The International Psoriasis Genetics Study: assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs

In an effort to confirm previously reported linkages to psoriasis, we analyzed 942 affected sibling pairs (ASPs) from 710 pedigrees for 53 polymorphic microsatellites spanning 14 psoriasis candidate regions at an intermarker spacing of ~5 cM. Maximum LOD score (MLS) analysis of ASPs yielded allele sharing of 60% for markers within the major histocompatibility complex (MHC) (P=2×10^-14), which yielded a gene-specific λ_s of 1.6. Across the remainder of the genome, the strongest evidence of allele sharing was obtained on chromosomes 16q (D16S3032; MLS=1.3; P=.007) and 10q22–q23 (D10S2327; MLS=1.1; P=.012). None of the remaining loci exceeded MLS=0.9, the value expected to occur by chance once in this study. In agreement with previous studies, strong linkage disequilibrium was also observed between psoriasis and the MHC (pedigree disequilibrium test P=3.9×10^-8 for D6S1014). Two psoriasis-associated MHC haplotypes were identified with the haplotype-based transmission/disequilibrium test. Analysis of only those families carrying either of these haplotypes significantly increased the chromosome 16q LOD score from 1.3 to 2.4 (P=.045). These results underscore the importance of the MHC in psoriasis and provide a rationale for more-detailed examination of candidate regions on chromosomes 16q and 10q.     

Insertion/Deletion Polymorphism and Serum Activity of the Angiotensin-Converting Enzyme in Turkish Patients with Obstructive Sleep Apnea Syndrome

This study determined the allelic frequency and genotypic distribution of an angiotensin-converting enzyme (ACE) polymorphism and serum ACE activity in Turkish patients with obstructive sleep apnea syndrome (OSAS). A colorimetric assay measured serum ACE activity in 73 of 97 subjects. Frequencies for II, ID, and DD genotypes were 19.6, 53.6, and 26.8% in the OSAS group and 15, 38, and 47% in the control group, respectively (P = 0.02). The I allele frequency was higher in the OSAS group than in the healthy control group (P = 0.02). Carrying the I allele (II or ID genotypes) increased OSAS risk 2.41 times in the Turkish population. Mean ACE activity was significantly lower in patients with the II genotype than in the DD genotype (P = 0.011), and ACE activity was significantly lower in patients with severe OSAS than in those with mild OSAS (P = 0.006). Our results suggest that II and ID genotypes of the ACE gene increase the risk of developing OSAS in the Turkish population.     

Preliminary evidence for an association between LRP-1 genotype and body mass index in humans

Background/Aims

The LDL receptor-related protein-1 gene (LRP-1) has been associated with obesity in animal models, but no such association has yet been reported in humans. As data suggest this increase in fat mass may be mediated through a mechanism involving the clearance of plasma triglyceride-rich lipoproteins (TGRL), where the LRP interacts with apolipoprotein E (ApoE) on chylomicron remnants, we aimed to examine (1) whether there was an association between 3 single nucleotide polymorphisms (SNPs) on LRP-1 with body mass index (BMI) and (2) whether any association between LRP-1 SNPs and BMI could be modified by polymorphisms on the ApoE gene when comparing the wild type ε3/ε3 genotype against mutant ApoE allele (ε2/ε4) carriers.

Methods/Results

We used data from 1,036 men and women (mean age±SD = 49±16 y) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. Mixed linear models, which controlled for age, sex, alcohol intake and smoking, as well as family pedigree and center of data collection were calculated. Models that used LRP-1 genotype as a predictor of BMI revealed that individuals who were homozygous for the minor allele at the LRP-1 {"type":"entrez-protein","attrs":{"text":"I10701","term_id":"592781","term_text":"I10701"}}I10701 locus had BMIs, on average, 1.03 kg/m² higher than major allele carriers (P = 0.03). In subsequent mixed linear models that included main effects of LRP-1 {"type":"entrez-protein","attrs":{"text":"I10701","term_id":"592781","term_text":"I10701"}}I10701 SNP and ApoE alleles, and an interaction term the two genotypes, there was no interaction detected between the LRP-1 {"type":"entrez-protein","attrs":{"text":"I70701","term_id":"3006836","term_text":"gb|I70701.1|I70701"}}I70701 genotype with either the ApoE ε2 or ε4 allele carriers (P>0.05).

Conclusions

This has implications for starting to understand pathways from genotype to human BMI, which may operate through TGRL uptake at the LRP-1 receptor. This may pave the way for future research into individualized dietary interventions.     

Association analysis of alcohol metabolizing enzymes <Emphasis Type="Italic">ADH1B,ADH7, CYP2E1</Emphasis> gene polymorphism with risk for coronary atherosclerosis

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5′-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B ^* G (+MslI) allele, CYP2E1 ^* C2 (+PstI) allele and CYP2E1 ^* C (-DraI) allele were 8.48 ± 1.86, 1.20 ± 0.69, and 10.00 ± 1.90%, respectively. The ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7 ^* C (-StyI) allele was 44.58 ± 3.21%. A significantly higher frequency of CYP2E1 PstI C2 allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03–20.01). The tendency to significant effect of A1A2 genotype in ADH1B MslI polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0.042) were also revealed. Association of A1A2 genotype in ADH1B MslI polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.     

Genetisches Modell der autosomal-rezessiv erblichen proximalen spinalen Muskelatrophie

Proximal spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases. According to the achieved milestones, SMA is divided into 3 groups: SMA types I–III. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene, which is located on chromosome 5. Wild type alleles usually have one or two SMN1 gene copies, disease alleles may show deletions, large scale deletions, or point mutations. The proposed genetic model is based on published data on SMA types I–III. The complex genetic model of SMA allows all parameters—even those which have not been assessed so far—to be calculated. The SMN1 allele frequencies included the following: normal allele b (1 copy of SMN1): ≈?0.9527; normal allele c (2 copies of SMN1): ≈?0.0362; deletion a (0 copies of SMN1): ≈?0.0104; point mutation d (1 copy of SMN1): ≈?0.0003; large scale deletion g (0 copies of SMN1): ≈?0.0004. The result is a gene frequency of approximately 1:90 and a carrier frequency of about 1:46.     

Reduction of prothrombin and Factor V levels following supplementation with omega-3 fatty acids is sex dependent: a randomised controlled study

BackgroundLCn-3PUFA comprised of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) offer cardioprotection involving a decrease in coagulant activity; however, the evidence is equivocal. We have previously demonstrated that the acute (24 h) effects and chronic (4 weeks) effects of LCn-3PUFA supplementation on platelet aggregation in human subjects are sex specific. This study investigated the mechanisms of the sex-dependent effects of LCn-3PUFA with 4 weeks supplementation of EPA-rich vs. DHA-rich oils on procoagulant and platelet activity in healthy subjects.DesignA double-blinded, placebo-controlled randomised trial was conducted in 94 healthy adults: male (n=41) and female (n=53). Platelet coagulation parameters including factors I, II, V, VII, VIII, IX, X, vWF:Ag and endogenous thrombin potential were measured at baseline and 4 weeks postsupplementation with EPA-rich or DHA-rich oil capsules.ResultsWe have previously reported that platelet aggregation is specifically reduced by supplementation with EPA in males and DHA in females. This sex-specific effect was also observed for decreases in plasma levels of Factor II (−7.9±3.8%, P=.026), Factor V (−6.5±4.5%, P=.022) and vWF:Ag (−7.3±2.1%, P=.034) and was most pronounced in males supplemented with EPA. In contrast, DHA-mediated reduction in platelet aggregation in females was not accompanied by any significant changes in the coagulation parameters tested.ConclusionSignificant interactions between sex and specific LCn-3PUFA exist to reduce procoagulant activity differentially in males vs. females and could have profound effects on managing risk of thrombotic disease.     

Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population

Recent data suggest that brain‐derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD‐I) or type II (BPD‐II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ² = 6.18, df = 2, P = 0.046; allele: χ² = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64–0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD‐I and BPD‐II separately. For BPD‐I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = ?2.27, df = 144, P = 0.025); for BPD‐II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD‐II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD‐I and BPD‐II.     

Association of AGTR1 (A1166C) and ACE (I/D) Polymorphisms with Breast Cancer Risk in North Indian Population

Renin angiotensin system (RAS) comprising Angiotensin converting enzyme (ACE), Angiotensin II (Ang II) and its receptor Angiotensin II receptor type I (AGTR1), plays a critical role in several diseases including cancer. A single nucleotide polymorphism (SNP) A1166C located in 3′ untranslated region (UTR) of AGTR1 and an insertion/deletion (I/D) polymorphism present in intron 16 of ACE gene have been associated with many diseases, but their association with Breast cancer (BCa) is still debatable. Here, we for the first time investigated the association of these polymorphisms in a North Indian BCa cohort including 161 patients and 152 healthy women. The polymorphisms were evaluated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) respectively. The association between these polymorphisms and BCa risk was estimated by calculating Odds Ratio (OR) and chi-square (χ²) test. The DD genotype/D allele of ACE (I/D) polymorphism and “AC and CC” genotype/C allele of AGTR1 (A1166C) polymorphism were associated with higher risk of BCa when evaluated independently. Furthermore, interaction analysis of “AC and CC” and DD genotype and combination of “C and D” alleles of both polymorphisms revealed significantly greater BCa risk than that observed independently. Conclusively, women harboring “AC or CC” genotype/C allele for AGTR1 (A1166C) polymorphism and DD genotype/D allele for ACE (I/D) polymorphisms have a predisposition to develop more aggressive disease with advanced staging and larger tumor size. Our study indicates importance of genetic screening based on these polymorphisms for women, who may have higher risk of BCa.     

Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus

The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double-blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and α-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-α (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM.     

Untersuchungen zur Populationsgenetik von Island,insbesondere der Region Dalasýsla

The authors report the results of a population genetic survey of the Dalasýsla region (West-Iceland). Our sample size includes n=193 male and female individuals of different age. These individuals are partly related. The following blood and serum groups were determined: ABO, MNS, Rh, P; Hp, Gc, Gm, InV, and Lp. In all these systems observed and expected phenotype frequencies are found to be in good agreement. The following gene frequencies turned out: p₁ ^A=.0888, p₂ ^A=.0456, q^B=.0293, r^O=.8363; p^MS=.2256, p^Ms=.4474, p^NS=.0540, p^Ns=.2730; cde=.4123, Cde=.0966, cDe=.0338, CDe=.2984, cDE=.1589; p^P=.4833; Hp¹=.5157, Hp²=.4843; Gc¹=.7340, Gc²=.2660; Gm¹=.1846, Gm^1,2=.1444, Gm¹²=.6710. The frequency of the phenotype InV (1) comes to 17,6%, that of Lp (a+) amounts to 21,6%.In general the Icelandic phenotype and allele frequencies correspond to the European ones, especially to those observed in Northern Europe. In connection with this the authors discuss briefly, to what extent the present day phenotype distributions (especially concerning the ABO system) of Iceland may be interpreted with regard to historical facts and events. It is pointed out that at any rate also selective acting factors should be taken into consideration in order to interpret really the present day distributions. Within Iceland certain inhomogeneities in the phenotype distributions are present. Factors such as small population sizes, geographical isolation, and gene-drift are most likely responsible for this.     

MHC binding peptides for designing of vaccines against Japanese encephalitis virus: A computational approach

Japanese encephalitis (JE), a viral disease has seen a drastic and fatal enlargement in the northern states of India in the current decade. The better and exact cure for the disease is still in waiting. For the cause an in silico strategy in the development of the peptide vaccine has been taken here for the study. A computational approach to find out the Major Histocompatibility Complex (MHC) binding peptide has been implemented. The prediction analysis identified MHC class I (using propred I) and MHC class II (using propred) binding peptides at an expectable percent predicted IC (50) threshold values. These predicted Human leukocyte antigen [HLA] allele binding peptides were further analyzed for potential conserved region using an Immune Epitope Database and Analysis Resource (IEDB). This analysis shows that HLA-DRB1*0101, HLA-DRB3*0101, HLA-DRB1*0401, HLA-DRB1*0102 and HLA-DRB1*07:01% of class II (in genotype 2) and HLA-A*0101, HLA-A*02, HLA-A*0301, HLA-A*2402, HLA-B*0702 and HLA-B*4402% of HLA I (in genotype 3) bound peptides are conserved. The predicted peptides MHC class I are ILDSNGDIIGLY, FVMDEAHFTDPA, KTRKILPQIIK, RLMSPNRVPNYNLF, APTRVVAAEMAEAL, YENVFHTLW and MHC class II molecule are TTGVYRIMARGILGT, NYNLFVMDEAHFTDP, AAAIFMTATPPGTTD, GDTTTGVYRIMARGI and FGEVGAVSL found to be top ranking with potential super antigenic property by binding to all HLA. Out of these the predicted peptide FVMDEAHFTDPA for allele HLA-A*02:01 in MHC class I and NYNLFVMDEAHFTDP for allele HLA-DRB3*01:01 in MHC class II was observed to be most potent and can be further proposed as a significant vaccine in the process. The reported results revealed that the immune-informatics techniques implemented in the development of small size peptide is useful in the development of vaccines against the Japanese encephalitis virus (JEV).     

Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number.

The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number.     

Polymorphism 192Q/R of the paraoxonase 1 gene in elderly men and long-lived people of the Tatar ethnic group

To study the molecular genetic basis of human aging and longevity, the allele and genotype frequencies of the 192Q/R polymorphism of PON1 were compared for ethnic Tatars of the younger (1–20 years), middle (21–55 years), elderly (56–74 years), senile (75–89 years), and long-lived (90–109 years) age groups (in total, 1116 people). The PON1 alleles were identified using PCR and restriction enzyme analysis. In the total samples, the frequencies of genotypes Q/Q, Q/R, and R/R were 46.15, 44.35, and 9.5%, respectively, and the frequencies of alleles Q and R were 68.32 and 31.68%, respectively. Some age groups significantly differed from each other in allele and genotype frequencies. The frequency of allele R in the senile group (28.46%) was significantly lower than in the younger group (37.42%, P = 0.009). However, the long-lived displayed significantly higher frequencies of allele R (P = 0.005) and genotype R/R (P = 0.01) as compared with the senile group.     

The functional effect of soybean extract and isolated isoflavone on myocardial infarction and ventricular dysfunction: The soybean extract on myocardial infarction

BackgroundMyocardial infarction is a public health problem. Functional food is an alternative treatment for cardiovascular diseases.ObjectiveThe objective was to analyze the functional and anatomopathological post-myocardial-infarction effects of soybean extract (SE) and isoflavone (IF).MethodsMyocardial infarction was induced in adult Wistar rats. After 5 days, an echocardiogram was performed to determine heart rate (HR), ejection fraction (EF), systolic volume (LVESV) and diastolic volume (LVEDV). Animals with ventricular dysfunction (EF<45%) were selected for study. The animals were divided into three groups: control (n=14), SE (n=15) and IF (n=12). The IF group received 120 mg/kg/day isolated IF, and the SE group received 12.52 g/day. After 30 days, a new echocardiogram was performed. A histological exam was carried out to determine the collagen. Activity of biochemical markers [arginase, lactate dehydrogenase (LDH) and malate dehydrogenase] was measured.ResultsThe animals of the control, IF and SE groups showed a reduction in EF after the infarction (P=.432, P=.017 and P=.320, respectively). An increase of LVESV and LVEDV was observed in all groups (P=.009, P=.001 and P=.140; and P=.003, P=.008 and P=.205, respectively). A reduction of HR was found in the SE group (P=.020). There was a greater activity of LDH in the SE group. A smaller quantity of mature collagen was found in the region proximal to the myocardial infarction in the SE group.ConclusionA protective effect in the SE group was observed 30 days after the myocardial infarction.     

Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites

Stature, bone size, and bone mass are interrelated traits with high heritability, but the major genes that govern these phenotypes remain unknown. Independent genomewide quantitative-trait locus studies have suggested a locus for bone-mineral density and stature at chromosome 11q12-13, a region harboring the low-density lipoprotein receptor–related protein 5 (LRP5) gene. Mutations in the LRP5 gene were recently implicated in osteoporosis-pseudoglioma and “high-bone-mass” syndromes. To test whether polymorphisms in the LRP5 gene contribute to bone-mass determination in the general population, we studied a cross-sectional cohort of 889 healthy whites of both sexes. Significant associations were found for a missense substitution in exon 9 (c.2047G→A) with lumbar spine (LS)–bone-mineral content (BMC) (P=.0032), with bone area (P=.0014), and with stature (P=.0062). The associations were observed mainly in adult men, in whom LRP5 polymorphisms accounted for 15% of the traits’ variances. Results of haplotype analysis of five single-nucleotide polymorphisms in the LRP5 region suggest that additional genetic variation within the locus might also contribute to bone-mass and size determination. To confirm our results, we investigated whether LRP5 haplotypes were associated with 1-year gain in vertebral bone mass and size in 386 prepubertal children. Significant associations were observed for changes in BMC (P=.0348) and bone area (P=.0286) in males but not females, independently supporting our observations of a mostly male-specific effect, as seen in the adults. Together, these results suggest that LRP5 variants significantly contribute to LS–bone-mass and size determination in men by influencing vertebral bone growth during childhood.     

2′-5′-Oligoadenylate synthetase 1 polymorphisms are associated with tuberculosis: a case-control study

Background

2′-5′-Oligoadenylate synthetase 1 (OAS1) plays an important role in inflammatory immune reactions. OAS1 polymorphisms have been associated with increased susceptibility to various diseases. We investigated the association of polymorphisms in OAS1 with tuberculosis (TB).

Methods

A total of 1215?TB cases and 1114 healthy controls were enrolled from two independent studies. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR) method. Associations between OAS1 polymorphisms (rs2240190, rs1131454, 10,774,671 and 11,066,453) and TB risk were established based on distributions of allelic frequencies using different genetic models.

Results

Significant association was observed between rs10774671, rs1131454 and TB. In the initial study, the G allele of rs10774671 was a significantly protective factor against TB (P?=?0.006) and the genotype of GG differed significantly between TB patients and controls under the codominant model (P?=?0.008) after Bonferroni correction. In the validation study, we also observed that the rs10774671 G allele (P?=?0.001) and GG genotype (P?=?0.001) were associated with TB. In addition, we found that the rs1131454 G allele (P?=?0.004) and GG genotype (P?=?0.001) were protective against TB in the Chinese Han population.

Conclusions

We report novel associations of polymorphisms in OAS1 with TB in the Chinese Tibetan and Han populations. Similar studies in different populations and functional studies are warranted to confirm our results.

     

<Emphasis Type="Italic">EPSTI1</Emphasis> polymorphisms are associated with systemic lupus erythematosus

Epithelial stromal interaction 1 (EPSTI1) is an interferon (IFN) response gene, which was originally identified as a stromal fibroblast-induced gene in breast cancer. Our previous study using a customized SNP chip found evidence of an association between EPSTI1 and susceptibility to the chronic inflammatory disease, systematic lupus erythematosus (SLE). This study aimed to validate whether polymorphisms in EPSTI1 are associated with susceptibility to SLE. We analyzed genotype and allele frequencies of SNPs at EPSTI1 using genomic DNA from 119 patients with SLE and 512 healthy controls. We found that the genotype frequencies of rs1044856 and rs1359184 in patients with SLE were significantly different from those found in the control group (P?=?0.03 and P?=?0.01, respectively). In addition, we found that genotype and allele frequencies of rs1359184 in female patients with SLE were significantly different from those found in female controls (P?=?0.02 and P?=?0.04, respectively). We identified two major haplotypes in EPSTI1 that were significantly different between patients with SLE and healthy controls (P?=?0.01 and P?=?0.05, respectively). Furthermore, we found that rs1359184 and rs1044856 in EPSTI1 were associated with antinuclear antibody (ANA) and erythrocyte sedimentation rate (ESR) levels in patients with SLE (P?=?0.0035 and P?=?0.021, respectively). Our findings indicate that polymorphisms in EPSTI1 are associated with susceptibility to SLE and that haplotypes at EPSTI1 may be useful genetic markers for SLE.     

Circulating levels of miR-7, miR-152 and miR-192 respond to vitamin D supplementation in adults with prediabetes and correlate with improvements in glycemic control

Vitamin D may play an important role in modifying the risk of type 2 diabetes. Supplementation with cholecalciferol has been shown to improve β cell function and to attenuate the rise in glycated hemoglobin in people at high risk of diabetes. We examined whether circulating microRNAs (miRNAs) reflect disease progression and/or respond to vitamin D supplementation. We measured plasma levels of select miRNAs implicated in diabetes in people with prediabetes treated either with placebo (n=21) or 2000 U of cholecalciferol daily (n=21) for 4 months in the Calcium and Vitamin D for Diabetes Mellitus trial and compared the baseline-adjusted changes after correcting for age, body mass index, race, time of study entry (season) and baseline disposition index. Circulating levels of miR-7 (sixfold reduction, P=.01), miR-152 (1.5-fold increase, P=.03), and miR-192 (1.7-fold reduction, P=.026) displayed significant treatment-by-time interactions between the placebo- and the vitamin-D-treated groups. Plasma levels of miR-7 were reduced in the vitamin D and increased in the placebo group. The change in miR-152 positively correlated with the change in levels of the circulating metabolite 25-hydroxyvitamin D (r=0.33, P=.046) and negatively correlated with the change in glycated hemoglobin (r=−0.37, P=.024). The change in miR-192 positively correlated with the change in fasting glucose (r=0.41, P<.011). In conclusion, reduction of circulating miR-7 and miR-192, accompanied by elevation of miR-152, reflects a beneficial metabolic response to vitamin D treatment in people with prediabetes. These miRNAs may be useful biomarkers in diabetes prevention trials and other studies of vitamin D.