations clearly cosegregated with obesity in family studies. Two common single-nucleotide polymorphisms, C861T (Cys287Cys) in CRF-R1 and G1047A (Ser349Ser) in CRF-R2, were also detected. G1047A did not associate with any obesity-related phenotype. In contrast, carriers of the CRF-R1 polymorphism, C861T, had a significantly higher body mass index (BMI). CONCLUSION: Mutations in the coding sequence of the CRF-R1 and CRF-R2 genes are unlikely to be a common monogenic cause of early-onset obesity. In an adult UK Caucasian population, the CRF-R1 C861T polymorphism is associated with increased BMI.     

Seasonal variation of C-reactive protein in apparently healthy Koreans

BACKGROUND: C-reactive protein (CRP) is known as an emerging recognized marker of the potential risk of myocardial infarction and stroke, and several studies have reported higher incidences of cardiovascular events during the winter months. Here, we investigated seasonal CRP variations using a high-sensitivity immunoradiometric assay in apparently healthy Koreans. METHODS: This study included 18,445 apparently healthy Koreans (12,064 men and 6381 women, 47.2 (11.5) years of age). Anthropometric indices of adiposity, metabolic variables, blood pressure (BP), and several cardiovascular risk factors were measured. High sensitivity CRP testing was performed by immunonephelometry. RESULTS: The mean (SD) CRP level in the study population was 1.66 (2.15) mg/L, and mean (SD) CRP levels in the spring, summer, fall and winter were 1.76 (2.30) mg/L, 1.51 (1.94) mg/L, 1.61 (2.08) mg/L, and 1.76 (2.30) mg/L, respectively. After adjusting for age, sex, diabetes, hypertension, regular exercise, smoking, and body mass index, the odds ratios of an elevated CRP in the spring, fall and winter season were 1.196 (95% CI, 1.024-1.396 p = 0.024), 1.086 (95% CI, 0.943-1.250 p = 0.251) and 1.258 (95% CI, 1.088-1.456 p = 0.002), respectively, as compared with the summer season. CONCLUSIONS: Our results indicate a highly significant seasonal variation in CRP levels, with higher values during winter and spring than in summer. Elevated plasma CRP levels can be related to an increased risk of cardiovascular events, which are more prominent during the winter months. To further elucidate this relationship additional studies are needed.     

Impaired arterial responsiveness in untreated gout patients compared with healthy non-gout controls: association with serum urate and C-reactive protein

To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n?=?34) and non-gout healthy controls (n?=?64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses. Both FMD (2.20?±?0.53 vs 3.56?±?0.31, p?=?0.021) and NMD (16.69?±?1.54 vs 24.51?±?0.90, p?=?0.00002) were impaired in the gout versus control group. Stratification for individual comorbidities suggested that no single risk factor accounted for impaired FMD/NMD in the gout subjects. However, the degree of association between gout and FMD, but not NMD impairment, was dampened after multivariable adjustment (FMD unadjusted beta?=???1.36 (SE 0.58), p?=?0.02; adjusted beta?=???1.16 (SE 0.78), p?=?0.14 and NMD unadjusted beta?=???7.68 (SE 1.78), p?<?0.0001; adjusted beta?=???5.33 (SE 2.46), p?=?0.03). Within the gout group, there was an inverse correlation between FMD and sUA (R?=???0.5, p?=?0.003), and between FMD and hsCRP (R?=???0.42, p?=?0.017), but not between NMD and sUA or hsCRP. Compared with healthy controls, subjects with gout have reduced arterial function. Individual comorbidities are insufficient to account for differences between gout and control groups, but multiple comorbidities may collectively contribute to impairment in endothelium-dependent arterial responsiveness. Endothelial impairment is also related to sUA and hsCRP, markers of gout severity and inflammation respectively. Studies to determine whether gout therapy may improve arterial responsiveness are warranted.     

HLA-DR/DQ haplotype in rheumatoid arthritis: novel allelic associations in UK Caucasians

OBJECTIVE: To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA). METHODS: HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method. RESULTS: Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRbeta molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident. CONCLUSION: These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region.     

Prevention of coronary heart disease with statins in UK South Asians and Caucasians.

AIMS: To determine the prevalence of subjects eligible for primary and secondary prevention of coronary heart disease (CHD) among the British South Asian population and to compare that with British Caucasians. METHODS AND RESULTS: We used the Health Survey for England 1998 and 1999 datasets, holding data on 9950 Caucasians and 1938 South Asians. Thresholds for treatment were a total cholesterol >3.5 mmol/l and either a history of cardiovascular disease or elevated estimated CHD risk, adjusted where necessary for ethnic differences. Separate analyses were performed for primary prevention risk thresholds of >15% and >30% over 10 years. The prevalence of previous myocardial infarction, angina, or stroke was higher in South Asian men than in Caucasian but the reverse was seen in women. More than 93% [95% confidence interval (CI) 88-97] of South Asian men and nearly 68% (95% CI 66-71) of Caucasian men older than 55 years have a CHD risk greater than 15% (equivalent to cardiovascular risk of 20%) and a cholesterol above 3.5 mmol/l and would be eligible for treatment with lipid-lowering drugs. The equivalent proportions in women are 55% (95% CI 46-65) and 18% (95% CI 16-20) in South Asians and Caucasians, respectively. CONCLUSION: Treating this proportion of the population will have a societal impact, the majority of older people becoming patients, and although it may well be cost-effective for individuals, it will require substantial new resources.     

C-reactive protein genotypes associated with circulating C-reactive protein but not with angiographic coronary artery disease: the LURIC study

Aims: Circulating C-reactive protein is associated with future cardiovascularevents. The causal role of C-reactive protein in the developmentof atherosclerosis remains controversial. Methods and results: We analysed the association between three genetic polymorphisms(PM) (–717C>T, rs2794521; +1059G>C, rs1800947; +1444C>T,rs1130864) at the C-reactive protein locus and related haplotypeswith both circulating C-reactive protein and angiographic coronaryartery disease (CAD). The concentration of C-reactive proteinwas similar in patients with stable CAD and in controls, butincreased in patients presenting with acute coronary syndromes.In models adjusting for the main confounding variables, theminor alleles of the +1059G>C (rs1800947) and the +1444C>TPM (rs1130864) were associated with decreased and increasedconcentrations of C-reactive protein, respectively. Haplotypes1 and 4 decreased, and haplotype 2 increased C-reactive protein,whereas haplotype 3 had no appreciable effect. None of the geneticvariants affecting circulating C-reactive protein was consistentlyassociated with the prevalence of angiographic CAD. Conclusion: A causal role of C-reactive protein in the development of CADwould require that genetic PM resulting in long-term modulationof the concentration of C-reactive protein be themselves associatedwith CAD. We were not able to detect such a relationship, whichcan be attributed to either a very small genetic effect sizeor the relationship between C-reactive protein and cardiovascularevents may reflect confounding and reverse causation.     

C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis

Infiltration of monocytes into the arterial wall is an early cellular event in atherogenesis. Recent evidence shows that C-reactive protein (CRP) is deposited in the arterial intima at sites of atherogenesis. In this study, we demonstrate that CRP deposition precedes the appearance of monocytes in early atherosclerotic lesions. CRP is chemotactic for freshly isolated human blood monocytes. A specific CRP receptor is demonstrated on monocytes in vitro as well as in vivo, and blockage of the receptor by use of a monoclonal anti-receptor antibody completely abolishes CRP-induced chemotaxis. CRP may play a major role in the recruitment of monocytes during atherogenesis.     

Lack of association of the vitamin D receptor gene with Graves' disease in UK Caucasians

OBJECTIVE: Vitamin D modulates the immune system by suppressing the proliferation of activated T cells, with its actions being directed through the vitamin D receptor (VDR). A number of single nucleotide polymorphisms (SNPs) have been identified in the VDR gene, of which several have been associated with autoimmune diseases, including type 1 diabetes and Graves' disease (GD) in Japanese females. The aim of this study was to test for association of polymorphisms of the VDR gene in the genetic susceptibility to GD in UK Caucasians. DESIGN: Target DNA for five previously published SNPs, four novel SNPs and one microsatellite marker was amplified by the polymerase chain reaction (PCR). Subsequent genotyping was performed using restriction fragment length polymorphism (RFLP) or microsatellite genotyping analysis, according to the type of VDR polymorphism. PATIENTS: We obtained DNA from a case-control dataset consisting of 768 patients with GD and 864 control subjects. All patients and control subjects were Caucasians born in the UK, and all gave informed, written consent. MEASUREMENTS: Frequencies of the alleles and genotypes of the ten VDR gene polymorphisms were compared between patients and control subjects using the chi2 test. Odds ratios were calculated using Woolf's method with Haldane's modification for small numbers and D prime (D') was calculated to assess the level of linkage disequilibrium (LD) between the ten polymorphisms. RESULTS: No differences in allele or genotype frequencies were observed between GD cases and control subjects for any of the nine SNPs studied. The S allele of the PolyA microsatellite marker was slightly more frequent in GD cases when compared with control subjects (chi2= 4.364, P = 0.04). Strongest LD between markers was observed towards the 3' end of the VDR gene but there was no evidence of association with disease. CONCLUSION: This is the largest and most comprehensive study of the VDR gene in GD to date and these data suggest that these polymorphisms of the VDR gene do not contribute to GD susceptibility in the UK.     

超敏C-反应蛋白和C-反应蛋白的测定对SARS的诊断价值

目的　研究血清超敏C -反应蛋白 (hs -CRP )和C -反应蛋白 (CRP)对严重急性呼吸综合征 (SARS)的诊断价值。方法　SARS病人 2 0例、细菌性肺炎病人 2 0例、健康对照 2 0例 ,血清hs -CRP和CRP采用胶乳免疫比浊法全自动定量测定。结果　hs -CRP和CRP测定结果分别为 :健康对照组 (0 6 9± 0 6 2 )mg/L和 (4 4± 0 9)mg/L、细菌性肺炎组 (10 79± 1 36 )mg/L和 (98 0± 2 8 9)mg/L、SARS组 (3 16± 3 72 )mg/L和 (11 0± 9 6 )mg/L。三组间差异均有显著意义 (P <0 0 1)。结论　SARS病人和细菌性肺炎病人早期血清hs -CRP和CRP均升高 ,但细菌性肺炎病人升高更加显著 ,比SARS组分别增加 2 4倍和 7 9倍 ,对SARS与细菌性性肺炎的鉴别诊断有重要意义     

C反应蛋白在动脉粥样硬化中的作用

C反应蛋白作为传统的炎性指标在诊断和治疗冠心病的作用越来越受到重视,但其在动脉粥样硬化及心脑血管事件中究竟起什么作用尚有争议。该文简述C反应蛋白在动脉粥样硬化相关的基础、临床研究结果及实际应用价值。