Burden of significant liver damage in people living with HIV after microelimination of the hepatitis C virus.

BACKGROUND: Once HIV/HCV-coinfection microelimination has been virtually achieved in some countries, there is no information about the burden of liver disease among people living with HIV (PLWH). The aim of this study was to define the current prevalence and causes of significant liver damage (SLD) in PLWH. METHODS: Cross-sectional study including 619 PLWH. SLD was defined as liver stiffness (LS) ≥ 7.2 kPa measured by transient elastography. Nonviral liver damage (NVLD) was considered if there was no evidence injury due to chronic hepatitis C virus (HCV) infection, active hepatitis B (HBV) or E virus infections. RESULTS: One hundred and twelve of 619 (18.2%) PLWH showed SLD, including 34/112 (5.5%) with LS ≥14 kPa. 72/112 (64.3%) had cured HCV infection, 4/112 (3.6%) active HBV infection, and 2/112 HBV/prior HCV coinfection. Thus, 40 (35.7%) showed NVLD. Metabolic associated steatohepatitis (MASH) was present in 29/40 (72.5%) of patients with NVLD, alcoholic liver damage in 2/40 (2.5%) and mixed steatohepatitis in 5/40 (12.5%). CONCLUSIONS: After HIV/HCV microelimination the burden of liver damage is high among PLWH. Persistent injury after HCV is a very frequent cause of SLD. However, NVLD, mainly due to MASH, is also a common condition in this population.

Incidence of recently acquired hepatitis C virus infection among HIV-infected patients in southern Spain.

OBJECTIVES: Spain is close to HCV microelimination, so rates of recently acquired HCV infection (RAHC) should decrease. Nowadays, men who have sex with men (MSM) carry the highest risk of HCV acquisition. Our aim was to estimate the incidence of and the factors associated with RAHC, together with reinfection rates, among patients sexually infected by HIV. METHODS: Primary RAHC infection was diagnosed when anti-HCV antibody seroconversion was documented. In anti-HCV positive patients, initially without HCV viraemia, a diagnosis of reinfection was established if plasma HCV RNA was detected. RESULTS: All 350 patients tested negative for anti-HCV at baseline and had at least one follow-up visit. Among them, there were 16 RAHC cases from 2016 to 2019. RAHC incidence rates [IR (95% confidence interval, CI)] per 100 person-years were 3.77 (0.5-12.9) in 2016, 1.85 (0.6-4.3) in 2017, 1.49 (0.4-3.8) in 2018 and 1.98 (0.6-4.5) in 2019. Only previous sexually transmitted infections [incidence rate ratio (IRR) = 18.23, 95% CI: 1.93-172.1; P = 0.011], male sex (IRR = 8.33, 95% CI: 1.38-54.15; P = 0.026) and sharing chem-sex drugs (IRR: 4.93, 95% CI: 1.17-20.76; P = 0.030), were independently associated with RAHC. Four out of 42 (9.5%) patients became reinfected. CONCLUSIONS: The incidence of RAHC among HIV-infected patients showed a decrease after 2016, although a lower but steady incidence of residual cases still remains. HCV reinfections showed a similar pattern. New infections were associated with sharing chem-sex drugs among MSM.

Similar prevalence of hepatic steatosis among patients with chronic hepatitis C with and without HIV coinfection.

Hepatic steatosis (HS) is frequently observed in HIV-infected patients. It is not known whether HIV infection is an independent risk factor for HS development. We aimed to analyze whether HIV coinfection was associated with a higher frequency of HS in patients with chronic hepatitis C. This was a retrospective cross-sectional study. 574 subjects with chronic hepatitis C virus (HCV) infection were included, 246 (43%) of them coinfected with HIV. All of them underwent transient elastography with controlled attenuation parameter (CAP) measurement. HS was defined as CAP ≥ 248 dB/m. 147 individuals (45%) showed HS in the HCV-monoinfected group and 100 (40.7%) in the HIV/HCV-coinfected group (p = 0.318). HS was associated with body mass index (BMI) [<25 Kg/m2 vs. ≥25 Kg/m2, 67 (23.5%) vs. 171 (62.9%); p = 0.001], with plasma HDL-cholesterol [<50 mg/dL vs. ≥50 mg/dL, 122 (48.6%) vs. 95 (37.5%), p = 0.012], with plasma triglycerides [<150 mg/dL vs. ≥150 mg/dL, 168 (40.2%) vs. 65 (52.4%); p = 0.016] and with plasma total cholesterol [<200 mg/dL vs. ≥200 mg/dL, 181 (41%) vs. 53 (52.5%); p = 0.035]. In the multivariate analysis, HS was associated with BMI [adjusted OR (AOR) = 1.264 (1.194-1.339); p = 0.001], age [AOR = 1.029 (1.001-1.058); p = 0.047] and HCV genotype 3 infection [AOR = 1.901 (1.081-2.594); p = 0.026]. HIV coinfection was not associated with HS [AOR = 1.166 (0.719-1.892); p = 0.534]. In conclusion, HIV coinfection is not related with an increased frequency of HS in HCV-infected patients.

Rural habitat as risk factor for hepatitis E virus seroconversion in HIV-infected patients: A prospective longitudinal study.

Our objective was to determine the incidence and clinical manifestations of acute hepatitis E virus (HEV) in HIV-infected patients. A prospective longitudinal study including HIV-infected HEV-seronegative patients was conducted; HEV seroconversion (to IgG and/or IgM) was the main outcome variable. All patients were tested for HEV antibodies every 3-6 months. For patients who developed HEV seroconversion, a data collection protocol was followed to identify associated clinical manifestations and analytical alterations. A total of 627 patients (89.9%) were followed during a median of 11.96 months (IQR: 8.52-14.52 months) and formed the study population. Forty-one patients developed detectable anti-HEV antibodies (7.2 cases per 100 patients/year). Our study found a high incidence of HEV in HIV-infected patients in southern Spain strongly associated with a rural habitat.

Fat mass and obesity-associated gene variations are related to fatty liver disease in HIV-infected patients.

OBJECTIVES: Fatty liver disease (FLD) is frequently observed in HIV-infected patients. Obesity and type 2 diabetes mellitus (T2DM) are strongly associated with FLD. Because genetic variants within the fat mass and obesity-associated (FTO) gene have been associated with both pathologies, our aim was to evaluate the association of single nucleotide polymorphisms (SNPs) within the FTO, previously related to obesity or T2DM, with FLD in HIV-infected patients. METHODS: FLD was defined as a value of the controlled attenuation parameter (CAP) ≥ 238 dB/m, obtained by transient elastography. Four SNPs within FTO intron 1 (rs11642841, rs8050136, rs9939609 and rs9940128) were genotyped in 421 individuals using a custom Golden Gate protocol. The results were replicated in a validation sample consisting of a further 206 HIV-infected patients. Multivariate logistic regression analyses were conducted in the entire population. RESULTS: Three SNPs (rs8050136, rs9939609 and rs9940128) were associated with FLD, with rs9940128 showing the strongest association. This polymorphism also showed an association with FLD in the validation sample. In total, rs9940128 was genotyped in 627 HIV-infected patients, including 267 (42.6%) FLD-diagnosed individuals. The frequency of FLD among rs9940128 AA carriers was 55.7% (63 of 113 individuals) and that in patients without this genotype was 39.7% (204 of 514 individuals) [P = 0.009; adjusted odds ratio 1.88; 95% confidence interval (CI) 1.17-3.01]. CONCLUSIONS: Variations within FTO may be predictors of FLD in HIV-infected patients independently of metabolic factors.

High frequency of potential interactions between direct-acting antivirals and concomitant therapy in HIV/hepatitis C virus-coinfected patients in clinical practice.

OBJECTIVES: The aim of the study was to analyse the frequency and degree of potential drug-drug interactions (DDIs) between direct-acting antivirals (DAAs) and concomitant medication used by HIV/hepatitis C virus (HCV)-coinfected patients, including antiretroviral therapy (ART) and other drugs. METHODS: All patients with HIV infection and viraemic HCV genotype 1, 3 or 4 coinfection attending a tertiary care centre in Spain (November 2014 to November 2015) were included in the study. DDIs were classified as major, i.e. drugs should not be co-administered, or minor, i.e. close monitoring, dosage alteration or change in timing may be required if drugs are co-administered, following the http://www.hep-druginteractions.org database recommendations. RESULTS: A total of 244 patients were included in the study, of whom 224 (92%) were previous injecting drug users. Major DDIs were found for: paritaprevir-r/ombitasvir plus dasabuvir (3D), in 60 (44%) of 138 individuals with genotype 1; paritaprevir-r/ombitasvir (2D), in 22 (37%) of 60 individuals with genotype 4; sofosbuvir/ledipasvir (SOF/LDV), in four (2%) of 198 patients with genotype 1 or 4; simeprevir (SMV) plus SOF, in 160 (81%) of 198 patients with genotype 1 or 4; daclatasvir (DCV) plus SOF, in seven (3%) of 244 patients with genotype 1, 3 or 4 (P < 0.001). Minor DDIs were found for: 3D, in 123 (89%) individuals with genotype 1; 2D, in 52 (87%) individuals with genotype 4; SOF/LDV, in 154 (78%) patients with genotype 1 or 4; SMV plus SOF, in 129 (65%) patients with genotype 1 or 4; DCV plus SOF, in 149 (61%) patients with genotype 1, 3 or 4 (P < 0.001). CONCLUSIONS: Drug-drug interactions between DAAs and ART or other commonly prescribed medications are frequently found among HIV/HCV-coinfected patients. Potential major and minor DDIs are more frequent with 3D, 2D and SMV plus SOF regimens.

Changes in liver steatosis evaluated by transient elastography with the controlled attenuation parameter in HIV-infected patients.

OBJECTIVES: There are scant data on the progression of hepatic steatosis (HS) in HIV infection. We therefore evaluated changes in HS over time in HIV-infected patients using the controlled attenuation parameter (CAP). METHODS: A prospective cohort of 326 HIV-infected patients was included in this study. All patients underwent a CAP measurement. Changes in steatosis were evaluated by calculating the median (Q1-Q3) difference between baseline and 12-month CAP values. RESULTS: The median (Q1-Q3) CAP was 221 (196-252) dB/m at baseline and 224 (198-257) dB/m at the 12-month visit (P = 0.617). Significant steatosis, that is, CAP ≥ 238 dB/m, was observed in 76 individuals (37%) at baseline and in 80 (39%) at the 12-month visit (P = 0.683). The following variables were associated with ΔCAP: plasma HIV RNA [< 50 vs. ≥ 50 HIV-1 RNA copies/mL: median (Q1-Q3) ΔCAP, 4 (-21, 27) vs. -21 (-49, 4) dB/m, respectively; P = 0.024]; body mass index (BMI) [no increase vs. increase: -13 (-40, 4) vs. 14 (-6, 32) dB/m, respectively; P < 0.001]; triglycerides [no increase vs. increase: -1 (-30, 22) vs. 15 (-3, 40) dB/m, respectively; P = 0.001]; fasting plasma glucose [not impaired vs. impaired: -4 (-31, 16) vs. 30 (15, 49) dB/m, respectively; P < 0.001]; and raltegravir [no vs. yes: 5 (-20, 29) vs. -11 (-37.5, 15) dB/m, respectively; P = 0.018]. The only factor independently associated with ΔCAP was BMI [B (standard error): 9.03 (1.9); P < 0.001]. CONCLUSIONS: Increases in CAP values over a period of 12 months in HIV-infected patients were strongly associated with elevations in BMI. Other metabolic factors and antiretroviral drugs were not predictors of CAP changes independent of BMI.

Longitudinal evaluation of hepatitis C viral persistence in HIV-infected patients with spontaneous hepatitis C clearance.

Hepatitis C virus (HCV) viral persistence in patients with spontaneous viral clearance is controversial. Several studies have shown HCV-RNA in peripheral blood mononuclear cells (PBMCs) and/or liver tissue among patients who have cleared the virus spontaneously, suggesting that viral persistence is a common situation that could involve the entire population studied. Thus, our aim was to evaluate HCV-RNA persistence in PBMCs and hepatocytes in subjects infected with the human immunodeficiency virus (HIV). A total of 1508 patients were prospectively followed and tested for anti-HCV antibodies and HCV-RNA to identify the patients who achieved spontaneous viral clearance. In all of the patients, the persistence of HCV-RNA in PBMCs was evaluated longitudinally during 2 years of follow-up. Fifty-nine patients fulfilled the inclusion/exclusion criteria and were included in the study. HCV-RNA was not detected in the PBMCs at baseline [59 PBMCs samples tested; 0 %; 95 % confidence interval (CI): 0-3.3 %] or during the follow-up (147 PBMCs samples tested; 0 %; 95 % CI: 0-2.02 %). Our study shows that HCV viral persistence is not a frequent occurrence in HIV-infected patients who have spontaneously resolved an HCV infection. Thus, the lack of serum HCV-RNA should continue to be addressed as the standard of healing.

Impact of HIV infection on sustained virological response to treatment against hepatitis C virus with pegylated interferon plus ribavirin.

It is commonly accepted that human immunodeficiency (HIV) coinfection negatively impacts on the rates of sustained virological response (SVR) to therapy with pegylated interferon plus ribavirin (PR). However, this hypothesis is derived from comparing different studies. The aim of this study was to determine the impact of HIV coinfection on SVR to PR in one single population. In a multicentric, prospective study conducted between 2000 and 2013, all previously naïve hepatitis C virus (HCV)-infected patients who started PR in five Spanish hospitals were analyzed. SVR was evaluated 24 weeks after the scheduled end of therapy. Of the 1046 patients included in this study, 413 (39%) were coinfected with HIV. Three hundred and forty-one (54%) HCV-monoinfected versus 174 (42%) HIV/HCV-coinfected patients achieved SVR (p < 0.001). The corresponding figures for undetectable HCV RNA at treatment week 4 were 86/181 (47%) versus 59/197 (30%), p < 0.001. SVR was observed in 149 (69%) HCV genotype 2/3-monoinfected subjects versus 91 (68%) HIV/HCV genotype 2/3-coinfected subjects (p = 0.785). In the HCV genotype 1/4-infected population, 188 (46%) monoinfected patients versus 82 (30%) with HIV coinfection (p < 0.001) achieved SVR. In this subgroup, absence of HIV coinfection was independently associated with higher SVR [adjusted odds ratio (95% confidence interval): 2.127 (1.135-3.988); p = 0.019] in a multivariate analysis adjusted for age, sex, baseline HCV RNA load, IL28B genotype, fibrosis stage, and type of pegylated interferon. HIV coinfection impacts on the rates of SVR to PR only in HCV genotype 1/4-infected patients, while it has no effect on SVR in the HCV genotype 2/3-infected subpopulation.

Association of complement receptor 2 polymorphisms with innate resistance to HIV-1 infection.

HIV-1 induces activation of complement through the classical and lectin pathways. However, the virus incorporates several membrane-bound or soluble regulators of complement activation (RCA) that inactivate complement. HIV-1 can also use the complement receptors (CRs) for complement-mediated antibody-dependent enhancement of infection (C-ADE). We hypothesize that hypofunctional polymorphisms in RCA or CRs may protect from HIV-1 infection. For this purpose, 139 SNPs located in 19 RCA and CRs genes were genotyped in a population of 201 Spanish HIV-1-exposed seronegative individuals (HESN) and 250 HIV-1-infected patients. Two SNPs were associated with infection susceptibility, rs1567190 in CR2 (odds ratio (OR) = 2.27, P = 1 × 10(-4)) and rs2842704 in C4BPA (OR = 2.11, P = 2 × 10(-4)). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Although not significant (P = 0.25, OR = 1.57), similar genotypic proportions were obtained for the CR2 marker rs1567190. The results of the two association analyses were combined through a random effect meta-analysis, with a significant P-value of 2.6 x 10(-5) (OR = 2.07). Furthermore, we found that the protective CR2 genotype is correlated with lower levels CR2 mRNA as well as differences in the ratio of the long and short CR2 isoforms.

Association of low-density lipoprotein receptor genotypes with hepatitis C viral load.

Several data suggest that low-density lipoprotein receptor (LDLR) is a co-receptor for hepatitis C virus (HCV). Soluble LDLR can inhibit HCV infectivity; greater plasma low-density lipoprotein levels are associated with treatment success; LDLR genotypes have a synergistic impact on the likelihood of achieving SVR with Peg-IFN plus RBV, as well as on viral kinetics after starting treatment. The objective of this study was to assess the impact of genetic polymorphisms in genes related to cholesterol synthesis and transport pathways on pre-treatment plasma HCV viral load (VL). A total of 442 patients infected with HCV and treatment naive were prospectively recruited. One hundred forty-four SNPs located in 40 genes from the cholesterol synthesis/transport and IL28B were genotyped and analyzed for genetic association with pre-treatment plasma HCV VL. SNPs rs1433099 and rs2569540 of LDLR showed association with plasma HCV VL (P=4 × 10(-4) and P=2 × 10(-3)) in patients infected with genotypes 1 and 4. A haplotype including the last three exons of LDLR showed association with the cutoff level of 600 000 IU ml(-1) VL for genotypes 1 and 4 (OR=0.27; P=8 × 10(-6)), as well as a quantitative VL (mean±s.d.: 6.19±0.9 vs CC+CG 5.58±1.1 logIU ml(-1), P=8 × 10(-5)). LDLR genotypes are a major genetic factor influencing HCV VL in patients infected with genotypes 1 and 4.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

GAB2 gene does not modify the risk of Alzheimer's disease in Spanish APOE 4 carriers.

OBJECTIVES: The genetic basis of Alzheimer's disease (AD) is being analyzed in multiple whole genome association studies (WGAS). The GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in a recent case-control WGAS conducted in the US. Given the potential application of these novel results in AD diagnostics, we decided to make an independent replication to examine the GAB2 gene effect in our series. DESIGN: We are conducting a multicenter population-based study of AD in Spain. PARTICIPANTS: We analyzed a total of 1116 Spanish individuals. Specifically, 521 AD patients, 475 controls from the general population and 120 neurologically-normal elderly controls (NNE controls). METHODS: We have genotyped GAB2 (rs2373115 G/T) and APOE rs429358 (SNP112)/rs7412 (SNP158) polymorphisms using real time-PCR technologies. RESULTS: As previously reported in Spain, APOE epsilon 4 allele was strongly associated with AD in our series (OR=2.88 [95% C.I. 2.16- 3.84], p=7.38E-11). Moreover, a large effect for epsilone 4/epsilone 4 genotype was also observed (OR=14.45 [95% C.I., 3.34-125.2], p=1.8E-6). No difference between the general population and the NNE controls series were observed for APOE genotypes (P > 0.61). Next, we explored GAB2 rs2373115 SNP singlelocus association using different genetic models and comparing AD versus controls or NNE controls. No evidence of association with AD was observed for this GAB2 marker (p > 0.17). To evaluate GAB2-APOE genegene interactions, we stratified our series according to APOE genotype and case-control status, in accordance with the original studies. Again, no evidence of genetic association with AD was observed in any strata of GAB2-APOE loci pair (p > 0.34). CONCLUSION: GAB2 rs2373115 marker does not modify the risk of Alzheimer's disease in Spanish APOE epsilon 4 carriers.

Whole-genome conditional two-locus analysis identifies novel candidate genes for late-onset Parkinson's disease.

Whole-genome epistasis analysis may add a new layer of knowledge to whole-genome association studies, permitting the identification of new candidate genes which are completely transparent during conventional single-locus analysis. We present the first whole-genome conditional two-locus analysis in Parkinson's disease (PD). We scanned the entire genome and selected markers that interacted with a set of well-known loci previously associated to PD (SNCA, Parkin, LRRK2, UCHL1, DJ-1, PINK and MAPT). Our work describes several loci potentially related to PD risk which interact with SNCA, PARK1 and LRRK2 markers. We propose conditional whole-genome two-locus association analysis as a valuable method that might be helpful in re-analysing and re-interpreting data from whole-genome association studies.

Identification of a 2244 base pair interstitial deletion within the human ESR1 gene in the Spanish population.

BACKGROUND: The ESR1 AGATA haplotype is composed of five markers located within introns 5 and 6 of the human oestrogen receptor 1 (ESR1) gene. This haplotype has been studied in several male urogenital tract anomalies and male infertility. In one of these studies, a deviation from Hardy-Weinberg equilibrium (DHW) was found for the ESR1 AGATA marker rs3020375 in two groups of healthy controls. In the present study, we investigated whether the observed DHW is caused by structural variants present within the ESR1 gene. PARTICIPANTS: 229 family units achieving pregnancy through assisted reproductive technologies (n = 129) or by natural means (n = 100), 2465 general Spanish population controls and 162 men with idiopathic infertility. MAIN OUTCOME MEASUREMENTS: Segregation analyses of genetic markers in family units and case-control genetic association studies. RESULTS: We identified a new interstitial deletion of 2244 base pairs within intron 6 of the human ESR1 gene as the cause for the observed DHW. This new variant presents a 10% allelic frequency in the general Spanish population and it is associated with idiopathic male infertility (OR = 1.51; p = 0.03). The percentage of infertile couples in which both members carried the ESR1 deletion (10.08%) was also a higher than expected value of 6% (p = 0.03). CONCLUSIONS: We have characterised a novel structural variation in human ESR1 gene. The available data indicate a deleterious action of the ESR1 deletion in both male and couple fertility. The potential effects of this deletion on other oestrogen-related diseases need to be determined.

CAPN10 alleles modify laryngeal cancer risk in the Spanish population.

AIMS: Laryngeal carcinoma is a common upper respiratory tract cancer with different environmental and genetic factors involved in its development. To date, CAPN10 has been found to be extensively associated with hyperinsulinaemia and type 2 diabetes mellitus, by different groups. In addition, some reports have shown evidence that hyperinsulinaemia exerts a protective effect on laryngeal cancer risk. On the other hand, low circulating levels of IGF-1 have been recently found in patients with laryngeal carcinoma. Our objective was to examine the contribution of CAPN10 alleles to the development of laryngeal cancer. METHODS: Cases and controls were recruited from central and southern Spain. Genotypes were determined using pyrosequencing technology. We analysed CAPN10 UCSNP-44, -43, -19, and -63 allelic distribution in 218 unrelated laryngeal cancer patients and 606 controls from the general population. RESULTS: We found that the UCSNP-44 allele-C is significantly under-represented among patients with laryngeal cancer (OR=0.685, p=0.02). CONCLUSION: These results indicate that some CAPN10 alleles may be exerting a protective effect on laryngeal cancer risk in the Spanish population.

Association of genetic markers within the KIT and KITLG genes with human male infertility.

BACKGROUND: There is much evidence involving the KIT tyrosine kinase receptor and its ligand KITLG in the survival and proliferation of germ cells. Animal models and functional studies in humans suggest that this signalling pathway plays a role in male infertility. METHODS: We studied three and two single-nucleotide polymorphisms (SNPs) (rs3819392, rs3134885, rs2237012, rs10506957 and rs995030) located within the genomic region of the KIT and KITLG genes, respectively. A total of 167 idiopathic infertile men (sperm counts <5 million spz/ml) and 465 unrelated healthy controls from the same geographical region were genotyped for these SNPs. RESULTS: We found a statistically significant association of the rs3819392 polymorphism, which is located within the KIT gene, with idiopathic male infertility. In addition, a deviation from the Hardy-Weinberg equilibrium (HWE) law was observed for rs10506957 polymorphism within the KITLG gene only in the infertile group. CONCLUSIONS: Our data indicate that the KIT/KITLG system may be involved in a low sperm count trait in humans.

Specific haplotypes of the CALPAIN-5 gene are associated with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The aim of the present study was to investigate the role of CALPAIN-5 (CAPN5) gene in PCOS susceptibility. METHODS: We analysed four intronic polymorphisms of the CAPN5 gene in 148 well-characterized women with PCOS and 606 unrelated controls. We performed a case-control study and an intracohort analysis of clinical characteristics associated with PCOS. RESULTS: Analysis of haplotypes distribution between PCOS population compared to controls showed a strong deviation (P = 0.00029). The haplotypes GGCA and GGTG were overrepresented in PCOS patients (P = 0.009 and P = 0.001, respectively). In addition, we identified several CAPN5 haplotypes associated with phenotypic differences observed between PCOS patients, such as the presence of obesity (P = 0.02), cardiovascular complications (P = 0.02), familial antecedents of obesity (P = 0.003) and of hypertension (P = 0.007) and type 2 diabetes mellitus aggregation (P = 0.04). CONCLUSIONS: These results suggest a role of CAPN5 gene in PCOS susceptibility in humans. Moreover, novel candidate risk alleles have been identified, within CAPN5 gene, which could be associated with important phenotypic and prognosis differences observed in PCOS patients.

Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient.

Progressive tumor growth may be associated with suppression of the immune response. Many different mechanisms may contribute to immune evasion. We investigated some of these mechanisms in melanoma cells lines generated from two patients. These cell lines show a complex pattern of altered HLA expression; however, the resulting phenotype did not satisfactorily explain the simultaneous evasion of T and NK cell cytotoxicity. Two additional alterations have now been detected in these melanoma cell lines: (1) resistance to FAS-induced apoptosis caused by defective FAS gene expression, and (2) constitutive expression of immunosuppressive cytokines. Our results show that several of the major mechanisms for immune evasion may coexist in a single tumor. This suggests that tumor progression may give rise to an extremely resistant phenotype, which may be an impediment to some immunotherapeutic strategies. We hypothesize that the simultaneous presence of several mechanisms involved in tumor immune evasion must be the result of progressive selection of characteristics that are advantageous for tumor survival in a competent host. Our findings do not support the possibility that FASL expression is a common mechanism of evasion of immune response in melanoma cells.