−1722T/C polymorphism (rs733618) of CTLA-4 significantly associated with systemic lupus erythematosus (SLE): A comprehensive meta-analysis

This study was to determine whether −318C/T (rs5742909), −1722T/C (rs733618) and −1661A/G (rs4553808) of Cytotoxic T-lymphocyte antigen-4 (CTLA-4) are associated with systemic lupus erythematosus (SLE). The meta-analysis for −318C/T (rs5742909) included 1163 cases and 1520 controls, for −1722T/C (rs733618) included 1016 cases and 1078 controls, and for −1661A/G (rs4553808) included 637 cases and 774 controls. For −318C/T (rs5742909), statistically significant differences were not noted between cases and controls {fixed/random: OR: 1.103, 95% CI: (0.907–1.341), p = 0.326}. For −1661A/G (rs4553808), also no significant difference existed {fixed: OR: 1.024, 95% CI: (0.843–1.244), p = 0.812; random: OR: 1.077, 95% CI: (0.780–1.300), p = 0.958}. But −1722T/C (rs733618) was significantly associated with SLE both in allele {fixed: OR: 0.699, 95% CI: (0.602–0.811), p = 0.000; random: OR: 0.748, 95% CI: (0.565–0.990), p = 0.042} and in genotype {CC/(CT + TT)} meta-analysis {OR: 0.422, 95% CI: (0.297–0.598), p = 0.000}. Also, we subdivided the −1722T/C group (rs733618) into Asia and Mixed subgroups, in Asia subgroup, the SNP was significantly associated with SLE {fixed: OR: 0.628, 95% CI: (0.528–0.746), p = 0.000; random: OR: 0.641, 95% CI: (0.470–0.875), p = 0.005}, in the Mixed subgroup, this polymorphism was not associated with SLE {fixed: OR: 0.946, 95% CI: (0.707–1.267), p = 0.711; random: OR: 0.973, 95% CI: (0.606–1.560), p = 0.908}. These results suggest that there is evidence of association between the CLTA-4 and SLE, especially −1722T/C polymorphism (rs733618).     

Menopausal symptoms and associated factors in HIV-positive women

Objective

To evaluate menopausal symptoms and their associated factors in HIV-positive women.

Methods

A cross-sectional study was conducted with 537 women of 40–60 years of age, 273 of whom were HIV-positive and 264 HIV-negative. The women were interviewed to obtain data on their sociodemographic characteristics and menopausal symptoms.

Results

The mean age of the seropositive women was 47.7 ± 5.8 years compared to 49.8 ± 5.3 for the seronegative women (p < 0.001). Bivariate analysis showed a lower prevalence of vasomotor symptoms in the seropositive group (p = 0.009), specifically hot flashes (p < 0.002) and sweating (p = 0.049). Vaginal dryness was also less prevalent in this group (p < 0.005). There were no statistically significant differences between the groups with respect to depression or insomnia. Multiple analysis showed that hot flashes were associated with being peri- or postmenopausal (PR = 2.12; 95%CI: 1.52–2.94). Vaginal dryness was less common in women without a partner (PR = 0.67; 95%CI: 0.49–0.90) and was associated with older age (PR = 1.03; 95%CI: 1.01–1.06) and being in the peri- or postmenopause (PR = 1.69; 95%CI: 1.10–2.60). Depression was inversely associated with being employed (PR = 0.74; 95%CI: 0.58–0.96) and directly associated with the presence of chronic diseases (PR = 1.30; 95%CI: 1.01–1.067). Insomnia was associated with a lower body mass index (PR = 0.96; 95%CI: 0.95–0.97) and with being peri- or postmenopausal (PR = 1.48; 95%CI: 1.11–1.97). No correlation was found between HIV serological status and any of the menopausal symptoms.

Conclusions

In this study, after controlling for confounding variables, HIV infection was not found to be associated with vasomotor, genitourinary or psychological symptoms or with insomnia.     

Genetic variations in toll-like receptor pathway and lung function decline in Cystic Fibrosis patients

The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying Cystic fibrosis (CF) lung disease severity. We assessed the impact of single nucleotide polymorphisms (SNPs) of TLR genes (TLR1 to TLR10, CD14, lipopolyssacharide-binding protein (LBP)) on lung function in CF patients. Each SNP was tested for time-dependent effect on FEV1, using six genetic models. In addition, we investigated associations between SNP genotypes and extreme subject specific slopes of FEV1 decline. Variant alleles of polymorphisms of TLR2 rs1898830, rs5743708, and rs3804100 demonstrated a consistent association with lung disease severity (p = 0.008, p = 0.006 and p = 0.029 respectively). Patients homozygous for variant C allele of TLR5 polymorphism rs5744174 are more frequently associated with extreme fast FEV1 decline (OR: 20 (95% Confidence Interval:1.85–216.18)). Patients homozygous AA for TLR1 polymorphism rs5743551 are more frequently associated with faster decline of FEV1 compared to heterozygous genotype (OR:7.33 (95% CI:1.63–33.11). Our findings indicate that variations in TLR1, TLR2 and TLR5 genes may influence CF lung function decline. Further functional analysis is required to provide new insights into the pathogenesis of TLRs in CF lung disease severity.     

Long-term adherence to the Mediterranean diet reduces the prevalence of hyperuricaemia in elderly individuals, without known cardiovascular disease: the Ikaria study

Background

The purpose of this study was to evaluate the impact of adherence to Mediterranean diet on serum uric acid (UA) levels in elderly individuals, without known cardiovascular disease.

Methods

During 2009, 281 females (75 ± 6 years old) and 257 males (75 ± 7 years old) permanent inhabitants of the island, were voluntarily enrolled. A diet score that assesses the inherent characteristics of the Mediterranean diet (MedDietScore, range 0-55) was applied. Serum levels of UA were determined using an enzymatic colorimetric test through the uricase-peroxidase method. Hyperuricaemia was defined as UA > 7 mg/dL in males and 6 mg/dL in females.

Results

Prevalence of hyperuricaemia was 34% in males and 25% in females (p = 0.02). Mean level of adherence to the Mediterranean diet was 35 ± 2. Linear regression analysis revealed that MedDietScore was inversely associated with UA levels (b ± SE: −1.48 ± 0.17, p < 0.001) in the overall sample, after controlling for hypertension, hypercholesterolemia, diabetes mellitus, creatinine clearance, physical activity, and coffee consumption. When the analysis was stratified by gender, MedDietScore was inversely associated with UA levels in males (b ± SE: −1.10 ± 0.42, p = 0.009), but not in females (b ± SE: 0.04 ± 0.41, p = 0.92).

Conclusion

Another cardioprotective effect of Mediterranean diet was revealed, through the modification of UA levels in elderly individuals. The potential different effect size as regards the relationship between diet and UA levels between genders, deserves further investigation.     

Factors related to increased daytime sleepiness during the menopausal transition as evaluated by the Epworth Sleepiness Scale

Background

Sleep disorders and sleep-apnea/hypopnea syndromes are very frequent in women, being misdiagnosed in many cases. The menopause, regardless of age, is associated to poor sleep quality and daytime sleepiness that can lead to impaired quality of life, and reduced productivity and functioning.

Objective

To assess daytime sleepiness and related risk factors among middle aged Ecuadorian women using the Epworth Sleepiness Scale (ESS).

Methods

In this cross-sectional study 149 women aged 40–59 years were assessed for hot flush presence and intensity using the Menopause Rating Scale (MRS) and requested to fill out the ESS and a questionnaire containing personal and partner data.

Results

Mean age of surveyed women was 47.6 ± 5.5 years, with 67.8% having less than 12 years of schooling, 33.6% being postmenopausal, and 2.7% on hormone therapy. A 10.1% were current smokers and 20.8% were sedentary. According to the MRS (item 1) 51.7% presented hot flushes, which were graded as severe–very severe in 42.8% of cases. Regarding the partner (n = 132), erectile dysfunction was present in 10.6%, premature ejaculation 6.1% and 17.4% abused alcohol. Mean total ESS score was 8 ± 4.4 (median 8), with 33.6% considered having some degree of daytime sleepiness (ESS score ≥10). Logistic regression analysis determined that postmenopausal status (OR 6.58, CI 95% [2.51–17.23], p = 0.001), sedentarism (OR 3.43, CI 95% [1.14–10.26], p = 0.02) and hot flush presence (OR 2.61, CI 95% [1.02–6.65], p = 0.04) among women were risk factors for increased daytime sleepiness (ESS total score ≥10) whereas partner faithfulness decreased this risk (OR 0.47, CI 95% [0.24–0.90], p = 0.02).

Conclusion

Increased daytime sleepiness in this middle aged series was related to female (hormonal status and sedentarism) and partner factors; several which are susceptible of intervention.     

The relation between depression,anhedonia and olfactory hedonic estimates—A pilot study in major depression

Several studies investigating olfactory hedonics in major depression have brought conflicting results and an analysis of the relation between severity of depression, anhedonia and olfactory hedonics is still lacking. In order to investigate olfactory perception in different depressive states, we carried out olfactory testing during a depressive episode (n = 37) and in a remitted state (n = 17). As expected, patients were significantly less depressed (p < 0.001) and less anhedonic (p = 0.001) in the remitted state. A comparison of olfactory perception between age- and gender-matched patients and healthy volunteers (n = 37) controlled for intrinsic olfactory deficits in major depression. In the depressive episode, we applied regression analyses to investigate the relation of olfactory hedonics, severity of depression and anhedonia. The Sniffin’ Sticks Test extended by analogue rating scales for intensity and hedonic estimates was employed for olfactory testing. Depression severity was assessed with the Beck Depression Inventory (BDI), anhedonia with the Snaith-Hamilton-Pleasure-Scale (SHAPS). Odour identification ability was significantly reduced during the depressive state. In contrast, no significant differences in hedonic and intensity estimates could be found between the depressive and the remitted state and healthy controls. During the depressive episode, we found a significant relation only between anhedonia and olfactory hedonics. We concluded that anhedonia has potential impact on olfactory hedonics in major depression. Our results indicate the need for (1) confirmatory studies in severe melancholic depression and (2) investigation of the impact of anhedonia on olfactory hedonics in psychiatric diseases other than major depression.     

The role of childhood abuse in HPA-axis reactivity in Social Anxiety Disorder: A pilot study

Background

Studies on depression have found that childhood abuse (CA) is associated with a persistent sensitization of the hypothalamic-pituitary-adrenal (HPA)-axis to stress in adulthood. So far, it is unknown whether this HPA-axis sensitization is specific to depression, or whether this is a more general outcome associated with CA in patients with mood and anxiety disorders. The aim of this study was to investigate whether CA is associated with enhanced cortisol reactivity to psychosocial stress in Social Anxiety Disorder (SAD).

Methods

Salivary cortisol levels before, during, and after exposure to psychosocial stress (i.e., Trier Social Stress Task, TSST) in SAD patients with a history of childhood abuse (SAD + CA, n = 9) were compared to cortisol levels in SAD patients without a history of childhood abuse (SAD − CA, n = 9), patients with PTSD related to childhood abuse (n = 16), and healthy controls without a history of childhood abuse (n = 16).

Results

Analyses showed that the SAD + CA group had a strongly increased cortisol reactivity (mean peak: 17.5 ± 1.9 nmol/l) compared to SAD − CA (mean peak: 9.0 ± 1.1 nmol/l), PTSD (mean peak: 9.0 ± 1.1 nmol/l) and healthy controls (mean peak: 9.6 ± 1.4 nmol/l), whereas baseline cortisol levels did not differ. The enhanced increase in the SAD + CA group was not explained by stronger anxiety in response to the TSST.

Conclusions

Consistent with the findings in depression, these results show for the first time that childhood abuse is also associated with strongly increased cortisol reactivity in SAD. When replicated in a larger sample, these findings may have important implications for the treatment of SAD.     

Neuronal calcium sensor-1 and cocaine addiction: A genetic association study in African-Americans and European Americans

Genes involved in drug reward pathways are plausible candidates for susceptibility to substance use disorders. Given the prominent role of dopamine in drug reward, dopamine receptor-interacting proteins (DRIPs) such as the neuronal calcium sensor-1 (NCS-1) protein have been hypothesized to play a role in the pathophysiology of cocaine addiction (CA). In this study, we investigated whether genetic variants in the NCS-1 gene confer risk to CA. We genotyped 8 SNPs (rs4837479, rs7849345, rs3824544, rs10819611, rs947513, rs2277200, rs7873936 and rs1342043) in our discovery sample (cases n = 796, controls n = 416) of African descent. Confirmation of associated or trending SNPs (rs7849345, rs10819611, rs1342043) was attempted using a replication sample of African American (AA) ethnicity (cases n = 335, controls n = 336) and European-American (EA) ancestry (cases n = 336, controls n = 656). Secondary sex specific analysis was also carried out for each SNP in both AA and EA individuals. Genotyping of the discovery cohort showed significant genotypic (p = 0.0005, corrected q-value) as well as allelic (p = 0.005, corrected q-value) associations of rs1342043 with CA in AAs; however, this marker could not be confirmed in either the AA or EA replication sample. Combined analysis of all AA samples (n = 1883) for rs1342043 showed a significant association with CA (genotypic p = 0.0001, allelic p = 0.002) with a gender specific effect for males (allelic p = 0.005, genotypic p = 0.0003). Our data suggest that genetic variants in the NCS-1 gene contribute to susceptibility of CA in individuals of African descent.     

Association study on the NAPG gene and bipolar disorder in the Chinese Han population

Background: Bipolar disorder is a mental health problem throughout the world. Chromosome 18p11 has been identified by several studies as a susceptiblilty region for bipolar disorder and NAPG, located on 18p11, has been suggested as being associated with bipolar disorder in European population. Methods: Our study employed five SNPs (rs2290279, rs495484, rs510110, rs617040 and rs473938) to investigate the role of NAPG in the Chinese Han population based on a sample of 465 controls vs. 499 bipolar patients. Results: Rs617040 was excluded from further analysis because of deviation from Hardy–Weinberg equilibrium. Rs473938 and rs2290279 showed significant association in both allele and genotype frequencies (rs473938: allele p = 0.0028 after 100,000 permutations, genotype p = 0.0018; rs2290279: allele p = 0.0042 after 100,000 permutations, genotype p = 0.0028). Several combinations of haplotype were found to be associated with bipolar disorder. Haplotype T–A–T of rs473938–rs2290279–rs495484 was defined by confidence intervals algorithm and had a p value of 0.0038 after 100,000 permutations. Conclusions: Our study supports NAPG as a candidate for susceptibility to bipolar disorder.     

IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection

Interleukin (IL)-21 may affect both T-cell and B-cell responses and was suggested to be involved in response to HBV infection. This study explored IL21rs907715 and rs2221903 and IL21R T-83C and rs3093301 polymorphisms and serum IL-21 and IgE levels in 395 patients with chronic HBV infection, 75 HBV infection resolvers and 174 healthy controls. IL21R T-83C was not polymorphic in the study populations. IL21 rs2221903 AG was less frequent in HBV patients than in resolvers (p < 0.001, OR = 0.364, 95% CI = 0.211–0.629) or in controls (p = 0.017, OR = 0.589, 95% CI = 0.381–0.911). IL21R rs3093301 TT was more frequent in HBV patients than in controls [p value after Bonferroni correction (p_c) = 0.022, OR = 1.908, 95% CI = 1.158–3.142] and more frequent in resolvers than in controls (p_c = 0.010, OR = 2.965, 95% CI 1.375–6.392). The carriage of IL21 rs2221903 AG/IL21R rs3093301 CT + IL21 rs2221903 AG/IL21R rs3093301 TT was less frequent in patients than in resolvers (p_c = 0.007, OR = 0.236, 95% CI = 0.096–0.579) and more frequent in resolvers than in controls (p_c = 0.014, OR = 4.354, 95% CI = 1.660–11.420). IL21 rs2221903 was, by interaction with IL21R rs3093301, associated with serum IL-21 and IgE levels in HBV patients. It is suggested that IL21 rs2221903 and IL21R rs3093301 polymorphisms may, independently or interactively, affect the susceptibility to and/or persistence of HBV infection potentially through altering IL-21 and IgE production.     

SNP/haplotype associations of CCR2 and CCR5 genes with severity of chagasic cardiomyopathy

Background

Chronic inflammation plays a major role in the tissue injury seen in the chronic chagasic cardiomyopathy. The CCR2 and CCR5 chemokine receptors are involved with the type of cellular infiltrate present in cardiac tissue and CCR5-gene variants were previously associated with this pathology.

Methods and results

This is a replication study in an independent cohort with larger sample size. Nine SNPs of CCR5 and CCR2 were typified to confirm the association previously found with Chagas disease. Evidence of association with severity was found for the A allele of rs1799864 of CCR2 (p_ad = 0.02; OR = 1.91, 95% CI = 1.10–3.30), the T allele of the rs1800024 of CCR5 (p_ad = 0.01; OR = 1.95, 95% CI = 1.13–3.38), and the HHF^∗2 haplotype (p = 0.03, OR = 1.65, 95% CI = 1.03–2.65). These results were replicated in the study combined with previous data. In this analysis it was replicated the allele T of rs2734648 (p_ad = 0.009, OR = 0.52, 95% CI = 0.32–0.85) with protection. In addition, the allele G of rs1800023 (p_ad = 0.043, OR = 0.61, 95% CI = 0.38–0.98), and the HHC haplotype (p = 0.004, OR = 0.62, 95% CI = 0.44–0.86) were also associated with protection. In contrast, the allele A of rs1799864 of CCR2 (p_ad = 0.009; OR = 1.90, 95% CI = 1.17–3.08); and the allele T of rs1800024 of CCR5 (p_ad = 0.005, OR = 1.98, 95% CI = 1.22–3.23) were associated with greater severity. No evidence of association between symptomatic and asymptomatic patients was observed.

Conclusions

These results confirm that variants of CCR5 and CCR2 genes and their haplotypes are associated with the severity but not with susceptibility to develop chagasic cardiomyopathy.     

Physicians’ reactions to uncertainty in the context of shared decision making

Objective

Physicians’ reactions towards uncertainty may influence their willingness to engage in shared decision making (SDM). This study aimed to identify variables associated with physician's anxiety from uncertainty and reluctance to disclose uncertainty to patients.

Methods

We conducted a cross-sectional secondary analysis of longitudinal data of an implementation study of SDM among primary care professionals (n = 122). Outcomes were anxiety from uncertainty and reluctance to disclose uncertainty to patients. Hypothesized factors that would be associated with outcomes included attitude, social norm, perceived behavioral control, intention to implement SDM in practice, and socio-demographics. Stepwise linear regression was used to identify predictors of anxiety from uncertainty and reluctance to disclose uncertainty to patients.

Results

In multivariate analyses, anxiety from uncertainty was influenced by female gender (β = 0.483; p = 0.0039), residency status (1st year: β = 0.600; p = 0.001; 2nd year: β = 0.972; p < 0.001), and number of hours worked per week (β = −0.012; p = 0.048). Reluctance to disclose uncertainty to patients was influenced by having more years in formal education (β = −1.996; p = 0.012).

Conclusion

Variables associated with anxiety from uncertainty differ from those associated with reluctance to disclose uncertainty to patients.

Practice implications

Given the importance of communicating uncertainty during SDM, measuring physicians’ reactions to uncertainty is essential in SDM implementation studies.     

Genetic evidence of TAP1 gene variant as a susceptibility factor in Indian leprosy patients

The heterodimeric transporter associated with antigen processing (TAP) gene loci is known to play a vital role in immune surveillance. We investigated a possible association of gene polymorphisms both in TAP1 and TAP2 in a cohort of clinically classified leprosy patients (n = 222) and in ethnically matched controls (n = 223). The TAP1 and TAP2 genes were genotyped for four single nucleotide polymorphisms TAP1 (rs1057141 Iso333Val and rs1135216 Asp637Gly) and TAP2 (rs2228396 Ala565Thr and rs241447 Ala665Thr) by direct sequencing and ARMS-PCR. The minor allele of TAP1 637G contributes to an increased risk to leprosy compared to controls (OR: 1.68, 95% CI 1.2–2.36, P = 0.0057). An increased risk for the variant minor allele of the TAP1 637G to multibacillary (BL + LL) or paucibacillary (BT + TT) infections was also observed [multibacillary vs. controls (OR: 1.56, 95% CI 1.07–2.28, P = 0.054); paucibacillary vs. controls (OR: 1.92, 95% CI 1.21–3.01, P = 0.013)]. In the dominant model, the genotypes of the TAP1 rs1135216AG + GG additionally contributed to an increased risk. Overall our findings demonstrate that the TAP1 gene variant (rs1135216 Asp637Gly) influences the susceptibility to clinically classified leprosy patients in Indian population.     

Sex-specific effects of CNTF, IL6 and UCP2 polymorphisms on weight gain

The human proteins ciliary neurotrophic factor (CNTF) and interleukin-6 (IL6) and their receptors share structural homology with leptin and its receptor. In addition, uncoupling protein-2 (UCP2) has been shown to participate the regulation of leptin on food intake. All three proteins are active in the hypothalamus. Experiments have shown that CNTF and IL6, like leptin, can influence body weight in humans and animals, while the effect of UCP2 is not consistent. In a Dutch general population (n = 545) we investigated associations of CNTF (null G/A, rs1800169), IL6 (174 G/C, rs1800795) and UCP2 (A55V, rs660339 and del/ins) polymorphisms with weight gain using interaction graphs and logistic regression analysis. The average follow-up period was 6.9 years. Individuals who gained weight (n = 264) were compared with individuals who remained stable in weight (n = 281).In women the CNTF polymorphism (odds ratio (OR) = 2.15, 95%CI: 1.27-3.64, p = 0.004) and in men the IL6 polymorphism by itself (OR = 2.26, 95%CI: 1.08-4.75, p = 0.03) or in combination with the CNTF polymorphism, were associated with weight gain. Furthermore, CNTF and IL6 polymorphisms in interaction with UCP2 polymorphisms had similar strong effects on weight gain in women and men, respectively. All observed effects were statistically shown to be independent of serum leptin level. These results are incorporated in a biological model for weight regulation with upstream effects of CNTF and IL6, and downstream effects of UCP2.The results of this study suggest a novel mechanism for weight regulation that is active in both women and men, but strongly influenced by sex.     

Phactr2 and Parkinson's disease

Attempts at replicating the first genome-wide association study (GWAS) in Parkinson's disease (PD) have not successfully identified genetic risk factors. The present study reevaluates data from the first GWAS and focuses on the SNP (rs11155313, located in the Phactr2 gene) with the lowest P-value in the Tier 2 patient-control series. We employed four case-control series to examine the nominated SNP rs11155313 and identified association in US (OR: 1.39, P = 0.032), Canadian (OR: 1.41, P = 0.014) and Irish (OR: 1.44, P = 0.034) patient-control series, but not in the Norwegian series (OR: 1.15, P = 0.27). When combining all four series the observed trend was statistically significant (OR: 1.30, P < 0.001). This study shows that reappraisal of publicly available results of GWAS may help nominate new risk factors for PD.     

The Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old

The free radical theory of aging states that reactive oxygen species (ROS) play a key role in age-related accumulation of cellular damage, and consequently influence aging and longevity. Therefore, variation in genes encoding proteins protecting against ROS could be expected to influence variation in aging and life span. The rs4880 and rs1050450 SNPs in the manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPX1) genes, respectively, are associated with age-related diseases and appear to affect the activities of the encoded variant proteins.In this study we genotyped these SNPs in 1650 individuals from the Danish 1905 cohort (follow-up time: 1998-2008, age at intake: 92-93 years, number of deaths: 1589 (96.3%)) and investigated the association with aging and longevity. We found decreased mortality of individuals holding either the MnSOD rs4880 C or the GPX1 rs1050450 T alleles (HR (MnSOD(CC/CT)) = 0.91, P = 0, p = 0.002 and HR (GPX1(TT/TC)) = 0.93, p = 0.008). Furthermore, a synergetic effect of the alleles was observed (HR = 0.76, p = 0.001). Finally, moderate positive associations with good self rated health, decreased disability and increased cognitive capacity were observed. Our results thus indicate that genetic variation in MnSOD and GPX1 may be associated with aging and longevity.     

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Aβ and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3′ un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein ?4 (APOE ?4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p = 0.042). In subjects with the APOE ?4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p = 0.027, allele p = 0.011). In the whole study group, the age, sex, and APOE ?4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI = 1.068–2.234, p = 0.027) whereas within only APOE ?4 allele carriers, the adjusted OR increased to 2.734 (95%CI = 1.236–5.862, p = 0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE ?4 allele.     

Role of hepatic HCV-RNA level on the severity of chronic hepatitis C and response to antiviral therapy

Background

Correlation between hepatic HCV-RNA and serum HCV-RNA, severity of liver disease and response to therapy is poorly known.

Objectives

To assess the influence of hepatic HCV-RNA level on severity of liver disease and response to therapy in a large cohort of chronic hepatitis C (CHC) patients.

Study Design

HCV-RNA was measured in frozen liver biopsies and serum samples from 130 CHC patients the day of liver biopsy prior to treatment. Liver fibrosis was assessed by Ishaq scoring. A Sustained Virological Response (SVR) was observed in 52% of the patients, non-response (NR) in 34%.

Results

Mean ± standard deviation hepatic HCV-RNA level was 7.69 ± 0.67 log₁₀ copies/mg of liver. Mean serum HCV-RNA level was 6.21 ± 0.72 log₁₀ copies/ml. There was a correlation between hepatic and serum HCV-RNA in genotype 1 and 4 (p = 0.008 and p = 0.03) and age (p = 0.006). Mean hepatic HCV-RNA was 7.70 ± 0.69 vs 7.67 ± 0.68 log₁₀ copies/mg of liver, in patients with significant fibrosis vs those with mild fibrosis, respectively (p = 0.7); 8.04 ± 0.68; 7.44 ± 0.47; 7.43 ± 0.49 and 7.44 ± 0.71 log₁₀ copies/mg of liver in genotypes 1, 2, 3 and 4, respectively (p = 0.0001); higher in women than in men (p = 0.04); 7.60 ± 0.63, 7.71 ± 0.54 and 7.96 ± 0.73 log₁₀ copies/mg in SVR, relapsers and NR, respectively (p = 0.1). Multivariate analysis showed that high hepatic HCV-RNA level was independently associated with genotype and response to therapy was associated with genotype independently from hepatic HCV-RNA level.

Conclusions

Hepatic HCV-RNA level was not associated with severity of liver disease. High level was strongly associated with HCV genotype independently from response to therapy.     

Association of GPR50, an X-linked orphan G protein-coupled receptor,and affective disorder in an independent sample of the Scottish population

A recent report detected association between GPR50, an orphan G protein-coupled receptor, and bipolar disorder (BD) in the Scottish population [29]. We sought to replicate this study in a second sample from the same population, consisting of 338 patients with BD, 359 patients with major depressive disorder (MDD) and 913 control individuals. In addition, the effect of GPR50 genotype on clinical phenotype and treatment response was assessed in a subset of 56 patients with early onset MDD (eoMDD). We identified an association with BD in women with an intronic SNP, rs1202874, that withstood correction for multiple testing (p = 0.0035, permuted p = 0.037, OR = 1.9, 95%CI 1.2–3.0). However, we failed to find an association with the previously associated Δ502-505 polymorphism (p = 0.2). Combined analysis of this and the original samples did detect association between the deletion and susceptibility to BD in females, but with a reduced effect size (p = 0.0006, permuted p = 0.0024, OR = 1.41, 95%CI 1.16–1.71). In the highly phenotyped eoMDD subgroup, we found an association between the Δ502-505 deletion polymorphism and age of onset (p = 0.049), number of episodes (p = 0.044), hypomanic symptoms (p = 0.019), and initial thinking time (p = 0.027), in women; and in family history of depression in men (p = 0.038), uncorrected for multiple testing. No association was seen between Δ502-505 genotype and treatment response at 3 months. To our knowledge this is the first association of rs1202874 with BD and is the second positive association at the GPR50 locus.