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Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.

Purpose The objectives of this study were to determine the inheritance pattern by which familial mesial temporal lobe epilepsy (FMTLE) is segregated in Mexican families, and to identify if there was an association between the clinical characteristics and the inheritance pattern. Method We included a total of 25 families with two or more members affected with MTLE during two years and elaborated a family pedigree for each family. The inheritance pattern was classified as autosomal dominant (AD) or autosomal recessive (AR), considering the affected members. We used statistical analysis association and differences between clinical characteristics and inheritance patterns. Results The affected families with the AD pattern were 15.7 fold times more likely to start seizures at 5 years of age or earlier than families with AR pattern, OR = 15.7 (IC 95% = 1.9-128.9). We observed a predominance and greater deja vu association (64.4% vs 31.3%; p = 0.021), OR = 3.9 (CI 95% = 1.1-13.5) in patients with AD versus AR pattern. Finally, we identified that patients with AD pattern had a likelihood of presenting emotional alterations 5.6 times higher than AR (OR = 5.6, IC = 1.1-27.5). Conclusion FMTLE is a heterogeneous syndrome, both phenotypically and genotypically; thus, our findings may be helpful for clinical use to perform an early diagnosis, to provide timely treatment, and to prevent comorbidities associated to this disease. However, in order to identify the possible genetic causes underlying these inheritance patterns, the use of molecular studies is necessary.

We present a case of malignant acanthosis nigricans (AN) that initially manifested in the oral cavity. In the present report, the patient had typical clinical and histological findings of oral and esophageal AN, with subtle skin changes, associated with a gallbladder adenocarcinoma. The importance of the clinical oral examination is emphasized because the recognition of oral lesions led to the diagnosis of AN and to the following detection of the internal malignancy. Since the tumours associated with AN are highly malignant, it is of the utmost importance to recognize the skin and mucous membrane changes in adults.

e17005 Background: In Mexico, cervical cancer (CaCU) is the second leading cause of death in women. New treatment strategies are now emerging specifically the pathway of PD-1. We evaluated the frequency of PD-L1 expression at mRNA level and analyzed the expression profiles associated with different levels of CD274 expression. Methods: We analyzed the mRNA of 17 controls and 59 cervical cancer tumors by an expression microarray that allows the analysis of 22,607 human genes. Tumors were classified based on the mRNA expression of CD274. The deregulated genes in each group of tumors were compared against the control group using a T-test and Fold Change value. Functional analysis was using the DAVID tool. Correlation gene analysis was performed using the Pearson test. Results: The 59 cervical cancer tumors were classified in 3 groups: CD274-, CD274 low expression and CD274 high expression. The 71.2% of the tumors of CaCU have CD274 expression, 20 tumors with low expression and 22 tumors with high expression. 786 altered genes in the CD274- group, 1759 in the group of low expression and 2465 in the group of high expression were found. We found 19 altered biological processes in the CD274- group, being the most significant, cell cycle, DNA replication and DNA repair. In the tumors CD274 low were found 20 biological processes altered and were similar to those identified in the CD274- tumors. In the group CD274 high, 28 altered biological processes were found, interestingly 5 biological processes associated with innate immune response and antigenic processing. We found 24 genes correlated with the CD274 expression related to the immune response. Conclusions: The frequency of CD274 expression in cervical cancer is similar to that found in other tumors, it would be interesting explore the correlation between mRNA and protein. The number of altered genes is higher in the group of high expression of CD274. In the CD274 high group genes associated with processes related to the immune response are altered. The genes that correlate with the expression of CD274 are mostly associated with the immune system, these results suggest that overexpression of CD274 is accompanied by other immune processes.

MicroRNAs (miRNAs) constitute an important class of non-coding RNA implicated in gene expression regulation. More than 1900 miRNA molecules have been identified in humans and their modulation during viral infection and it is recognized to play a role in latency regulation or in establishing an antiviral state. The liver cells are targets during DENV infection, and alteration of liver functions contributes to severe disease. In this work the miRNAs expression profile of the human hepatoma cell line, Huh-7, infected with DENV-2 was determined using microarray and real-time PCR. Let-7c is one of the miRNAs up-regulated during DENV infection in the hepatic Huh-7 as well as in the macrophage-monocytic cell line U937-DC-SIGN. Let-7c overexpression down-regulates both DENV-2 and DENV-4 infection. Additionally, we found that the transcription factor BACH1, a let-7c target, is also down-regulated during DENV infection. In accordance with this finding, HO-1, the main responsive factor of BACH1 was found up-regulated. The up-regulation of HO-1 may contribute to the stress oxidative response in infected cells.

The aim of this report was to investigate the contribution of HLA-DRB1/DQB1 alleles to the expression of cervical cancer (CC) and squamous intraepithelial lesion (SIL) in Mexican patients. A total of 257 women were included in the study: 61with low-grade squamous intraepithelial lesions (LSIL), 30 with high-grade (HSIL), 73 with CC and 93 healthy females. All were Mexican Mestizos. For HLA class II typing, PCR-SSOP methodology was used. HPV-16 viral DNA was detected by PCR with specific primers for E6-E7 region. HPV-16 was found in 52% of the patients with CC as well as in 19% of women with HSIL and in 12.5% of females with LSIL. HLA-DRB1 ∗04:03 (OR = 5.88) was found increased in patients with HSIL as compared with controls, although significance ( p = 0.04) was lost after correction (pc = NS ). HLA-DRB1 ∗04:03 seems to influence the risk for developing HSIL, disregarding the presence of HPV-16. HLA-DRB1 ∗01:01 (OR = 0.12; p = 0.01) may confer protection to the development of CC. An analysis performed stratifying by the presence of HPV-16 infection showed that the frequency of HLA-DRB1 ∗04:07 (OR = 2.71) was increased in CC patients infected with HPV-16, confirming that the HLA association is HPV dependent. These results shed light on the influence that this virus may have in the expression of CC in the susceptible host. Genetic background is, therefore, a crucial factor in understanding the etiopathogenesis of CC in HPV-positive patients.

Cervical cancer (CC) is the second most common cause of death from cancer among women worldwide and about 80% of the half of million new cases detected every year, occurs in less-developed countries. Human papillomavirus is an obligate factor for the development of CC, since some HPVtype are detected in 100% of CC. HPV16 and HPV18 are the most common viral types, accounting for about 50% and 15% of CC, respectively. HPV infection is the most common sexual transmitted infection, with an estimated prevalence of about 2-44% among sexually active young women. However, only a very small fraction of these infections evolve to CC (1-2 out of 1000), indicating that some other factors should be important in the evolution of the disease. Preventive vaccines against HPVs 16 and 18 have been developed, and in phase III clinical trials they have demonstrated 100% efficacy for prevention of persistent infection and high risk cervical squamous intraepithelial neoplasias positive for these HPV types, suggesting that these vaccines, if made widely available, will dramatically reduce the burden of CC.