Unrelated Healthy Control Subjects Research Articles

QEEG - spectral power density of brain regions in predicting risk, resistance and resilience for bipolar disorder: A comparison of first degree relatives and unrelated healthy subjects

BackgroundTemperament stems from the brain circuitry. Genetic differences among people are attributable to differences in neurophysiological function. Affective temperament is proposed endophenotype for bipolar affective disorder. QEEG - spectral power density is thought to be an index of general affective and cognitive brain activity. The association of spectral power density with types of affective temperament may enlighten endophenotypes for bipolar affective disorder disposition. MethodTEMPS-A scale and rest QEEG were done on 25 euthymic patients, their healthy first degree relatives (n = 25) and 25 unrelated healthy control subjects. All patients were on lithium maintenance therapy. ResultsF4 and T4 delta wave activity were similar between patients and first degree relatives, while Pz alpha activity was similar in first degree relatives and unrelated healthy subjects (p = 0.025, p = 0.001, p = 0.010). Cyclothymic and hyperthymic temperament scores were similar between patients and first degree relatives but higher than unrelated healthy subjects (p = 0.015, p = 0.010). F7 beta and F7–O2 high beta power were correlated with hyperthymic and irritable temperaments respectively in bipolar subjects (r = 0.439, 0.387; 0.405, 0.364; 0.226, 0.351). T3-F4-T4 delta powers were correlated with cyclothymic temperament in patients and their first degree relatives (r = 0.443, 0.420, 505). Pz alpha power and hyperthymic temperament were inversely correlated in first degree relatives and unrelated healthy subjects (r = -0.256 and -0.311). ConclusionMedial temporal network may be associated with bipolar affective disorder heritability. On the other hand, left dorsolateral prefrontal beta and high beta activities may be a neural marker for disorder resistance together with right occipital high beta power.

Monocytes of Chronic Fatigue Syndrome Patients, their Family Members without CFS, and Unrelated Healthy Donors: Searching for Differences

Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by fatigue that does not improve with rest and worsens with exertion. ME/CFS may involve inflammation in the brain and/or be associated with viral infections. Increased numbers of pro-inflammatory monocytes in blood are a hallmark of infection. Biomarkers for, and information about, the CFS disease process are greatly needed. Here we queried circulating monocytes. In a pilot study, CFS patients and family members without CFS from three families were compared in order to reduce genetic and environmental variables. The patients conformed to the Fukuda 1994 standards. Unrelated healthy control subjects matched to the patients were included in the study. Blood monocytes were stained and analyzed by flow cytometry: counted with TruCountR beads, or stained after isolation and overnight culture of isolated peripheral blood monocytes. M1 pro-inflammatory monocytes are CD16A negative, while anti-inflammatory monocytes are CD16A positive; CD2 is a marker for dendritic monocytes, and changes in forward scatter could indicate in vitro activation. Notably, there were statistically significant differences between the lower percentages of M1 monocytes of the CFS patients compared to the controls; however, these differences were not significant between the patients and their family members without CFS. Also, the CD16A MFIs of the patients' monocytes were lower compared to controls but not to family members. One conclusion is that it is important to include family members without CFS as a control group in the search for biomarkers to diagnose CFS.

In the absence of specific advice, what do patients eat and avoid? Results from a community based diet study in patients suffering from rheumatoid arthritis (RA) with a focus on potassium

141 consenting symptomatic chronic RA patients [mean age 46 years) center and 165 unrelated healthy control subjects (mean age 36 years) completed a a-priori validated food frequency questionnaire in a cross-sectional non-random design study under the supervision of a nutritionist. All patients were under standard rheumatology care. A 3 day retrospective recall record captured dietary data for all subjects. National Indian guidelines were adopted for diet analytics. Standard statistical analysis was carried out; significant p<0.05. Daily diet was found to be significantly deficient in calories and consumption of proteins, calcium and potassium when compared to healthy subjects. It was also inadequate for several nutrients when compacted to recommended daily allowance. The proportion of carbohydrates (65%), proteins (15%) and fat (25%) in daily diet was consistent with Indian standards (healthy). Women patients reported higher deficiency. 44% patients consumed vegetarian diet and showed lesser pain and better function compared to non-vegetarians (not significant). 44% patients reported dietary restriction; higher swollen joint counts in patients following any dietary restriction (p=0.01) or Ayurveda (ancient Indian medicinal system) advise (p=0.01) or consuming night shade vegetables (p=0.002). Dietary inadequacy and in particular for protein and potassium was identified in patients of RA. Any form of dietary restriction did not seem to improve RA. Specific dietary needs of RA patients and in particular impact of potassium deficiency needs further research.

Association between T-182C, G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients

Objective: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population.Methods: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction.Results: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution.Conclusions: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities.

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives.

SummaryForkhead box P3 (FoxP3)+ regulatory T cells (Tregs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)‐2 receptor alpha chain]. Low‐dose IL‐2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg) subsets in 45 SLE patients, 103 SLE‐unaffected first‐degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25‐encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+FoxP3+CD45RO–CD31+ recent thymic emigrant Tregs. This first component effect influenced the proportions of circulating CD4+FoxP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up‐regulated CD25 strongly in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 up‐regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs, but not to their circulating numbers. Both effects were found related to T cell IL‐2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up‐regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg‐directed therapies can be monitored more effectively when taking this distinction into account.

Association of CpG-SNP and 3'UTR-SNP of WFS1 with the Risk of Type 2 Diabetes Mellitus in an Iranian Population.

Type 2 diabetes mellitus (T2DM) is one of the most common multifactorial disorders in Iran. Recent genome wide association studies (GWASs) and functional studies have suggested that WFS1 may predispose individuals to T2DM. However, to date, the possible association of such variants with T2DM in Iranians remained unknown. Here, we investigated the association of the two polymorphisms of WFS1 (rs1801214 a CpG-SNP, and rs1046320 a 3’UTR-SNP) with T2DM in an Iranian population. The study population comprised 432 unrelated Iranian individuals including 220 patients with T2DM, and 211 unrelated healthy control subjects. Genotyping was performed using PCR-RFLP, and confirmed with sequencing. In a logistic regression analysis, the rs1801214-T allele was associated with a significantly lower risk of T2DM assuming the log-additive model (OR: 0.68, 95% CI: 0.52-0.91, P= 0.007539). Moreover, the G allele of rs1046320 was associated with a lower risk of T2DM assuming the log-additive model (OR: 0.68, 95% CI: 0.50- 0.91, P= 0.008313). Haplotype analysis revealed that haplotypes that carry at least one protective allele are associated with a lower risk of T2DM. This is a first evidence for the association of WFS1 rs1801214, and rs1046320 with T2DM in an Iranian population.

Association between the APOE ε4 Allele and Late-Onset Alzheimer's Disease in an Ecuadorian Mestizo Population.

Alzheimer's disease (AD) is the most common neurodegenerative disease. It has two main pathological hallmarks: amyloid plaques and neurofibrillary tangles. The APOE ε4 allele has been recognized as the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) in several populations worldwide, yet the risk varies by region and ethnicity. The aims of this study were to describe APOE allele and genotype frequencies and examine the relationship between the APOE ε4 allele and LOAD risk in an Ecuadorian Mestizo population. We carried out a case-control study comprising 56 individuals clinically diagnosed with probable AD (≥65 years of age) and 58 unrelated healthy control subjects (≥65 years of age). Genotyping was performed using the real-time PCR method. Our data showed that allelic and genotypic frequencies follow the trends observed in most worldwide populations. We also found a high-risk association between APOE ε4 allele carriers and LOAD (OR = 7.286; 95% CI = 2.824–18.799; p < 0.001). Therefore, we concluded that APOE ε4 must be considered an important genetic risk factor for LOAD in the Ecuadorian Mestizo population. Additionally, we suggest that in mixed populations the effects of admixture and ethnic identity should be differentiated when evaluating genetic contributions to Alzheimer's disease risk.

Predictive value of premorbid IQ, negative symptoms, and age for cognitive and social functions in Japanese patients with schizophrenia: A study using the Japanese version of the Brief Assessment of Cognition in Schizophrenia.

Enduring cognitive impairment in patients with schizophrenia represents a global health burden. The Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and the Japanese Adult Reading Test were administered to 288 patients with chronic schizophrenia and 308 unrelated healthy control subjects. The Japanese version of self-reported Social Functioning Scale (SFS) was administered to a subpopulation of 157 patients with schizophrenia. In patients with schizophrenia, premorbid IQ and age were significantly related to most of the BACS subdomains, composite score, and intra-individual variability of BACS subdomains, whereas negative symptoms were significantly related to all BACS indices. Dosages of the first-generation antipsychotics had a significant negative impact on Tower of London task and intra-individual variability of BACS subdomains. The relationship of symbol coding with age was significantly lower in patients than in healthy control subjects. Multiple regression analysis revealed that negative symptoms were significantly negatively related to the total SFS scale, whereas better performance of token motor task was associated with higher total SFS. The present study revealed the role of premorbid IQ, age, and negative symptoms in predicting cognitive performance, and the significant correlation of negative symptoms and token motor task with social function in patients with schizophrenia.

MAP3K1 May be a Promising Susceptibility Gene for Type 2 Diabetes Mellitus in an Iranian Population.

Considering that MAPK (mitogen- activated protein kinase) signaling pathway has an important role in the progression of inflammatory cytokine secretion in type 2 diabetes mellitus (T2DM), we have recently investigated the reported genetic polymorphism from genome wide association study in MAP3K1 (mitogen-activated protein kinase kinase kinase 1) in diabetes as an important member of MAPK signaling. This study aimed to investigate the possible association of rs10461617 at the upstream of MAP3K1 gene in an Iranian case-control study with the risk of T2DM. The study population was comprised of 342 unrelated Iranian individuals including 177 patients with T2DM and 165 unrelated healthy control subjects. Genotyping was performed using PCR-RFLP and confirmed with sequencing. In a logistic regression analysis, the rs10461617A allele was associated with a significantly higher risk of T2DM assuming the log- additive model (OR: 1.44, 95% CI: 1.01-2.05, P = 0.039). In conclusion, we provided the first evidence for the association of rs10461617 at the upstream of MAP3K1 with the risk of T2DM in an Iranian population.

The serotonin transporter gene (triallelic 5-HTTLPR polymorphism) may associate with male depression in Han Chinese population

Background: Pharmacological, neurobehavioral, and therapeutic evidence have implicated serotonin in the pathogenesis of depression. There are conflicting reports on the association of genetic variants of serotonin transporter gene (5-HTTLPR) with major depressive disorder. The 5-HTTLPR is thought to have three primary allelic variants (rs25531): LA, LG, and S. The present study examined whether major depression was associated with tri-allelic 5-HTTLPR polymorphisms in a Han Chinese population. Materials and Methods: Bi-allelic and tri-allelic 5-HTTLPR polymorphisms were assessed in 305 patients with major depressive disorder (MD) and 313 unrelated healthy control subjects. In addition, to reduce clinical heterogeneity, subtype analyses were performed for clinically important variables, including family history of major affective disorder, age at onset, and severity of MD. Results: The bi-allelic 5-HTTLPR polymorphism was not associated with MD and its clinical subgroups. However, the tri-allelic 5-HTTLPR polymorphism was associated with major depression and with specific subgroups. In particular, in male subjects, patients with a low expressing genotype ( S'/S' ) were at higher risk for MD than those with high expressing genotypes ( S'/L' and L'/L' ). This positive association was only observed in the subgroups of late-onset and moderate severity MD. Conclusions: The present study suggests that the tri-allelic 5-HTTLPR polymorphism might be a risk factor for susceptibility to either MD or its clinical subtypes in the Han Chinese male population but not in the female population. However, these results should be validated in a larger patient population that includes different ethnic samples or subdiagnosis groups.

Candidate gene analysis supports a role for polymorphisms at TCF7L2 as risk factors for type 2 diabetes in Sudan.

BackgroundGenetic susceptibility to type 2 diabetes (T2D) is multifactorial. A growing number of genes have been identified as risk factors for T2D across multiple ethnicities in trans-ancestry meta-analysis of large-scale genome-wide association studies. Few studies have looked at these genes in Sub-Saharan African populations. This study was undertaken to look for associations between T2D and single nucleotide polymorphisms (SNPs) in a number of the top candidate genes in a selected Sudanese population.MethodsA total 240 T2D cases and 128 unrelated healthy control subjects were included in this study. Age, sex, weight and height were recorded, blood pressure and biochemical profiles of glucose and lipids were analysed. Single nucleotide polymorphism (SNP) genotyping was performed using the Sequenom MassARRAY® system. Fourteen SNPs were selected across 7 genes: CAPN10 (rs2975760 and rs5030952), PPARG (rs17036314 and rs1801282), IGF2BP2 (rs4402960 and rs1470579), CDKAL1 (rs9465871), HHEX (rs1111875), TCF7L2 (rs7903146, rs11196205 and rs12255372), and KCNJ11 (rs5215, rs1800467 and rs5219). Allelic and haplotype association analyses were performed under additive models in PLINK. P ≤ 0.007 (=0.05/7 genes) was the P-value required to achieve correction for multiple testing.ResultsA significant genetic association between the SNPs rs7903146 (odds ratio 1.69, 95 % confidence interval 1.21–2.38, P = 0.002) and rs12255372 (odds ratio 1.70, 95 % confidence interval 1.20–2.41, P = 0.003) at TCF7L2 and T2D was found in Sudanese population. These associations were retained after adjusting for age, sex and BMI (e.g. rs7903146: odds ratio 1.70, P adj:age/sex/BMI = 0.005). The strongest haplotype association (odds ratio 2.24; P adj:age/sex/BMI = 0.0003) comprised the two point haplotype T_C across rs7903146 and rs11196205. Stepwise logistic regression demonstrated that SNP rs7903146 added significant main effects to rs11196205 or rs12255372, whereas the reverse was not true, indicating that the main effect for association with T2D in this population is most strongly tagged by SNP rs7903146. Adjusted analyses also provided support for protection from T2D associated with minor alleles at SNPs rs2975760 at CAPN10 (odds ratio 0.44, 95 % confidence interval 0.20-0.97, P adj:age/sex/BMI = 0.042) and rs1111876 at HHEX (odds ratio 0.60, 95 % confidence interval 0.39- 0.93, P adj:age/sex/BMI = 0.022).ConclusionsMultiethnic associations between T2D and SNPs at TCF7L2, CAPN10 and HHEX extend to Sub-Saharan Africa, specifically Sudan.

The rs3737964 single-nucleotide polymorphism of the chloride channel-6 gene as a risk factor for coronary heart disease.

The present study investigates the association of single-nucleotide polymorphisms (SNPs) on the chloride channel-6 (CLC-6) gene with coronary heart disease (CHD) in China. We carried out a large case-control study among 1193 CHD patients and 1200 unrelated healthy control subjects. Information on the participants' health status was collected through the modified Inter-heart questionnaire. Genomic DNA from peripheral blood samples was analyzed for the genotypes of rs3737964 and rs3737965 SNPs on the CLC-6 gene using Taqman probe-based quantitative real-time PCR (qPCR). We compared the collected data between the case group and the control group by chi-square test and t/nonparametric test. Furthermore, we performed logistic regression to evaluate factors associated with CHD. The frequency of TT genotypes in rs3737964 was significantly higher in CHD patients compared to the control group, with an odds ratio (OR) of 2.32 (95% confidence interval, CI: 1.17-4.06, P=0.016). The association of CHD with TT genotype was even stronger in smoking population after adjusting for confounders (OR=3.19, 95% CI: 1.04-9.79, P=0.043). Multivariate logistic regression showed the CHD risk associated with TT genotype in rs3737964 was particularly among population who were more than 60years old, smoking, and male (P=0.023, 0.008 and 0.043, respectively). The present study has revealed that rs3737964 SNP of CLC-6 was associated with CHD. In particular, subjects with TT genotype who were 60-plus years old, with smoking habit or were male were more susceptible to CHD.

Alterations in Intestinal Microbiota Correlate With Susceptibility to Type 1 Diabetes.

We tested the hypothesis that alterations in the intestinal microbiota are linked with the progression of type 1 diabetes (T1D). Herein, we present results from a study performed in subjects with islet autoimmunity living in the U.S. High-throughput sequencing of bacterial 16S rRNA genes and adjustment for sex, age, autoantibody presence, and HLA indicated that the gut microbiomes of seropositive subjects differed from those of autoantibody-free first-degree relatives (FDRs) in the abundance of four taxa. Furthermore, subjects with autoantibodies, seronegative FDRs, and new-onset patients had different levels of the Firmicutes genera Lactobacillus and Staphylococcus compared with healthy control subjects with no family history of autoimmunity. Further analysis revealed trends toward increased and reduced abundances of the Bacteroidetes genera Bacteroides and Prevotella, respectively, in seropositive subjects with multiple versus one autoantibody. Canonical discriminant analysis suggested that the gut microbiomes of autoantibody-positive individuals and seronegative FDRs clustered together but separate from those of new-onset patients and unrelated healthy control subjects. Finally, no differences in biodiversity were evident in seropositive versus seronegative FDRs. These observations suggest that altered intestinal microbiota may be associated with disease susceptibility.

Molecular signatures differentiate immune states in type 1 diabetic families.

Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined. Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1−dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy autoantibody-negative (AA−) high HLA−risk siblings (HRS) (DR3 and/or DR4) and AA− low HLA−risk siblings (LRS) (non-DR3/non-DR4). Signatures, scored with a novel ontology-based algorithm, and confirmatory studies differentiated the RO T1D, uHC, HRS, and LRS plasma milieus. Relative to uHC, T1D family members exhibited an elevated inflammatory state, consistent with innate receptor ligation that was independent of HLA, AA, or disease status and included elevated plasma IL-1α, IL-12p40, CCL2, CCL3, and CCL4 levels. Longitudinally, signatures of T1D progressors exhibited increasing inflammatory bias. Conversely, HRS possessing decreasing AA titers revealed emergence of an IL-10/transforming growth factor-β−mediated regulatory state that paralleled temporal increases in peripheral activated CD4+/CD45RA−/FoxP3high regulatory T-cell frequencies. In AA− HRS, the familial innate inflammatory state also was temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age.

Synergistic effects of BuChE non-UU phenotype and paraoxonase (PON1) 55 M allele on the risk of systemic lupus erythematosus: influence on lipid and lipoprotein metabolism and oxidative stress, preliminary report

There is some evidence indicating lipid peroxidation can affect progression of atherosclerosis, cardiovascular diseases (CVDs) and glomerulonephritis in systemic lupus erythematosus (SLE) patients. Human butyrylcholinesterase (BuChE) and paraoxonase-1 (PON1) are two major bioscavenger enzymes that are associated with inflammation, oxidative stress and lipid metabolism. Hyperlipidemia, increase in lipid oxidation reactions and defects in antioxidant status may lead to increased oxidative stress and high frequency of CVDs in SLE. It has also been suggested that deficiency in the function of the antioxidant system and an increase in reactive oxygen release (ROS) may play an important role in the pathogenesis of SLE. This study is the first investigation to examine the association of BuChE phenotypes, PON1 (L55M; PON-55-M) polymorphism, the levels of malondialdehyde (MDA), neopterin, lipid-lipoprotein and activities of BuChE and arylesterase activity (ARE) of PON with severity of SLE. The present case-control study consisted of 109 SLE patients and 101 gender- and age-matched, unrelated healthy control subjects from the population of west Iran. We found that the PON-55-M allele and BuChE non-UU act synergistically to increase the risk of SLE by 2.5 times (1.03-6.7, p = 0.044). There was a significant negative correlation between severity of SLE with serum BuChE activity (R = -0.31, p < 0.001) and positive correlation with serum neopterin level. The SLE patients with the PON-55-M (M/L + M/M) allele or with BuChE non-UU phenotype had significantly lower serum ARE and BuChE activities than those with PON-55-L/L or BuChE-UU phenotypes, respectively. In addition, their serum levels of MDA, neopterin and LDL-C were significantly elevated, suggesting that these individuals are more susceptible to CVD. However, further studies are needed to shed more light on the contribution of the M allele of PON1 and non-UU phenotypes of BuChE in the development of SLE in different ethnicities.

PTPN22 profile indicates a novel risk group in Alopecia areata

Alopecia areata (AA) is a genetically determined autoimmune hair loss disorder. A polymorphism in protein tyrosine phosphatase N22 (PTPN22), which normally suppresses T-cell proliferation, has been associated with human autoimmune disease, including AA in European populations. PTPN22 genotype frequency in known to vary geographically. Accordingly, we conducted a case-control study of the PTPN22 1858C/1858T (C1858T) genotype frequency in North American Caucasians and non-Caucasians. Allele status was determined in 365 AA patients, 196 healthy related control subjects (RC) and 77 unrelated healthy control subjects (UrC). We found that AA patients are more likely to carry the PTPN22 C1858T genotype than UrCs (p=0.075), and this association reached significance in patients with the most severe disease presentation (Alopecia universalis vs. UrC, p=0.024). PTPN22 C1858T genotype frequency in RC did not differ from AA patients (p=0.657), but was significantly increased in comparison with UrC (p=0.050). PTPN22 1858C/T genotype frequency increased in related control subjects most closely associated with patients (one family members of AA patients vs. UrC subjects, p=0.040). Our data suggests that AA patients (particularly those that are severely affected) and closely related control subjects may belong to a shared inheritance group with increased disease risk, distinct from secondary and tertiary relatives and unrelated individuals. These findings have implications for the study of candidate genes and susceptibility to AA that may influence future clinical monitoring of unaffected, but closely related family members of patients.

Metabolic phenotype and cardiovascular risk factors in the first degree relatives of Chinese women with polycystic ovary syndrome

To test the hypothesis that the first degree relatives of Chinese women with polycystic ovarian syndrome (PCOS) have higher risk of cardiovascular disease than those without PCOS.The metabolic phenotype and risks of cardiovascular disease were evaluated in 110 family members of 35 women with PCOS and 85 unrelated healthy control subjects without family history of diabetes and PCOS ( four age- and weight-matched subgroups ).The prevalence of impaired glucose tolerance was 51.4％ in mothers and 57.5％ in fathers with their daughters suffering from PCOS.The first degree relatives of PCOS women had significantly higher serum fasting insulin level,homeostasis model assessment for insulin resistance,insulin area under the curve,and lower insulin sensitivity index in all subgroups than the control subjects( P＜0.05 ).The control subjects had significantly elevated high molecular weight-adiponectin levels and decreased high sensitive-C reactive protein levels compared to the first degree relatives of PCOS women in all subgroups.Parents and brothers,but not sisters,of women with PCOS had significantly higher total cholesterol and low density lipoprotein-cholesterol ( P＜ 0.05 ),as well as triglyceride levels ( P＜ 0.05 ),compared with control subjects.The first degree relatives of PCOS women had features of insulin resistance and increased risk of cardiovascular disease. Key words: Polycystic ovarian syndrome ; First degree relatives ; Insulin resistance ; Cardiovascular disease

Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD‐1.3A genotype in patients with systemic lupus erythematosus

A genetic polymorphism in the programmed death 1 (PD-1) gene encoding the coinhibitory PD-1 immunoreceptor, PD-1.3A, is associated with systemic lupus erythematosus (SLE). The aim of this study was to assess PD-1 receptor expression in patients with SLE, in comparison with relatives and unrelated healthy controls, and to identify correlations of lower expression levels of PD-1 receptor with the PD-1.3A genotype. Patients with SLE, patients' relatives, and unrelated healthy control subjects from Iceland and Sweden were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3/anti-CD28, and PD-1 expression was analyzed by flow cytometry. PD-1.3A/G genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. PD-1 expression on PBMCs was induced after antibody stimulation, showing increases of 2.1-fold in SLE patients, 3.1-fold in relatives, and 5.1-fold in healthy controls. The frequency of PD-1+ cells was significantly lower in SLE patients compared with relatives and healthy controls. PD-1 expression on PD-1+ cells and on CD4+CD25+ T cells was significantly lower in SLE patients and relatives compared with healthy controls. PD-1 expression was significantly elevated on CD25(high) cells. Levels of PD-1 expression on CD25(high) and CD25(intermediate) cells were significantly lower in SLE patients compared with healthy controls. PD-1 was expressed on both FoxP3- and FoxP3+ cells. Lower expression of PD-1 was significantly correlated with the PD-1.3A/G genotype. The results demonstrate significantly lower PD-1 receptor expression in SLE patients and their relatives and reveal a significant correlation of lower PD-1 expression with the PD-1.3A allele. Thus, PD-1.3A may contribute to abnormalities in PD-1 receptor expression on CD4+CD25+ T cells in patients with SLE, providing support for an important role of the PD-1 pathway in SLE and, possibly, in other autoimmune diseases.

Analysis of 14 genetic polymorphisms for risk factors in Malaysian essential hypertension with or without type 2 diabetes mellitus subjects

Objectives The objective of this study was to determine the association of insertion/deletion (I/D), G2350A and T3892C polymorphisms of angiotensin converting enzyme (ACE) gene, A20C and A6G polymorphism of angiotensinogen (AGT) gene, BglI and MboI polymorphisms of renin gene, I/D of alpha 2B adrenoceptor gene, Gly460Trp of aldosterone synthase gene, Lys173Arg of adducin gene, A6244G polymorphism of the insulin receptor gene, S477X polymorphism of the lipoprotein lipase gene, C511T polymorphism of the interleukin gene and C825T polymorphism of the G protein beta 3 subunit (GNβ3) gene in essential hypertension (EHT) with or without type 2 diabetes mellitus (T2DM) of Malaysian subjects. Methods This cross-sectional study includes 70 EHT without T2DM, 65 EHT with T2DM and 75 unrelated healthy control subjects. Genomic DNA was extracted from the peripheral blood. The polymerase chain reaction (PCR)-restriction fragment length polymorphism, mutagenically PCR and the hot-start PCR methods were carried out to detect the genotypes of the various genetic polymorphisms. All the PCR products and the restricted fragments were resolved electrophoretically on agarose and polyacrylamide gels. Statistical analyses was done using SPPS version 14.0. Results Among the 14 genetic polymorphisms, only I/D and G2350A polymorphism of ACE gene, I/D polymorphism of alpha adrenoceptor gene and A6G variant of AGT gene differed significantly (p 0.05) when compared to control subjects. Conclusions The alleles of I/D and G2350A polymorphisms of ACE, A6G of AGT and I/D of alpha 2B adrenoceptor genes can be considered as possible genetic markers or predisposing risk factors for EHT with or without T2DM in Malaysian subjects.

Association of the 17-hydroxysteroid dehydrogenase type 5 gene polymorphism (−71A/G HSD17B5 SNP) with hyperandrogenemia in polycystic ovary syndrome (PCOS)

To evaluate the association of an activating single-nucleotide polymorphism (SNP) at position -71 of the promoter of 17beta-hydroxysteroid dehydrogenase type 5 gene (-71A/G HSD17B5 SNP) and polycystic ovary syndrome (PCOS) in a well characterized cohort of caucasian PCOS women with biochemical hyperandrogenemia. The PCOS patients and unrelated healthy control subjects were genotyped for the -71A/G HSD17B5 SNP. The acquired genotypic data was tested for association with PCOS and other quantitative phenotypic traits of the syndrome in PCOS patients. Subjects were recruited from the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, at the University Hospital of Patras, Greece. Genotyping and biochemical determinations took place at the Laboratory of Molecular Endrocinology, University of Patras Medical School, Rion, Greece. Participants comprised 150 caucasian Greek PCOS women with biochemical hyperandrogenism and chronic anovulation and polycystic ovarian morphology on ultrasound and 51 healthy control subjects. HSD17B5 genotype, serum testosterone, serum androstenedione. No association of the -71A/G HSD17B5 SNP with PCOS was detected. However, the -71G HSD17B5 variant was associated with increased serum testosterone levels and decreased androstenedione/testosterone ratio. The -71G HSD17B5 variant is not a major component of the molecular pathogenetic mechanisms of PCOS, although it might contribute to the severity of hyperandrogenemia in women with PCOS and biochemical hyperandrogenism.