The association of SNP276G>T at adiponectin gene with circulating adiponectin and insulin resistance in response to mild weight loss

OBJECTIVE: The purpose of this study was to determine whether common single nucleotide polymorphisms (SNPs) at the adiponectin (ADIPOQ) locus influence changes in circulating adiponectin and the features of insulin resistance in response to a weight loss intervention.Subjects:In total, 294 nondiabetic/overweight-obese Koreans participated in a clinical intervention study lasting 12 weeks involving a caloric reduction of -300kcal/day. METHODS: Plasma adiponectin, blood lipids, glucose and insulin concentrations were measured at baseline and after weight loss. Insulin resistance was estimated by homeostasis model assessment insulin resistance (HOMA-IR) derived from fasting glucose and insulin concentrations. We genotyped for three SNPs, 45T>G, 276G>T and -11377C>G. RESULTS: At baseline, HOMA-IR was significantly higher in GG homozygotes than in carriers of the T allele at SNP276G>T of the adiponectin gene (P<0.05). With regard to SNP45T>G and SNP -11377C>G, we did not find any genotype related differences in baseline levels of HOMA-IR and adiponectin. In the 45/276 haplotype test, homozygous for the TG haplotype had significantly lower concentrations of plasma adiponectin (P<0.05). After the 12-week weight loss intervention, the significant decreases in HOMA-IR (P<0.001) and increases in adiponectin (P<0.01) were observed in GG homozygotes at SNP276, which were not shown in carriers of the T allele. Furthermore, there was a significant difference in the decreases in HOMA-IR between the GG homozygotes and carriers of the T allele at SNP276 (P<0.05). Regarding SNP45T>G and SNP -11377C>G, there was no association between SNP45T>G and SNP -11377C>G and decreases in HOMA-IR. In the 45/276 haplotype test, there was a significant difference in changes of adiponectin levels among those with different haplotype combinations (P<0.05). CONCLUSION: The SNP276G>T of the ADIPOQ gene is associated with different responses of circulating adiponectin and insulin resistance to mild weight loss in overweight-obese subjects.     

Association of polymorphisms in IL-12/IFN-gamma pathway genes with susceptibility to pulmonary tuberculosis in Indonesia

Upon infection with mycobacteria the IL-12/IFN-gamma axis plays an essential role in the activation of cell-mediated immunity required for the elimination of pathogens. Mutations in genes of the IL-12/IFN-gamma axis are known to cause extreme susceptibility to infection with environmental mycobacteria, and subtle variations in these genes may influence susceptibility to more virulent mycobacteria. We analyzed the distribution of polymorphisms in four essential genes from the IL-12/IFN-gamma axis, IL12B, IL12RB1, IFNG and IFNGR1, in 382 pulmonary tuberculosis patients and 437 healthy controls from an endemic region in Jakarta, Indonesia. The IL12RB1 gene was sequenced in a subset of individuals. Nine known single nucleotide polymorphisms (SNPs) and two new silent variations, 135G>A and 1056C>T, were detected in IL12RB1. Six functional SNPs (-2C>T, 467G>A, 641A>G, 1312C>T, 1573G>A, 1781G>A) in IL12RB1, an IL12B promoter insertion/deletion polymorphism and CA repeats in IFNG and IFNGR1 were analyzed in the cohort. The IFNGR1 allele CA(12) (p=0.004) and genotype CA(12)/CA(12) (p=0.01; OR 0.5) were associated with protection from pulmonary tuberculosis. Interestingly, IL12B promoter heterozygosity was associated with protection from tuberculosis in BCG-vaccinated individuals (p=0.03; OR=0.6). This new finding supports the role that IL-23-of which IL12B encodes a subunit--plays in generation of memory T cells.     

Rare RHCE phenotypes in black individuals of Afro-Caribbean origin: identification and transfusion safety

The molecular backgrounds of variants encountered in Afro-Caribbean black individuals and associated with the production of clinically significant antibodies against high-incidence antigens (anti-RH18, anti-RH34) and against Rhe epitopes were determined. We showed that RH:-18 phenotypes are produced by 3 distinct RHCE alleles: ceEK carrying 48G>C (exon 1), 712A>G, 787A>G, 800T>A (exon 5); ceBI carrying 48G>C (exon 1), 712A>G (exon 5), 818C>T (exon 6), 1132C>G (exon 8); and the already known ceAR allele carrying 48G>C (exon 1), 712A>G, 733C>G, 787A>G, 800T>A (exon 5), and 916A>G (exon 6). The RH:-34 phenotype is produced by the (C)ce(s) haplotype described previously and composed of a hybrid D-CE(3-8)-D gene with 4 extra mutations next to a ce(s) allele (733C>G; exon 5) with an extra mutation in exon 7 (1006G>T). Partial Rhe with risk of immunization against lacking epitopes can be produced by the new ce(s) allele carrying an extra mutation in exon 3 (340C>T) and by the ceMO allele described previously. A population of sickle cell disease patients was screened to estimate the incidence of these rare alleles, with the conclusion that a procedure is required to detect the associated phenotypes in black donors to ensure transfusion safety for patients. We also described a new variant [ce(s)(748)] and variants carrying different altered alleles in nonimmunized patients and for whom the risk of immunization is discussed.     

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity

The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: -4931T>C, -4451C>A, -2659G>C, -1877A>G, -1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the -1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy.     

C-reactive protein genetics is associated with carotid artery compliance in men in The Cardiovascular Risk in Young Finns Study

Although C-reactive protein (CRP) is known to predict cardiovascular events, its status as a causal risk factor is still controversial. CRP gene single nucleotide polymorphisms (SNPs) have been shown to associate with CRP concentration, but no direct independent effect on early atherosclerotic changes has been demonstrated. We aimed to determine if CRP gene polymorphisms or haplotypes are associated with CRP concentration or carotid artery compliance (CAC), an indicator of subclinical atherosclerosis. We genotyped CRP gene polymorphisms -717A>G, -286C>T>A, +1059G>C, +1444C>T and +1846G>A and measured CRP concentration and CAC in 2283 young adults participating in The Cardiovascular Risk in Young Finns Study. A strong association was found between CRP genotypes and CRP concentration, which was also seen at the haplotype level. Linear regression analysis showed an independent effect of each SNP on CRP concentration after adjustment for risk factors, except for +1444 in males. Moreover, -286C>T>A, +1444C>T and +1846G>A were associated with CAC in males, but not in females. Men carrying the SNP -286 allele C had increased CAC after adjusting for risk factors. These data suggest that the presence of high producer CRP genotype is deleterious to carotid elasticity in men.     

Evaluation of subclinical atherosclerosis by computed tomography coronary angiography and its association with risk factors in familial hypercholesterolemia

ObjectiveTo investigate the association of four common single nucleotide polymorphisms (SNPs) at ABCG5 (i7892A>G, i18429C>T, Gln604GluC>G, i11836G>A) and five at ABCG8 (5U145T>G, Tyr54CysA>G, Asp19HisG>C, i14222T>C, and Thr400LysG>T) with plasma lipids concentrations and to explore the interaction between those SNPs and smoking in patients with FH.Methods and ResultsABCG5/G8 SNPs were genotyped in 500 subjects with genetic diagnosis of FH. Carriers of the minor A allele at the ABCG5_i11836G>A SNP displayed significantly higher HDL-C concentrations (P = 0.023) than G/G subjects. In addition, carriers of the minor G allele at the ABCG5_Gln604GluC>G SNP had significantly lower VLDL-C (P = 0.011) and lower TG (P = 0.017) concentrations than homozygous C/C. Interestingly, a significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5 (i7892A>G, i18429C>T, i11836G>A) SNPs displayed significantly lower HDL-C, higher TC and higher TG respectively, only in smokers. On the other hand, nonsmokers carriers of the minor alleles at ABCG5 (i18429C>T and Gln604GluC>G) SNPs had significantly lower TG concentrations (P = 0.012 and P = 0.035) compared with homozygous for the major allele.ConclusionsOur data support the notion that ABCG5/G8 genetic variants modulate plasma lipids concentrations in patients with FH and confirm that this effect could be influenced by smoking. Therefore, these results suggest that gene-environmental interactions can affect the clinical phenotype of FH.     

Associations of hypertension and its complications with variations in the xanthine dehydrogenase gene

Hyperuricemia and oxidative stress participate in the pathophysiology of hypertension and its complications. Xanthine dehydrogenase (XDH) produces urate and, in its oxidase isoform, reactive oxygen species. Here we have studied whether or not the genetic variations in XDH could be implicated in hypertension and its complications. By sequencing the promoter region and all exons of XDH in 48 subjects, we identified three missense mutations (G172R, A932T, N1109T) in a heterozygous state in addition to 34 variations, including 15 common single nucleotide polymorphisms (SNPs). The three missense mutations and eight common SNPs (11488C>G, 37387A>G, 44408A>G, 46774G>A, 47686C>T, 49245A>T, 66292C>G, and 69901A>C) were genotyped in 953 hypertensive Japanese subjects and in 1,818 subjects from a general Japanese population. Four hypertensive patients with rare missense mutations (G172R or N1109T) in homozygous form had severe hypertension. Multivariate logistic regression analysis showed a significant association of three SNPs with hypertension in men: 47686C>T (exon 22, odds ratio [OR]: 1.52, p = 0.047) and 69901A>C (intron 31, OR: 3.14, p = 0.039) in the recessive model, and 67873A>C (N1109T) (exon 31, OR: 1.84, p = 0.018) in the dominant model. After full adjustment for all confounding factors, only one polymorphism (69901A>C) was found to be associated with carotid atherosclerosis in the dominant model (p = 0.028). Multiple logistic regression analysis showed that one SNP (66292C>G) was significantly associated with chronic kidney disease (CKD: estimated creatinine clearance < 60 ml/min) in the recessive model (p = 0.0006). Our results suggest that genetic variations in XDH contribute partly to hypertension and its complications, including atherosclerosis and CKD.     

Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency among Jordanians

Background/Aims: In Jordan, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a significant health problem, and the incidence was reported to be about 3.6%. The aims of this study are to investigate the most common molecular mutations of the G6PD gene among Jordanians in northern Jordan and to examine the correlation between the genotype and phenotype of this enzyme deficiency. Methods: Seventy-five blood samples were collected from patients attending King Abdullah University Hospital and Princess Rahma Teaching Hospital. The G6PD gene was scanned for mutations using a DNA sequencing technique. Results: Our results showed 11 variations (7 exonic and 4 intronic) as follows: c.202 G>A (rs1050828), c.376 A>G (rs1050829), c.404 A>C (CM962574 single-nucleotide polymorphism), c.542 A>T (rs5030872), c.563 C>T (rs5030868), c.1003 G>A (rs5030869), c.1311 C>T (rs2230037), c.486-90 C>T, c.486-60 C>G (rs2515904), c.770+175 C>T (rs2515905) and c.1311 C>T (rs2230037). Among these, G6PD Mediterranean (c.563 C>T) was the most common in our patients, with a frequency of 76.2%, followed by G6PD A- (c.202 G>A + c.376 A>G) with 19%, and an equal frequency of 1.6% was found for G6PD Chatham (c.1003 G>A), G6PD Santamaria (c.542 A>T + c.376 A>G) and G6PD Cairo (c.404 A>C). Conclusion: This is the first report of G6PD Santamaria and Cairo among our Jordanian population.     

Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augsburg

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the development of several components of metabolic syndrome (MetS). The present study investigated the association of nine MCP-1 single nucleotide polymorphisms (SNPs) with MetS, type 2 diabetes mellitus and metabolic risk factors. SUBJECTS AND METHODS: The population-based study sample comprised 1630 subjects aged 55-74 years from KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4). Genotyping was carried out by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis of allele-dependent primer extension products. RESULTS: The MCP-1 SNP c.-3813C>T exhibited trends for differences between the genotype groups in triglycerides, 2-h glucose and uric acid (P = 0.0084, 0.014, 0.027). Other trends were observed for c.-928G>C associated with height and fasting glucose (P = 0.0024, 0.033), for c.105T>C with height and leukocytes (P = 0.0095, 0.047), for c.*65C>T and c.*3879C>T with MCP-1 levels (both P = 0.012) and for c.-2138A>T with interleukin-6 levels. After correction for multiple testing, none of the analysed SNPs, except c.-928G>C in men showed a significant association with MetS, T2DM or other analysed parameters. Haplotype MCP-1*1 and c.-928G>C in men (P = 0.0002, 0.0004) were significantly associated with an increase in height. CONCLUSIONS: This is the first study to investigate the associations of MCP-1 SNPs with MetS. We found trends for several components of MetS. These parameters were hyperlipidaemia, fasting and 2-h glucose, and uric acid. A new finding is that MCP-1*1 haplotype is associated with height. Further investigation in larger populations is needed to clarify the involvement of MCP-1 in MetS.     

Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A

The HLA class I/II alleles and the tumor necrosis factor alpha (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (-827C>T, -308G>A, -238A>G, and 670A>G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malm? International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA -308 A/A genotype within this haplotype compared with 39.7% for TNFA -308 G/G patients and 46.9% for TNFA -308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the -308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P < .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P = .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA -308G>A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.     

Combined carriership of TLR9-1237C and CD14-260T alleles enhances the risk of developing chronic relapsing pouchitis

AIM: To investigate the single nucleotide polymorphisms (SNPs) in genes involved in bacterial recognition and the susceptibility to pouchitis or pouchitis severity. METHODS: Analyses of CD14 -260C>T, CARD15/ NOD2 3020insC, Toll-like receptor (TLR)4 +896A>G, TLR9 -1237T>C, TLR9+2848G>A, and IRAKM + 22148G>A SNPs were performed in 157 Meal-pouch anal anastomosis (IPAA) patients (79 patients who did not develop pouchitis, 43 infrequent pouchitis patients, 35 chronic relapsing pouchitis patients) and 224 Italian Caucasian healthy controls. RESULTS: No significant differences were found in SNP frequencies between controls and IPAA patients. However, a significant difference in carriership frequency of the TLR9-1237C allele was found between the infrequent pouchitis and chronic relapsing pouchitis groups [P = 0.028, odd's ratio (OR) = 3.2, 95%d = 1.2-8.6]. This allele uniquely represented a 4-locus TLR9 haplotype comprising both studied TLR9 SNPs in Caucasians. Carrier trait analysis revealed an enhanced combined carriership of the alleles TLR9 -1237C and CD14 -260T in the chronic relapsing pouchitis and infrequent pouchitis group (P = 0.018, OR = 4.1, 95%CI = 1.4 -12.3). CONCLUSION: There is no evidence that the SNPs predispose to the need for IPAA surgery. The significant increase of the combined carriership of the CD14 -260T and TLR9 -1237C alleles in the chronic relapsing pouchitis group suggests that these markers identify a subgroup of IPAA patients with a risk of developing chronic or refractory pouchitis.     

Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes

OBJECTIVE: To determine associations of methotrexate (MTX) efficacy and toxicity with single-nucleotide polymorphisms (SNPs) in genes coding for folate pathway enzymes in patients with early rheumatoid arthritis (RA). METHODS: Patients (n=205) with active RA received MTX at an initial dosage of 7.5 mg/week, which was increased to 15 mg/week and combined with folic acid (1 mg/day) after 4 weeks. If the Disease Activity Score in 44 joints (DAS44) was >2.4 at 3 months, MTX was increased to 25 mg/week. MTX efficacy was evaluated at 3 and 6 months and compared for genotypes in 3 analyses: patients with and without good response (DAS441.2), and patients with and without moderate improvement (DeltaDAS44>0.6). The association between MTX-related adverse drug events (ADEs) and genotype was evaluated by comparing genotypes between patients with and without ADEs, specifically pneumonitis, gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme levels. The following SNPs were analyzed: methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, dihydrofolate reductase (DHFR) -473G>A, DHFR 35289G>A, and reduced folate carrier 80G>A. In case of significant differences, odds ratios (ORs) were calculated. RESULTS: At 6 months, MTHFR 1298AA was associated with good improvement relative to 1298C (OR 2.3, 95% confidence interval [95% CI] 1.18-4.41), which increased with increased copies of the MTHFR 677CC haplotype. In contrast, MTHFR 1298C allele carriers developed more ADEs (OR 2.5, 95% CI 1.32-4.72). CONCLUSION: Patients with MTHFR 1298AA and MTHFR 677CC showed greater clinical improvement with MTX, whereas only the MTHFR 1298C allele was associated with toxicity. In the future, MTHFR genotypes may help determine which patients will benefit most from MTX treatment.     

Detection of 12 new mutations in Gaucher disease Brazilian patients

Gaucher disease is the most frequent lysosome storage disease and presents an autosomal recessive mode of inheritance. It is caused by mutations at the GBA gene leading to deficient activity of the glucocerebrosidase enzyme. This report describes 12 new mutations [c.38A>G (K-27R), c.220G>A (G35S), c.448G>A (E111K), IVS4+1G>A, c.746C>T (A210V), c.776A>G (Y220C), c.793delC (Q226_fs4X), c.1102C>T (R329C), c.1300C>T (R395C), c.1309G>A (V398I), c.1324-1326delATT (delI403) and c.1583T>C (I489T)] and 4 novel silent alterations [c.342C>T (F75), c.528C>T (D137), c.1011C>T (D298) and c.1092G>A (G325)] detected among 40 unrelated Brazilian type 1 Gaucher disease patients by a combination of RFLP, dHPLC and DNA sequencing procedures. The R329C mutation, previously described in a Parkinson's disease patient (A. Lwin, E. Orvisky, O. Goker-Alpan, M.E. LaMarca, E. Sidransky. Glucocerebrosidase mutations in subjects with Parkinsonism. Mol. Genet. Metab. 81 (2004) 70-73), is described here for the first time in a Gaucher disease patient. Several genotype-phenotype correlations could be established, contributing significantly to the panel of reported mutations and conferring predictive value to their detection.     

Obese subjects carrying the 11482G>A polymorphism at the perilipin locus are resistant to weight loss after dietary energy restriction

CONTEXT: Dietary treatment of obesity could be improved if predictive information about the individual's genetic response to diet was available. Adipose tissue has been the focus of efforts to identify candidate genes. Perilipin is a major protein found in adipocytes, and perilipin knockout mice are lean and resistant to diet-induced obesity. OBJECTIVE: The objective of the study was to examine the association of several polymorphisms at the perilipin (PLIN) locus with obesity and weight reduction in response to a low-energy diet in obese patients. DESIGN: This study was a 1-yr randomized (depending on the PLIN genotype) trial with three follow-up evaluations. SETTING: The study was conducted at a university research center. SUBJECTS: One hundred fifty obese patients (body mass index, 42 +/- 8 kg/m2) at baseline and 48 patients who completed the dietary follow-up treatment for weight loss participated in the study. INTERVENTIONS: Subjects completed a 1-yr low-energy diet. MAIN OUTCOMES MEASUREMENTS: Body weight (BW) at baseline and 3, 6, and 12 months was measured. RESULTS: The minor A-allele at the PLIN 11482G>A polymorphism was associated with lower baseline BW. Moreover, we found a gene-diet interaction (P = 0.015) between this polymorphism and weight loss in patients that completed the 1-yr dietary treatment. Diet resulted in significant decreases in BW (from 114.3 +/- 3.9 kg at baseline to 105.5 +/- 3.5 kg at 1 yr; P lineal trend, 0.020) in GG patients (n = 33). Conversely, carriers of the minor A allele (n = 15) did not show significant changes in BW (from 105.0 +/- 4.6 kg at baseline to 104.3 +/- 4.4 kg at 1 yr; P lineal trend, 0.985). This gene-diet interaction remained statistically significant, even after adjustment for differences in BW at baseline and for other potential confounders. CONCLUSIONS: PLIN11482A carriers were resistant to weight loss, suggesting that this polymorphism may predict outcome of BW reduction strategies based on low-energy diets.     

Polymorphisms of KCNJ11 (Kir6.2 gene) are associated with Type 2 diabetes and hypertension in the Korean population.

AIMS: Kir6.2 is found in the pancreatic B-cell, cardiac and skeletal muscle and non-vascular smooth muscle. KCNJ11, encoding Kir6.2, has been shown to be associated with both Type 2 diabetes mellitus and cardiovascular disease in several populations. In this study, we investigated whether polymorphisms in KCNJ11 are associated with Type 2 diabetes and other metabolic phenotypes in the Korean population. METHODS: We sequenced KCNJ11 to identify common polymorphisms using 24 Korean DNA samples. Of the 14 polymorphisms found in KCNJ11, six common ones [genomic sequence (g.)-1709A>T, g.-1525T>C, g.67G>A (E23K), g.570C>T (A190A), g.1009A>G (I337V), and g.1388C>T] were genotyped in 761 Type 2 diabetic patients and in 630 non-diabetic subjects. RESULTS: All the polymorphic loci in KCNJ11 are in strong linkage disequilibrium in the Korean population and act as one haplotype block. g.67G>A and g.1009A>G were associated with an increased risk of Type 2 diabetes [age, sex, and body mass index (BMI)-adjusted odds ratios (OR) = 1.376 (1.085-1.745), P = 0.008 and 1.411 (1.111-1.791), P = 0.005, respectively], as was one haplotype (A-T-A-C-G-C in the order of polymorphisms as shown above) containing g.67A and g.1009G [OR = 1.359 (1.080-1.709), P = 0.009]. The haplotype (A-T-A-C-G-C) was also strongly associated with hypertension [OR = 1.655 (1.288-2.126), P < 0.001]. CONCLUSIONS: Polymorphisms in KCNJ11 are associated with Type 2 diabetes and also with hypertension in the Korean population.     

Association between TNF and IL-1 bloc polymorphisms and plasma MCP-1 concentration

BACKGROUND: Circulating MCP-1 concentration was found to be increased in cardiovascular diseases and is of high interest in the list of biomarkers of atherosclerosis. TNF-alpha, LT-alpha, IL-1alpha and IL-1beta are four proinflammatory cytokines that regulate MCP-1 concentration in vitro. We hypothesized that specific genetic polymorphisms in TNF, LTA, IL-1A and IL-1B genes could modulate plasma MCP-1 concentration. METHODS: Plasma MCP-1 concentration was quantified with a biochip array analyzer in 395 adults from the Stanislas family study. TNF -308G>A, LTA 252A>G (A=TNFB2, G=TNFB1), IL-1A -889C>T and IL-1B 3954C>T were genotyped with a prototypic multilocus genotyping assay. RESULTS: Among the four polymorphisms studied only LTA 252A>G and TNF -308G>A were significantly associated with plasma MCP-1 concentration (p=0.005 and p=0.038, respectively) after adjustment for covariates (age, sex, smoking, monocyte count and hematocrit). Carriers of the 252A allele or the -308G had lower MCP-1 concentrations than carriers of the 252G or the -308A alleles, respectively. Moreover, as TNF and LTA genes were in linkage disequilibrium, the TNF bloc haplotypes were compared with respect to MCP-1 concentration, and a significant association (p=0.021) was observed, due only to the LTA polymorphism. This association remained significant even after adjustment for TNF-alpha and hs-CRP concentrations. CONCLUSION: A functional polymorphism within the TNF bloc could modulate MCP-1 concentration and seems more likely to be near to the LTA 252A>G polymorphism than to the TNF -308G>A one. In addition, the association found in healthy French adults is independent of other actors of inflammation such as TNF-alpha and hs-CRP.     

Perilipin polymorphism interacts with saturated fat and carbohydrates to modulate insulin resistance

Background and aimsMacronutrient intakes and genetic variants have been shown to interact to alter insulin resistance, but replications of gene–nutrient interactions across independent populations are rare, despite their critical importance in establishing credibility. We aimed to investigate a previously demonstrated saturated fat and carbohydrate interaction for insulin resistance for perilipin (PLIN1), a regulator of adipocyte metabolism.Methods and resultsWe investigated the previously shown interaction for PLIN1 11482G > A (rs894160) on insulin resistance in US men (n = 462) and women (n = 508) (mean ± SD, 49 ± 16 years). In multivariable linear regression models, we found an interaction (P < 0.05) between the ratio of saturated fat to carbohydrate intake as a continuous variable and PLIN1 11482G > A for HOMA-IR (homeostasis model assessment of insulin resistance) in women. For carriers of the minor allele but not for non-carriers, as the ratio of saturated fat to carbohydrate intake increased, predicted HOMA-IR increased (P = 0.002). By dichotomizing the ratio of saturated fat to carbohydrate intake into high and low, we found significant interaction terms for insulin and HOMA-IR (P < 0.05). When the ratio of saturated fat to carbohydrate was high, insulin and HOMA-IR were higher in minor allele carriers (P = 0.004 and P = 0.003, respectively), but did not differ when the ratio was low. Similar patterns or trends were observed when saturated fat and carbohydrate were dichotomized into high and low as individual macronutrients.ConclusionsReplication of the previously reported interaction between macronutrient intakes and PLIN1 genotype for insulin resistance reinforces the potential usefulness of applying genotype information in the dietary management of insulin resistance.     

胆固醇24S-羟化酶基因多态性与散发性阿尔茨海默病的相关性研究

目的探讨胆固醇24S-羟化酶(CYP46)基因多态性是否为散发性阿尔茨海默病(SAD)的遗传易感基因。方法选择SAD患者108例作为SAD组,同期选择年龄、性别相匹配的健康老年人118例作为对照组,用变性高效液相色谱法对CYP46基因的核苷酸序列进行扫描,比较2组变异位点的基因型和等位基因频率分布。结果在外显子-内含子交界区检出10个不同的变异位点,5个多态性位点(IVS2—150AG,IVS3+43CT,IVS3—130CT,IVS5+51GC,IVS7—65TC)是较好的遗传标记。SAD组和对照组在IVS2—150AG基因型AG+GG的分布频率差异无统计学意义(χ~2=1.369,P=0.242);SAD组和对照组等位基因G的分布频率差异无统计学意义(χ~2=0.003,P=0.956)。SAD组和对照组携带载脂蛋白E(apoE)ε4与非携带apoEε4者上述基因分布差异均无统计学意义(P0.05)。IVS2—150AG与SAD无相关性。结论 CYP46是一个较为保守的基因,其内含子2上的多态性位点IVS2—150AG与SAD的发病无关。     

Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel variants in SEC23B gene

SEC23B gene encodes an essential component of the coat protein complex II (COPII)-coated vesicles. Mutations in this gene cause the vast majority the congenital dyserythropoietic anemia Type II (CDA II), a rare disorder resulting from impaired erythropoiesis. Here, we investigated 28 CDA II patients from 21 unrelated families enrolled in the CDA II International Registry. Overall, we found 19 novel variants [c.2270 A>C p.H757P; c.2149-2 A>G; c.1109+1 G>A; c.387(delG) p.L129LfsX26; c.1858 A>G p.M620V; c.1832 G>C p.R611P; c.1735 T>A p.Y579N; c.1254 T>G p.I418M; c.1015 C>T p.R339X; c.1603 C>T p.R535X; c.1654 C>T p.L552F; c.1307 C>T p.S436L; c.279+3 A>G; c. 2150(delC) p.A717VfsX7; c.1733 T>C p.L578P; c.1109+5 G>A; c.221+31 A>G; c.367 C>T p.R123X; c.1857_1859delCAT; p.I619del] in the homozygous or the compound heterozygous state. Homozygosity or compound heterozygosity for two nonsense mutations was never found. In four cases the sequencing analysis has failed to find two mutations. To discuss the putative functional consequences of missense mutations, computational analysis and sequence alignment were performed. Our data underscore the high allelic heterogeneity of CDA II, as the most of SEC23B variations are inherited as private mutations. In this mutation update, we also provided a tool to improve and facilitate the molecular diagnosis of CDA II by defining the frequency of mutations in each exon.     

Vascular endothelial growth factor (VEGF) gene (VEGFA) polymorphism can predict the prognosis in acute myeloid leukaemia patients

Increased angiogenesis, mediated by vascular endothelial growth factor (VEGF), was associated with poor prognosis in acute myeloid leukaemia (AML) patients. The current study investigated the impact of VEGF gene ( VEGFA ) single nucleotide polymorphisms (SNPs) on treatment outcomes for AML. Four VEGFA SNPs were analysed for −2578C>A (rs699947), −460T>C (rs833061), +405G>C (rs2010963) and +936 C>T (rs3025039) loci in 138 AML patients. The +936 CC/CT genotype showed strong correlation with favourable leukaemia-free survival (LFS) at 2 years (51·3%) versus with +936 CC genotype (33·6%, P  =   0·03). Strong linkage disequilibrium was noted among loci −2578, −460 and +405, but not with +936. Accordingly, four haplotypes were generated based on the genotypes of −2578, −460 and +405 as follows: CTC (40·2%), CTG (35·0%), ACG (22·0%) and ATC (1·2%). The LFS and event-free survival (EFS) inversely correlated with CTG haplotype ( P  =   0·03 for LFS; P  =   0·05 for EFS). We scored the VEGFA polymorphism marker based on +936 C>T genotype and CTG haplotype for −2578, −460 and +405, which demonstrated a good correlation with the treatment outcomes: LFS ( P  =   0·01), EFS ( P  =   0·03) and overall survival ( P  =   0·01). The VEGFA +936 C>T genotype and CTG haplotype seemed to have an additive effect to predict the prognosis in AML patients.