Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort.

BACKGROUND: Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation. METHODS: We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107). RESULTS: Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9×10-9) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4×10-10) and variants in IRF4 (p=2.8×10-57), SLC45A2 (p=2.2×10-130), HERC2 (p=2.8×10-176), OCA2 (p=2.4×10-121) and MC1R (p=7.7×10-22) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold <5×10-9) at ZRANB2-AS2, PIK3R1, EPHA7, MAD1L1, CACUL1 and MAP3K9. CONCLUSION: Considering multiple-related genetic phenotypes improve associated genome signal detection. These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits.

Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD.

BACKGROUND/OBJECTIVE: Many controversies regarding the association of liver miRNAs with obesity and nonalcoholic fatty liver diseases (NAFLD) call for additional validations. This study sought to investigate variations in genes and hepatic miRNAs in a sample of obese patients with or without NAFLD and human hepatocytes (HH). SUBJECTS/METHODS: A total of 60 non-consecutive obese women following bariatric surgery were recruited. Subjects were classified as NAFLD (n=17), borderline (n=24) and controls (n=19) with normal enzymatic profile, liver histology and ultrasound assessments. Profiling of 744 miRNAs was performed in 8 obese women with no sign of hepatic disease and 11 NAFLD patients. Additional validation and expression of genes related to de novo fatty acid (FA) biosynthesis, uptake, transport and ß-oxidation; glucose metabolism, and inflammation was tested in the extended sample. Induction of NAFLD-related genes and miRNAs was examined in HepG2 cells and primary HH treated with palmitic acid (PA), a combination of palmitate and oleic acid, or high glucose, and insulin (HG) mimicking insulin resistance in NAFLD. RESULTS: In the discovery sample, 14 miRNAs were associated with NAFLD. Analyses in the extended sample confirmed decreased miR-139-5p, miR-30b-5p, miR-122-5p and miR-422a, and increased miR-146b-5p in obese subjects with NAFLD. Multiple linear regression analyses disclosed that NAFLD contributed independently to explain miR-139-5p (P=0.005), miR-30b-5p (P=0.005), miR-122-5p (P=0.021), miR-422a (P=0.007) and miR-146a (P=0.033) expression variance after controlling for confounders. Decreased miR-122-5p in liver was associated with impaired FA usage. Expression of inflammatory and macrophage-related genes was opposite to decreased miR-30b-5p, miR-139-5p and miR-422a, whereas increased miR-146b-5p was associated with FABP4 and decreased glucose metabolism and FA mobilization. In partial agreement, PA (but not HG) led to decreased miR-139-5p, miR-30b-5p, miR-422a and miR-146a in vitro, in parallel with increased lipogenesis and FA transport, decreased glucose metabolism and diminished FA oxidation. CONCLUSION: This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients.

Association studies and rodent models suggest a major role for BDNF (brain-derived neurotrophic factor) in feeding regulation. Altered BDNF blood levels have been associated with eating disorders (ED) and their related psychopathological traits. Since the influence of BDNF on self-reported eating disorder inventory scores (EDI) has not been tested, we investigated the correlation of EDI scales with BDNF plasma levels. BDNF levels were measured by (ELISA), and the EDI questionnaire was administered in a total of 81 ED patients. The relationship between BDNF levels and EDI scores was calculated using a general linear model. After correcting for multiple testing, BDNF plasma levels negatively correlated with the EDI total score (R (2) = 0.26; p = 4.09 x 10(-4)), interoceptive awareness (R (2) = 0.26; p = 1.96 x 10(-4)), and maturity fears (R (2) = 0.13; p = 6.92 x 10(-4)). When subdividing according to the main diagnoses, interoceptive awareness presented significant correlations with BDNF blood levels in both the anorexia nervosa (R (2) = 0.33, p = 0.0026) and bulimia nervosa groups (R (2) = 0.10; p = 0.008). Our data suggest that BDNF levels may influence the severity of the ED by modulating the associated psychopathology, in particular through the impairment of interoceptive awareness.

Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia.

Murine models and association studies in eating disorder (ED) patients have shown a role for the brain-derived neurotrophic factor (BDNF) in eating behavior. Some studies have shown association of BDNF -270C/T single-nucleotide polymorphism (SNP) with bulimia nervosa (BN), while BDNF Val66Met variant has been shown to be associated with both BN and anorexia nervosa (AN). To further test the role of this neurotrophin in humans, we screened 36 SNPs in the BDNF gene and tested for their association with ED and plasma BDNF levels as a quantitative trait. We performed a family-based association study in 106 ED nuclear families and analyzed BDNF blood levels in 110 ED patients and in 50 sib pairs discordant for ED. The rs7124442T/rs11030102C/rs11030119G haplotype was found associated with high BDNF levels (mean BDNF TCG haplotype carriers = 43.6 ng/ml vs. mean others 23.0 ng/ml, P = 0.016) and BN (Z = 2.64; P recessive = 0.008), and the rs7934165A/270T haplotype was associated with AN (Z =-2.64; P additive = 0.008). The comparison of BDNF levels in 50 ED discordant sib pairs showed elevated plasma BDNF levels for the ED group (mean controls = 41.0 vs. mean ED = 52.7; P = 0.004). Our data strongly suggest that altered BDNF levels modulated by BDNF gene variability are associated with the susceptibility to ED, providing physiological evidence that BDNF plays a role in the development of AN and BN, and strongly arguing for its involvement in eating behavior and body weight regulation.

Increased cerebral activity in Parkinson's disease patients carrying the DRD2 TaqIA A1 allele during a demanding motor task: a compensatory mechanism?

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.

Central nervous system toxoplasmosis in AIDS patients: efficacy of an intermittent maintenance therapy.

Fifty-five episodes of central nervous system (CNS) toxoplasmosis developing in 43 of the 329 AIDS cases seen at our institution were diagnosed during a 34-month period and were prospectively studied. Acute episodes were treated with a pyrimethamine/sulfadiazine (P/S) combination for a mean of 21 days. Because of a previously known major allergy to sulfonamides, three episodes were treated with clindamycin instead of sulphadiazine. In those patients who accepted maintenance therapy, a combination of P/S or pyrimethamine and clindamycin (P/C) was administered 2 days per week. Thirty-six patients (83.7%) survived the first episode. Four of these 36 were lost to further study. Six of the 12 (50%) who decided not to undergo maintenance therapy relapsed (mean follow-up: 12 months). Fourteen patients were given P/S and none relapsed while they were on maintenance therapy (mean follow-up: 10.3 months). Six patients received an intermittent maintenance treatment with P/C and one relapsed 2 months after starting the maintenance therapy (mean follow-up: 13.7 months). We conclude that an intermittent (2 days per week) maintenance treatment for CNS toxoplasmosis with P/S was effective in preventing relapses, although prospective randomized studies remain to be done.

MRI and genetic correlates of cognitive function in elders with memory impairment.

The present study investigated the relationship between genetic variation, MRI measurements and neuropsychological function in a sample of 58 elders exhibiting memory decline. In agreement with previous reports, we found that the epsilon4 allele of the apolipoprotein E (APOE) and the D allele of the angiotensin converting enzyme (ACE) polymorphisms negatively modulated the cognitive performance. Further, we found an association between the A allele of the apolipoprotein C1 (APOC1) polymorphism and poorer memory and frontal lobe function. No clear associations emerged between MRI measures of white matter lesions (WML) or hippocampal sulcal cavities (HSC) and the cognitive performance after controlling for age effects. Further, the degree of WML or HSC lesions was in general not predisposed genetically except for the presence of the A allele of the APOC1 polymorphism that was related to a higher severity of HSC scores. Our results suggest that WML or HSC do not represent important brain correlates of genetic influences on cognitive performance in memory impaired subjects.

(1)H-MR spectroscopy is sensitive to subtle effects of perinatal asphyxia.

The authors performed neuropsychological and (1)H-MRS studies in 18 subclinical patients with antecedents of perinatal asphyxia (PA) and in 18 matched control subjects. Patients with PA showed reduced values of N-acetylaspartate (NAA) in both the basal ganglia and the midtemporal region (MTR) and reduced NAA/choline values in the MTR. Neuropsychological testing showed group differences in tasks related to attention and memory. These results indicate persistent dysfunctions in cerebral structures vulnerable to hypoxia and demonstrate the utility of MRS for the long-term evaluation of cerebral sequelae of neonatal asphyxia.

Hyperintense globus pallidus on T1-weighted MRI in cirrhotic patients is associated with severity of liver failure.

Hyperintense globus pallidus on T1-weighted MRI is present in most patients with advanced liver disease. We evaluated the relationship between the signal intensity of the globus pallidus and clinical or laboratory data of 77 patients eligible for liver transplantation. There was a significant correlation between the intensity of the signal and the Child-Pugh score (as indication of severity of liver disease), presence of postural tremor, previous episodes of variceal bleeding or hepatic encephalopathy, prothrombin activity, serum aspartate and alanine aminotransferase, bilirubin, and the indocyanine green (ICG) hepatic clearance, a very sensitive marker of liver function. The multivariate analysis disclosed that the ICG hepatic clearance and previous episodes of variceal bleeding were independently associated with the signal intensity in the globus pallidus. MRI repeated in 21 patients 10 to 20 months after transplant showed a disappearance of the lesion in all cases. We conclude that the hyperintense globus pallidus is secondary to the severity of the liver disease, and is reversible when liver function returns to normal.

MR in trichloroethane poisoning.

We present a case of acute trichloroethane intoxication caused by inhalation of typewriter correction fluid. CT and MR findings revealed lesions in the basal ganglia and cortex similar to those observed in patients with methanol and carbon monoxide poisoning.

Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy.

We report three patients in whom neurologic symptoms and cortical laminar necrosis developed after immunosuppressive treatment (cyclosporin A and FK 506) and polychemotherapy (vincristine and methotrexate). Initial neuroradiologic studies showed cortical and white matter involvement. Follow-up studies showed cortical hyper-intense lesions on T1-weighted MR images, consistent with cortical laminar necrosis. The clinical and radiologic data indicate that a transient hypoxic-ischemic process could have been responsible for the encephalic lesions in these three patients.

Hepatoerythropoietic porphyria: neuroimaging findings.

CT and MR findings in two patients with hepatoerythropoietic porphyria are presented. CT scans showed atrophy and cortical mineralization at the same level. MR examination performed in one of the two patients showed mainly frontal cortical atrophy and punctate bright signal on T1- and T2-weighted sequences.

Hepatoblastoma. An attempt to apply histologic classification to aspirates obtained by fine needle aspiration cytology.

We applied cytologic and architectural diagnostic criteria to the aspiration smears of six cases of hepatoblastoma (HBL) in order to establish whether it is possible to obtain a reliable cytologic diagnosis of this neoplasm and to subclassify it based on cytologic evidence alone. We describe two groups of HBL, undifferentiated and differentiated. The undifferentiated group comprises anaplastic and embryonal subtypes, and the differentiated group comprises fetal and macrotrabecular subtypes. Our findings suggest that the fetal and macrotrabecular subtypes have a rather characteristic cytologic pattern, permitting us to differentiate between the two and to distinguish them from the other two subtypes. The differential diagnosis between the anaplastic and embryonal subtypes is more complex and can be difficult to carry out using cytologic criteria exclusively. The immunophenotypic pattern reflects the degree of maturity of each subtype and helps with cytologic subclassification. The cytologic differential diagnosis of undifferentiated HBL must include hepatic metastases of small round cell tumors of childhood. The cytologic differential diagnosis between differentiated HBL and hepatocellular carcinoma may be very difficult. We suggest that the cytologic subclassification of HBL is possible with the reservation that the predominant pattern may mask other, associated patterns.

[Vertebral hemangioma and quiescent myeloma: association of therapeutic significance]. / Hemangioma vertebral y mieloma quiescente: asociación de trascendencia terapéutica.

Smouldering myeloma is a monoclonal gammopathy in which the M component is higher than 30 g/l and the proportion of plasma cells in the bone marrow is higher than 10% with no anemia, renal failure, hypercalcemia, osteolysis or other features due to the monoclonal gammopathy. The recognition of this clinical variant of myeloma resides in the fact that treatment should be deferred until there are clinical or biologic data indicating evident disease progression. Vertebral hemangioma is a relatively frequent benign tumor in the general population which, although usually asymptomatic, may cause local or radicular bone pain. A patient who fulfilled the criteria of myeloma and who complained of localized bone pain in the spinal column is herein presented. Following a study of the dorsolumbar column by computerized tomography and magnetic resonance, bone lesions with radiologic images characteristic of vertebral hemangioma, clearly different from those observed in myelomatous lesions, were identified. This finding conditioned the treatment, which included radiotherapy for the vertebral hemangioma and no treatment for the smouldering myeloma.

[Magnetic resonance of the spinal cord: a densitometric analysis]. / Resonancia magnética de la médula ósea vertebral: análisis densitométrico.

BACKGROUND: Images obtained by magnetic resonance can present changes in a variety of haematologic disorders. The vertebral magnetic resonance signal depends chiefly on the relationship between fatty and cellular components of the haemopoietic bone marrow. A quantitative analysis of signal can be performed either during the magnetic resonance examination or on the computer-stored images. In this work, a densitometric grey-scale method is presented allowing to analyze the signal intensity on printed magnetic resonance images for those cases in which the computer-stored information is lacking. PATIENTS AND METHODS: A comparative study between magnetic resonance signal and the result of the densitometric analysis was carried out in 29 patients with different haematologic disorders. In order to achieve a suitable standardization, an internal control in both measures was used, i.e., the magnetic resonance signal intensity and the grey intensity of an area of spinal cord, respectively, yielding two ratios: magnetic resonance ratio and grey ratio. RESULTS: The precision analysis of the densitometric method gave the following results: within-batch coefficient of variation was 1.78%, between-batch coefficient of variation was 1.94% and overall reproducibility 6.4%. The correlation between magnetic resonance ratio and grey ratio was very high, i.e., 0.98 (p < 0.001). Moreover, the regression line displayed on ideal location since it originated in the point 0 and showed a slope of 45 degrees. CONCLUSION: The densitometric method presented in this paper can be useful for the quantitative analysis of the magnetic resonance signal intensity generated by the haemopoietic bone marrow, for those cases in which the computer-stored information is lacking.

[Occult involvement of bone marrow in Hodgkin's disease: detection with magnetic resonance]. / Afección oculta de la médula ósea en la enfermedad de Hodgkin: detección por resonancia magnética.

Although bone marrow biopsy is considered the best procedure to detect bone marrow involvement by Hodgkin's disease (HD), in recent years several studies have emphasized the value of magnetic resonance imaging (MRI). We present the case of a patient with HD apparently localized in a laterocervical lymph node, who also referred disestasiae at a region corresponding to D10 metamera. Bone marrow biopsy, vertebral TC and 67-Ga scintigraphy were all normal. However, a node of 1 cm in diameter was detected by MRI in the tenth dorsal vertebra. Because of the topographic coincidence between the patient's symptomatology and the MRI findings, the HD was considered to be in advanced stage and CMOPP/ABV chemotherapy was administered, this resulting in a rapid improvement of symptoms and disappearance of the MRI abnormalities. Since in the present case, the MRI determined a change in disease stage and treatment, the role of MRI as a complementary exploration of bone marrow biopsy to detect marrow involvement by HD is reviewed.

[Postherpetic vasculopathy. A study of 3 cases in immunosuppressed patients]. / Vasculopatía postherpética. Estudio de tres casos en pacientes inmunodeprimidos.

We report three cases of postherpetic vasculopathy in immunologically compromised patients. Two had ophthalmic herpes zoster, contralateral to the physical signs, and the third case developed after disseminated herpes zoster. The initial CT images consisted of small ischemic infarcts in capsular regions and basal ganglia. The arteriography showed images consistent with vasculitis or thrombosis of great vessels of the Willis' polygon, which were ipsilateral to the herpetic lesion in two cases. In one patient the neurological defect remained stable, while the other two developed new ischemic episodes, all in the same cerebral hemisphere. It can be assumed from the delayed development of neurologic disease after cutaneous lesions that some cases go unnoticed if the zoster infection is not specifically looked for in retrospect.

[Primary cerebral lymphoma in 10 patients with AIDS. Comparative clinico-radiologic study with cerebral toxoplasmosis, cerebral tuberculoma and primary cerebral lymphoma in non-immunodepressed patients]. / Linfoma cerebral primario en 10 pacientes con SIDA. Estudio clínico-radiológico comparativo con toxoplasmosis cerebral, tuberculoma cerebral y linfoma cerebral primario en pacientes no inmunodeprimidos.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is the second cause of cerebral masses in patients with the acquired immunodeficiency syndrome (AIDS). The present study evaluated the possible presence of clinical or radiologic signs permitting differentiation of AIDS patients and PCNSL from those with cerebral masses of other etiologies. METHODS: Clinical history and cranial computerized tomography (CT) of patients with PCNSL and AIDS from the Hospital Clinic i Provincial in Barcelona were reviewed. Results were compared with those of patients with PCNSL without evidence of immunosuppression and with those with AIDS and cerebral toxoplasmosis or tuberculoma diagnosed during the same period. RESULTS: Of 685 patients with AIDS, 10 were identified with PCNSL. The clinical picture was not different to that observed in patients with AIDS and cerebral toxoplasmosis or tuberculomas. In contrast to PCNSL in non immunodepressed patients, the cerebral CT in patients with PCNSL and AIDS demonstrated hyperdense lesions in only 44% and contrast enhancement was not homogeneous in any case. These characteristics were similar to those observed in the CT of patients with cerebral toxoplasmosis or tuberculoma with the exception that only 8% of the lesions by toxoplasmosis were spontaneously hyperdense. CONCLUSIONS: The clinical-radiological data of primary central nervous system lymphoma in patients with the acquired immunodeficiency syndrome are similar to those observed in other etiologies. However, the presence of a sole spontaneously hyperdense region in cranial computerized tomography is more suggestive of primary central nervous system lymphoma than cerebral toxoplasmosis.

[Surgical treatment combined with radiotherapy and chemotherapy in an unselected population of patients with malignant glioma]. / Tratamiento quirúrgico combinado con radioterapia y quimioterapia en una población no seleccionada de pacientes con glioma maligno.

BACKGROUND: Malignant gliomas are tumors of bad prognosis with a mean survival of 12 months. In the present report 74 patients diagnosed of malignant glioma were studied with the following aims: 1) evaluate how many could receive combined radiotherapy (RT) and chemotherapy (BCNU) treatment following surgery and 2) analyze whether the patients treated presented a survival similar to that described in the literature. METHODS: The records of 74 patients operated on for malignant glioma between 1987-1990 and consecutively included in a protocol of treatment with RT and BCNU were reviewed. RESULTS: Out of the total of 74 patients, 29 (39%) were considered evaluable. The medians of progression free interval and survival were of 10 and 16 months, respectively in these patients. Forty-five (61%) patients could not fulfill the protocol mainly because of tumoral progression prior to completion of RT and severe post surgical complications. The evaluable patients were significantly younger (p = 0.004) and tumoral exeresis wider (p = 0.0003) than in those who were not evaluable. CONCLUSIONS: Most of the patients operated on for malignant glioma may not receive treatment considered as standard, principally due to tumor progression in the first weeks following surgery and the presence of severe post surgical complications.