Research

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10 pages, 1033 KiB

Open AccessArticle

Genetic Epidemiology in Latin America: Identifying Strong Genetic Proxies for Complex Disease Risk Factors

by Carolina Bonilla and Lara Novaes Baccarini

Genes 2020, 11(5), 507; https://doi.org/10.3390/genes11050507 - 04 May 2020

Viewed by 2351

Epidemiology seeks to determine the causal effects of exposures on outcomes related to the health and wellbeing of populations. Observational studies, one of the most commonly used designs in epidemiology, can be biased due to confounding and reverse causation, which makes it difficult [...] Read more.

Epidemiology seeks to determine the causal effects of exposures on outcomes related to the health and wellbeing of populations. Observational studies, one of the most commonly used designs in epidemiology, can be biased due to confounding and reverse causation, which makes it difficult to establish causal relationships. In recent times, genetically informed methods, like Mendelian randomization (MR), have been developed in an attempt to overcome these disadvantages. MR relies on the association of genetic variants with outcomes of interest, where the genetic variants are proxies or instruments for modifiable exposures. Because genotypes are sorted independently and at random at the time of conception, they are less prone to confounding and reverse causation. Implementation of MR depends on, among other things, a strong association of the genetic variants with the exposure, which has usually been defined via genome-wide association studies (GWAS). Because GWAS have been most often carried out in European populations, the limited identification of strong instruments in other populations poses a major problem for the application of MR in Latin America. We suggest potential solutions that can be realized with the resources at hand and others that will have to wait for increased funding and access to technology. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

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13 pages, 425 KiB

Open AccessArticle

CLOCK Polymorphisms in Attention-Deficit/Hyperactivity Disorder (ADHD): Further Evidence Linking Sleep and Circadian Disturbances and ADHD

by Marina Xavier Carpena, Mara H. Hutz, Angélica Salatino-Oliveira, Guilherme V. Polanczyk, Cristian Zeni, Marcelo Schmitz, Rodrigo Chazan, Julia P. Genro, Luis Augusto Rohde and Luciana Tovo-Rodrigues

Genes 2019, 10(2), 88; https://doi.org/10.3390/genes10020088 - 28 Jan 2019

Cited by 19 | Viewed by 5316

Abstract

Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). CLOCK, considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and CLOCK may provide additional [...] Read more.

Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). CLOCK, considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and CLOCK may provide additional information to understand the correlation between ADHD and sleep problems. In this study, we aimed to explore the association between ADHD and CLOCK, using several genetic markers to comprehensively cover the gene extension. A total of 259 ADHD children and their parents from a Brazilian clinical sample were genotyped for eight single nucleotide polymorphisms (SNPs) in the CLOCK locus. We tested the individual markers and the haplotype effects using binary logistic regression. Binary logistic and linear regressions considering ADHD symptoms among ADHD cases were conducted as secondary analysis. As main result, the analysis showed a risk effect of the G-A-T-G-G-C-G-A (rs534654, rs1801260, rs6855837, rs34897046, rs11931061, rs3817444, rs4864548, rs726967) haplotype on ADHD. A suggestive association between ADHD and rs534654 was observed. The results suggest that the genetic susceptibility to circadian rhythm attributed to the CLOCK gene may play an important role on ADHD. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

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10 pages, 255 KiB

Open AccessArticle

Polymorphisms in RAS/RAF/MEK/ERK Pathway Are Associated with Gastric Cancer

by Patricio Gonzalez-Hormazabal, Maher Musleh, Marco Bustamante, Juan Stambuk, Raul Pisano, Hector Valladares, Enrique Lanzarini, Hector Chiong, Jorge Rojas, Jose Suazo, V. Gonzalo Castro, Lilian Jara and Zoltan Berger

Genes 2019, 10(1), 20; https://doi.org/10.3390/genes10010020 - 28 Dec 2018

Cited by 28 | Viewed by 3610

Abstract

The RAS/RAF/MEK/ERK pathway regulates certain cellular functions, including cell proliferation, differentiation, survival, and apoptosis. Dysregulation of this pathway leads to the occurrence and progression of cancers mainly by somatic mutations. This study aimed to assess if polymorphisms of the RAS/RAF/MEK/ERK pathway are associated [...] Read more.

The RAS/RAF/MEK/ERK pathway regulates certain cellular functions, including cell proliferation, differentiation, survival, and apoptosis. Dysregulation of this pathway leads to the occurrence and progression of cancers mainly by somatic mutations. This study aimed to assess if polymorphisms of the RAS/RAF/MEK/ERK pathway are associated with gastric cancer. A case-control study of 242 gastric cancer patients and 242 controls was performed to assess the association of 27 single nucleotide polymorphisms (SNPs) in the RAS/RAF/MEK/ERK pathway genes with gastric cancer. Analyses performed under the additive model (allele) showed four significantly associated SNPs: RAF1 rs3729931 (Odds ratio (OR) = 1.54, 95%, confidence interval (CI): 1.20–1.98, p-value = 7.95 × 10⁻⁴), HRAS rs45604736 (OR = 1.60, 95% CI: 1.16–2.22, p-value = 4.68 × 10⁻³), MAPK1 rs2283792 (OR = 1.45, 95% CI: 1.12–1.87, p-value = 4.91 × 10⁻³), and MAPK1 rs9610417 (OR = 0.60, 95% CI: 0.42–0.87, p-value = 6.64 × 10⁻³). Functional annotation suggested that those variants or their proxy variants may have a functional effect. In conclusion, this study suggests that RAF1 rs3729931, HRAS rs45604736, MAPK1 rs2283792, and MAPK1 rs9610417 are associated with gastric cancer. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

22 pages, 360 KiB

Open AccessArticle

Association between Polymorphisms in Inflammatory Response-Related Genes and the Susceptibility, Progression and Prognosis of the Diffuse Histological Subtype of Gastric Cancer

by Tatiane K. Furuya, Carlos E. Jacob, Michele T. P. Tomitão, Lizeth C. C. Camacho, Marcus F. K. P. Ramos, José Eluf-Neto, Venâncio A. F. Alves, Bruno Zilberstein, Ivan Cecconello, Ulysses Ribeiro, Jr. and Roger Chammas

Genes 2018, 9(12), 631; https://doi.org/10.3390/genes9120631 - 13 Dec 2018

Cited by 18 | Viewed by 3599

Abstract

The chronic inflammatory microenvironment and immune cell dysfunction have been described as critical components for gastric tumor initiation and progression. The diffuse subtype is related to poor clinical outcomes, pronounced inflammation, and the worst prognosis. We investigated the association of polymorphisms in inflammatory [...] Read more.

The chronic inflammatory microenvironment and immune cell dysfunction have been described as critical components for gastric tumor initiation and progression. The diffuse subtype is related to poor clinical outcomes, pronounced inflammation, and the worst prognosis. We investigated the association of polymorphisms in inflammatory response-related genes (COX-2, OGG1, TNFB, TNFA, HSPA1L, HSPA1B, VEGFA, IL17F, LGALS3, PHB, and TP53) with gastric cancer susceptibility, progression and prognosis in a Brazilian sample, focusing on the diffuse subtype. We also performed the analysis regarding the total sample of cases (not stratified for tumor subtypes), allowing the comparison between the findings. We further investigated the polymorphisms in linkage disequilibrium and performed haplotype association analyses. In the case-control study, rs1042522 (TP53) was associated with a stronger risk for developing gastric cancer in the sample stratified for diffuse subtype patients when compared to the risk observed for the total cases; CTC haplotype (rs699947/rs833061/rs2010963 VEGFA) was associated with risk while rs699947 was associated with protection for gastric malignancy in the total sample. Regarding the associations with the clinicopathological features of gastric cancer, for the diffuse subtype we found that rs699947 and rs833061 (VEGFA) were associated with outcomes related to a worse progression while rs5275 (COX-2), rs909253 (TNFB), and rs2227956 (HSPA1L) were associated to a better progression of the disease. In the total sample, rs699947 and rs833061 (VEGFA), rs4644 (LGALS3), and rs1042522 (TP53) were able to predict a worse progression while rs5275 (COX-2), rs2227956 (HSPA1L), and rs3025039 (VEGFA) a better progression. Besides, rs909253 (TNFB) predicted protection for the overall and disease-free survivals for gastric cancer. In conclusion, these results helped us to clarify the potential role of these polymorphisms in genes involved in the modulation of the inflammatory response in the pathogenesis of gastric cancer. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

18 pages, 318 KiB

Open AccessArticle

Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population

by Sebastián Morales, Tomas De Mayo, Felipe Andrés Gulppi, Patricio Gonzalez-Hormazabal, Valentina Carrasco, José Miguel Reyes, Fernando Gómez, Enrique Waugh and Lilian Jara

Genes 2018, 9(9), 427; https://doi.org/10.3390/genes9090427 - 22 Aug 2018

Cited by 21 | Viewed by 3915

Abstract

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American [...] Read more.

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4–0.9] p = 0.006 and OR = 0.6 [95% CI 0.5–0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

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10 pages, 1452 KiB

Open AccessArticle

Description of Genetic Variants in BRCA Genes in Mexican Patients with Ovarian Cancer: A First Step towards Implementing Personalized Medicine

by Jesus Rolando Delgado-Balderas, Maria Lourdes Garza-Rodriguez, Gabriela Sofia Gomez-Macias, Alvaro Barboza-Quintana, Oralia Barboza-Quintana, Ricardo M. Cerda-Flores, Ivett Miranda-Maldonado, Hugo Mauricio Vazquez-Garcia, Lezmes Dionicio Valdez-Chapa, Mauro Antonio-Macedo, Michael Dean and Hugo A. Barrera-Saldaña

Genes 2018, 9(7), 349; https://doi.org/10.3390/genes9070349 - 11 Jul 2018

Cited by 4 | Viewed by 4533

Abstract

Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe [...] Read more.

Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe BRCA1 and BRCA2 gene variants in Mexican patients with ovarian cancer. Sequencing of BRCA1 and BRCA2 genes from tumors of 50 Mexican patients with ovarian cancer was made in a retrospective, non-randomized, and exploratory study. We found genetic variants in 48 of 50 cases. A total of 76 polymorphic variants were found in BRCA1, of which 50 (66%) had not been previously reported. Furthermore, 104 polymorphic variants were found in BRCA2, of which 63 (60%) had not been reported previously. Of these polymorphisms, 5/76 (6.6%) and 4/104 (3.8%) were classified as pathogenic in BRCA1 and BRCA2, respectively. We have described the genetic variants in BRCA1 and BRCA2 of tumors from Northeast Mexican patients with sporadic ovarian cancers. Our results showed that the use of genetic testing helps recognize patients that carry pathogenic variants which could be beneficial for personalized medicine treatments. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

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Review

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25 pages, 441 KiB

Open AccessReview

Genetic Epidemiology of Breast Cancer in Latin America

by Valentina A. Zavala, Silvia J. Serrano-Gomez, Julie Dutil and Laura Fejerman

Genes 2019, 10(2), 153; https://doi.org/10.3390/genes10020153 - 18 Feb 2019

Cited by 33 | Viewed by 8407

Abstract

The last 10 years witnessed an acceleration of our understanding of what genetic factors underpin the risk of breast cancer. Rare high- and moderate-penetrance variants such as those in the BRCA genes account for a small proportion of the familial risk of breast [...] Read more.

The last 10 years witnessed an acceleration of our understanding of what genetic factors underpin the risk of breast cancer. Rare high- and moderate-penetrance variants such as those in the BRCA genes account for a small proportion of the familial risk of breast cancer. Low-penetrance alleles are expected to underlie the remaining heritability. By now, there are about 180 genetic polymorphisms that are associated with risk, most of them of modest effect. In combination, they can be used to identify women at the lowest or highest ends of the risk spectrum, which might lead to more efficient cancer prevention strategies. Most of these variants were discovered in populations of European descent. As a result, we might be failing to discover additional polymorphisms that could explain risk in other groups. This review highlights breast cancer genetic epidemiology studies conducted in Latin America, and summarizes the information that they provide, with special attention to similarities and differences with studies in other populations. It includes studies of common variants, as well as moderate- and high-penetrance variants. In addition, it addresses the gaps that need to be bridged in order to better understand breast cancer genetic risk in Latin America. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

21 pages, 955 KiB

Open AccessReview

Human Genetic Adaptation to High Altitude: Evidence from the Andes

by Colleen G. Julian and Lorna G. Moore

Genes 2019, 10(2), 150; https://doi.org/10.3390/genes10020150 - 15 Feb 2019

Cited by 74 | Viewed by 10147

Abstract

Whether Andean populations are genetically adapted to high altitudes has long been of interest. Initial studies focused on physiological changes in the O₂ transport system that occur with acclimatization in newcomers and their comparison with those of long-resident Andeans. These as well [...] Read more.

Whether Andean populations are genetically adapted to high altitudes has long been of interest. Initial studies focused on physiological changes in the O₂ transport system that occur with acclimatization in newcomers and their comparison with those of long-resident Andeans. These as well as more recent studies indicate that Andeans have somewhat larger lung volumes, narrower alveolar to arterial O₂ gradients, slightly less hypoxic pulmonary vasoconstrictor response, greater uterine artery blood flow during pregnancy, and increased cardiac O₂ utilization, which overall suggests greater efficiency of O₂ transfer and utilization. More recent single nucleotide polymorphism and whole-genome sequencing studies indicate that multiple gene regions have undergone recent positive selection in Andeans. These include genes involved in the regulation of vascular control, metabolic hemostasis, and erythropoiesis. However, fundamental questions remain regarding the functional links between these adaptive genomic signals and the unique physiological attributes of highland Andeans. Well-designed physiological and genome association studies are needed to address such questions. It will be especially important to incorporate the role of epigenetic processes (i.e., non-sequence-based features of the genome) that are vital for transcriptional responses to hypoxia and are potentially heritable across generations. In short, further exploration of the interaction among genetic, epigenetic, and environmental factors in shaping patterns of adaptation to high altitude promises to improve the understanding of the mechanisms underlying human adaptive potential and clarify its implications for human health. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

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17 pages, 491 KiB

Open AccessReview

Tuberculosis Genetic Epidemiology: A Latin American Perspective

by Marc Woodman, Ilsa L. Haeusler and Louis Grandjean

Genes 2019, 10(1), 53; https://doi.org/10.3390/genes10010053 - 16 Jan 2019

Cited by 27 | Viewed by 7359

Abstract

There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With improvements in genome sequencing technology, it is now possible to study the genetic diversity of tuberculosis with much [...] Read more.

There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With improvements in genome sequencing technology, it is now possible to study the genetic diversity of tuberculosis with much greater resolution. Although tuberculosis bacteria do not engage in horizontal gene transfer, the genome is far more variable than previously thought. The study of genome-wide variation in tuberculosis has improved our understanding of the evolutionary origins of tuberculosis, the arrival of tuberculosis in Latin America, the genetic determinants of drug resistance, and lineage-specific associations with important clinical phenotypes. This article reviews what is known about the arrival of tuberculosis in Latin America, the genetic diversity of tuberculosis in Latin America, and the genotypic determinants of clinical phenotypes. Full article

(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)

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