- Research article
- Open Access
Distribution of allelic and genotypic frequencies of IL1A, IL4, NFKB1 and PAR1 variants in Native American, African, European and Brazilian populations
© Amador et al. 2016
- Received: 13 October 2015
- Accepted: 2 February 2016
- Published: 16 February 2016
The inflammatory response plays a key role at different stages of cancer development. Allelic variants of the interleukin 1A (IL1A), interleukin 4 (IL4), nuclear factor kappa B1 (NFKB1) and protease-activated receptor 1 (PAR1) genes may influence not only the inflammatory response but also susceptibility to cancer development. Among major ethnic or continental groups, these polymorphic variants present different allelic frequencies. In admixed populations, such as the Brazilian population, data on distribution of these polymorphisms are limited. Here, we collected samples of cancer-free individuals from the north, northeast, midwest, south and southeast regions of Brazil and from the three main groups that gave rise to the Brazilian population: Native Americans from the Brazilian Amazon, Africans and Europeans. We describe the allelic distributions of four IL1A (rs3783553), IL4 (rs79071878), NFKB1 (rs28362491) and PAR1 (rs11267092) gene polymorphisms, which the literature describes as polymorphisms with a risk of cancer or worse prognosis for cancer.
The genotypic distribution of the four polymorphisms was statistically distinct between Native Americans, Africans and Europeans. For the allelic frequency of these polymorphisms, the Native American population was the most distinct among the three parental populations, and it included the greatest number of alleles with a risk of cancer or worse prognosis for cancer. The PAR1 gene polymorphism allelic distribution was similar among all Brazilian regions. For the other three markers, the northern region population was statistically distinct from other Brazilian region populations.
The IL1A, IL4, NFKB1 and PAR1 gene polymorphism allelic distributions are homogeneous among the regional Brazilian populations, except for the northern region, which significantly differs from the other four Brazilian regions. Among the parental populations, the Native American population exhibited a higher incidence of alleles with risk of cancer or worse prognosis for cancer, which can indicate greater susceptibility to this disease. These genetic data may be useful for future studies on the association between these polymorphisms and cancer in the investigated populations.
- Inflammatory response
- Native Americans
- IL1A gene
- IL4 gene
- NFKB1 gene and PAR1 gene
External factors that modify tissue homeostasis, such as microorganism infection, tissue injury and exposure to contaminants may induce inflammatory processes . Chronic inflammation is associated with the appearance of malignant cells and these cells’ proliferation, invasion and metastasis processes .
The inflammatory response may be modulated through gene expression variations due to structural genetic polymorphisms or regulatory regions. Therefore, an individual genetic composition may influence not only the inflammatory response but also susceptibility to cancer development [3, 4].
Recently, many studies have tested the association between different forms of cancer and functional variants of genes responsible for the inflammatory process [5–8], such as interleukin 1A (IL1A), interleukin 4 (IL4), nuclear factor kappa B1 (NFKB1) and protease-activated receptor 1 (PAR1) [9–12].
The gene for the pro-inflammatory cytokine IL1A presents an insertion/deletion (INDEL) polymorphism (3′UTR indel TTCA, rs3783553) in a binding site for the microRNAs miR-122 and miR-378 that modifies the connection between these microRNAs. The insertion (Ins) allele is related to higher gene expression . Different investigations have demonstrated that individuals homozygous for the insertion (Ins/Ins) are less susceptible to developing gastric cancer, nasopharyngeal cancer, hepatocellular carcinoma and cervical cancer [13–16].
Interleukin-4 (IL4), which is an anti-inflammatory cytokine gene, presents a VNTR polymorphism (intron 3 VNTR—70 bp, rs79071878) located on the third intron. Different alleles for this polymorphism modulate gene expression. The allele with two repeats (A2) is related to higher gene expression, while the allele with three repeats (A3) is related to lower expression [17, 18]. A homozygous genotype for higher IL4 expression (A2/A2) is associated with a worse prognosis in bladder cancer patients and with oral and pharyngeal cancers [19, 20].
Transcription factor NFKB1 plays an important role in the inflammatory process, and it can influence cancer development and aggressiveness, increasing tumour angiogenesis and repressing the immune response . The NFKB1 gene carries an INDEL polymorphism in the promoter region (−94 indel ATTG, rs28362491) that exerts a regulatory effect on gene expression. The insertion allele is associated with an increase in promoter activity and protein synthesis .
Several studies on the association between rs28362491 and the risk of developing cancer show conflicting results [9, 23–25]. In a recent meta-analysis of 21 case–control studies, Yang et al.  showed that the insertion allele for this polymorphism is significantly associated with a risk of developing oral, prostate and ovary cancers. The analyses also reveal similar results in Asian populations, but not in European populations, which suggests ethnic variations in predisposition to different types of cancer.
The receptor PAR1 is a member of the superfamily of G protein-coupled membrane receptors . These receptors regulate processes ranging from vascular integrity to systemic inflammation. Activation of the PAR1 receptor in epithelial cells, macrophages and endothelial cells promotes the release of pro-inflammatory mediators, such as TNF, IL1β, IL2, IL6, CXCL8 and CCL2 . The PAR1 gene features an INDEL polymorphism (−506 indel—13 bp, rs11267092) located in the promoter region . The deletion allele (Del) is related to a better prognosis in breast, stomach and oesophagus cancers [29–31].
The polymorphisms described above exhibit common features. (1) They are functional polymorphisms that alter the expression of genes that participate in and for metabolic pathways associated with carcinogenesis. (2) Such genes are associated with different types of cancer with high incidence in the Brazilian population, especially prostate, stomach, oesophagus, breast and cervical cancers . (3) The genes vary in populations with different ethnic and geographic origins . (4) Information on allele distributions in Native Americans and admixed populations, such as the Brazilian population, is limited. (5) From a technical perspective, all of the investigated polymorphisms are small INDELs; therefore, genotyping may be performed using a single PCR step followed by capillary electrophoresis, which is an accessible and low-cost laboratory technique.
The Brazilian population is one of the most heterogeneous populations worldwide that is formed by an admixture of Native Americans, Europeans and Africans. This heterogeneity has been well-documented in several genetic investigations [34–39]. The admixture process occurred through different means between the Brazilian geographic regions. Therefore, the Native American contribution is more pronounced in Northern Brazil; the African contribution is more elevated in Northeast Brazil; and the South features a European predominance with little Native American and African influence .
We must know the distribution of allelic frequencies of these polymorphisms [IL-1A (rs3783553), IL4 (rs79071878), NFKB1 (rs28362491) and PAR1 (rs11267092)] for association studies on cancer, data for which is limited on Brazilian populations. Thus, the aim of this study is to characterize allelic distributions in a representative sample of the Brazilian population from all geographic regions of the country.
Distribution of the polymorphisms in IL-1A, IL4, NFKB1 and PAR1 genes in Brazilian regions and parental populations
Comparison of the genotypic distribution of polymorphisms in IL1A, IL4, NFKB1 and PAR1 genes between the studied populations
χ2 (df = 2)
χ2 (df = 2)
χ2 (df = 2)
χ2 (df = 2)
Native Americans × Africans
Native Americans × Europeans
Africans × Europeans
North × Northeast
North × Midwest
North × Southeast
North × South
Northeast × Midwest
Northeast × Southeast
Northeast × South
Midwest × Southeast
Midwest × South
Southeast × South
For the geographic region comparisons (Table 2), rs11267092 (PAR1 gene) showed no significant difference between the Brazilian regions. The distributions of the other three polymorphisms (rs3783553, rs79071878 and rs28362491) were statistically similar between the northeast, south and southeast regions.
The analyses showed statistically significant differences in the rs3783553, rs79071878 and rs28362491 polymorphism distributions between the northern population and the populations in the other regions, except the rs3783553 polymorphism in the midwest region (p = 0.543). This polymorphism exhibited a significantly different distribution in the midwest population compared with the northeast, south and southeast regions.
All polymorphisms investigated here have been previously described as associated with a predisposition to some form of cancer [14, 15, 21, 24, 25], as well as compared with the prognosis of the disease [19, 29–31]. We proposed a different approach to analysing the population data. Under this new approach, the proportion of individuals who are allele carriers are considered at risk for cancer or worse prognosis for cancer (referred to as potentially deleterious alleles ), including the deletion allele for rs3783553, allele A2 for rs79071878, the insertion allele for rs28362491, and the insertion allele for rs11267092.
Based on this analysis, the proportion of potentially deleterious alleles is higher in the Native American population (50 %) than the African (44 %) and European (35 %) populations. Among Brazilians, the proportion of potentially deleterious alleles is 40 %. Likewise, the proportion of individuals who are carriers of six or more alleles associated with cancer is greater among the Native Americans (8.6 %) than the Africans (5.2 %) and Europeans (1.9 %), and the proportion of Brazilians (4.2 %) is intermediate among the ancestral population values. The proportion of carriers is not evenly distributed between the geographic regions. The proportion is smaller in the Northeast Brazil population (2.7 %), intermediate in Midwest and South Brazil populations (mean = 3.4 %) and more elevated in the North (5.0 %) and Southeast Brazil populations (6.5 %).
This is the most comprehensive study on the rs3783553, rs79071878, rs28362491 and rs11267092 polymorphism variations in Brazil and among its ancestral populations. This is also the first study to describe the variability of these markers in Native American populations.
We evaluated the distribution of allele and genotype frequencies for these four markers among the pairs of ancestral and Brazilian populations using the Chi-square test with the due statistical corrections (false discovery rate) to avoid spurious correlations. This test is adequate to compare two or more populations for a qualitative variable . Furthermore, our sample size is representative of the populations studied here (928 Brazilians, 222 Native Americans, 211 Africans and 268 Europeans) and adequate for using INDEL-type polymorphisms, which present a low mutation rate compared with other types of polymorphisms .
The data from the ancestral populations investigated here reveal considerable heterogeneity between continental populations. All investigated markers present δ values greater than 30 %, except for the NFKB1 gene polymorphism. In this set of markers, the Native American populations were the most differentiated among the investigated continental populations.
Frequencies of the deletion allele in the polymorphisms of the IL1A, IL4, NFKB1 and PAR1 genes in Brazil and in other world populations
Number of Chromosomes
1000 Genomes 
1000 Genomes 
1000 Genomes 
Despite the frequency differences between the parental populations and the intense and heterogeneous process of admixture that formed the current Brazilian population, the allelic distribution is relatively homogeneous throughout most of the country. In general, only the northern population exhibits an allele distribution that significantly differs from the other geographic regions for three of the four investigated markers.
We understand that these differences may be explained by a greater contribution of Native Americans to the northern populations. Previous estimates using different types of genetic markers show that the greatest Native American genetic contribution among Brazilians occurs in North populations [36, 38, 39, 43]. Moreover, data generated in the present work show that Native Americans form the most differentiated group of all the continental populations that form the Brazilian population. Therefore, we believe that, conjunctively, these two factors may explain the observed differentiation in the Northern Brazil population.
Our analyses involving potentially deleterious alleles demonstrate that the Native American population presents a higher proportion (50 %) of these alleles compared with the other parental populations (44 and 35 % for African and European, respectively). This analysis holds when considering the proportion of carriers with six or more (among eight possible) potentially deleterious alleles.
However, we cannot evaluate how this genetic composition may be associated with a higher incidence of cancer in this population because Native American populations form traditional communities that reside in outlying areas of urban centres. Epidemiological data are not available on the incidence of different types of cancer among these populations.
Despite the absence of epidemiological data, recent studies demonstrate that different forms of cancer are associated with a higher (or lower) contribution from Native American ancestry in admixed populations from South America. The investigations were associated with acute lymphoblastic leukaemia , breast cancer  and gastric cancer [45–47].
In summary, our study shows that the allelic distribution of the IL-1A (rs3783553), IL4 (rs79071878), NFKB1 (rs28362491) and PAR1 (rs11267092) gene polymorphisms differs between European, African and Native American populations. Further, the same heterogeneity is not observed between regional populations in Brazil, except for the northern region, which significantly differs from the other four Brazilian regions.
Moreover, the results show that the Native American population includes a greater proportion of carriers with six or more alleles associated with cancer, which suggests that this population may have a higher risk of developing (or worse prognosis for) diseases associated with these alleles. The presented genetic data may be useful for future studies on the association between these polymorphisms and cancer in these populations.
The study population consists of 928 non-related and cancer-free adult individuals, recruited in ten Brazilian Federal Units, between the years of 2009 and 2010. In the present work, 180 individuals (90 male and 90 female) residing in the states of Pará (60), Amazonas (60) and Rondônia (60) represented the North region; 187 individuals (107 male and 80 female) residing in the states of Ceará (135) and Pernambuco (52) represented the Northeast region; 186 individuals (95 male and 91 female) residing in the states of Goiás (101), Mato Grosso do Sul (49) and Distrito Federal (36) represented the Midwest region; 184 individuals (90 male and 94 female) residing in the state of São Paulo represented the Southeast region; and 191 individuals (96 male and 95 female) residing in the state of Rio Grande do Sul represented the South region. Additional details may be found in a previous study .
In addition, we investigated a sample of 701 individuals representative of the main ethnic groups that originated the Brazilian population: 222 Native Americans from nine tribes of the Brazilian Amazon (Tiriyó, Waiãpi, Zoé, Urubu-Kaapor, Awa-Guajá, Parakanã, Wai Wai, Gavião, Zoró) ; 211 Africans (Angola, Mozambique, Congo Republic, Cameroon, Ivory Coast) ; and 268 Europeans (all from Portugal and Spain) that have been commonly studied in previous investigations on Brazilian ancestry [37, 39].
Informed consent for DNA analysis was obtained from healthy individuals for research purposes. Ethics approval was obtained from the local committee of Instituto de Ciências da Saúde, Universidade Federal do Pará.
Genotyping of investigated polymorphisms
Characteristics of the investigated markers
Primers sequences (5′–3′)
Multiplex PCR products were separated and analyzed by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument (Applied Biosystems), using GS-500 LIX as pattern of molecular weight (Applied Biosystems), G5 virtual filter matrix and POP7 (Applied Biosystems). After data collect, samples were analyzed in GeneMapper®3.7 software (Applied Biosystems).
Allelic and genotypic frequencies were obtained by direct counting and δ value (delta value) was determined by substracting values of allele frequency in the studied parental populations, as described by Santos et al. . Hardy–Weinberg equilibrium deviations were tested in Arlequin 3.1 software . Differences in genotypic frequencies between Brazilian regions and parental populations were measured by Chi-square test (χ2 test, df = 2) in BioEstat software . FDR (False Discovery Rate) method was used to correct multiple analyses . These analyses were performed in the statistical package R Calculation. P value was considered significant if lower than 0.05.
MATA carried out the molecular genetic studies, undertook the bibliographic review, analyzed the data and wrote the paper. GCC revised the manuscript and participated of the techniques development. ARS, JFG, LG and NPCS contributed to the discussion. SS coordinated the study and also contributed to the discussion. All authors read and approved the final version of the manuscript.
This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Pró-Reitoria de Pesquisa de Pós-Graduação da Universidade Federal do Pará (PROPESP/UFPA) and Fundação de Amparo e Desenvolvimento da Pesquisa (FADESP).
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Rasch S, Algül H. A clinical perspective on the role of chronic inflammation in gastrointestinal cancer. Clin Exp Gastroenterol. 2014;7:261–72.PubMed CentralPubMedGoogle Scholar
- Sun B, Karin M. The therapeutic value of targeting inflammation in gastrointestinal cancers. Trends Pharmacol Sci. 2014;35:349–57.PubMed CentralView ArticlePubMedGoogle Scholar
- Gu X, Shen Y, Fu L, Zuo H, Yasen H, He P, Guo H, Shi Y, Yusufu M. Polymorphic variation of inflammation-related genes and risk of non-Hodgkin lymphoma for Uygur and Han Chinese in Xinjiang. Asian Pac J Cancer Prev. 2014;15:9177–83.View ArticlePubMedGoogle Scholar
- Wang Q, Zhang C, Walayat S, Chen HW, Wang Y. Association between cytokine gene polymorphisms and cervical cancer in a Chinese population. Eur J Obstet Gynecol Reprod Biol. 2011;158:330–3.View ArticlePubMedGoogle Scholar
- Lu Z-H, Gu X-J, Shi K-Z, Li X, Chen D-D, Chen L. Association between genetic polymorphisms of inflammatory response genes and the risk of ovarian cancer. J Formos Med Assoc. 2016;115:31–7View ArticlePubMedGoogle Scholar
- Mandal RK, Agrawal T, Mittal RD. Genetic variants of chemokine CCL2 and chemokine receptor CCR2 genes and risk of prostate cancer. Tumor Biol. 2014;36:375–81.View ArticleGoogle Scholar
- Wang Z, Liu Q-L, Sun W, Yang C-J, Tang L, Zhang X, Zhong X-M. Genetic polymorphisms in inflammatory response genes and their associations with breast cancer risk. Croat Med J. 2014;55:638–46.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang Y, Mao Y, Sun Y. Genetic polymorphisms of IL-6 and IL-10 genes correlate with lung cancer in never-smoking Han population in China. Int J Clin Exp Med. 2015;8:1051–8.PubMed CentralPubMedGoogle Scholar
- Gao J, Xu H-L, Gao S, Zhang W, Tan Y-T, Rothman N, Purdue M, Gao Y-T, Zheng W, Shu X-O, Xiang Y-B. Genetic polymorphism of NFKB1 and NFKBIA genes and liver cancer risk: a nested case-control study in Shanghai, China. BMJ Open. 2014;4:e004427.PubMed CentralView ArticlePubMedGoogle Scholar
- Yu Y, Zheng S, Zhang S, Jin W, Liu H, Jin M, Chen Z, Ding Z, Wang L, Chen K. Polymorphisms of inflammation-related genes and colorectal cancer risk: a population-based case-control study in China. Int J Immunogenet. 2014;41:289–97.View ArticlePubMedGoogle Scholar
- Kopp TI, Andersen V, Tjonneland A, Vogel U. Polymorphisms in NFKB1 and TLR4 and interaction with dietary and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study. PLoS One. 2015;10:e0116394.PubMed CentralView ArticlePubMedGoogle Scholar
- De Martino M, Haitel A, Schatzl G, Klatte T. The protease activated receptor 1 gene variation IVSn -14 A > T is associated with distant metastasis and cancer specific survival in renal cell carcinoma. J Urol. 2013;190:1392–7.View ArticlePubMedGoogle Scholar
- Gao Y, He Y, Ding J, Wu K, Hu B, Liu Y, Wu Y, Guo B, Shen Y, Landi D, Landi S, Zhou Y, Liu H. An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1α 3′ untranslated region confers risk for hepatocellular carcinoma. Carcinogenesis. 2009;30:2064–9.View ArticlePubMedGoogle Scholar
- Zeng X-F, Li J, Li S-B. A functional polymorphism in IL-1A gene is associated with a reduced risk of gastric cancer. Tumour Biol. 2014;35:265–8.View ArticlePubMedGoogle Scholar
- Yang ZH, Dai Q, Zhong L, Zhang X, Guo QX, Li SN. Association of IL-1 polymorphisms and IL-1 serum levels with susceptibility to nasopharyngeal carcinoma. Mol Carcinog. 2011;50:208–14.View ArticlePubMedGoogle Scholar
- Pu Y, Zhang Z, Zhou B, Chen P, Zhang K, Song Y, Gao Q, Wang K, Quan Y, Xi M, Zhang L. Association of an insertion/deletion polymorphism in IL1A 3′-UTR with risk for cervical carcinoma in Chinese Han Women. Hum Immunol. 2014;75:740–4.View ArticlePubMedGoogle Scholar
- Kesarwani P, Ahirwar D, Singh R, Manchanda PK, Mittal RD. Do IL-4 intron 3 VNTR and IL-6 (-174) G/C variants reflect ethnic variation? A comparative study between the global and North Indian populations. Asian Pac J Cancer Prev. 2008;9:76–80.PubMedGoogle Scholar
- Nakashima H, Miyake K, Inouoe Y, Shimizu S, Akahoshi M, Tunaka Y, Otsuka T, Harada M. Association between IL-4 genotype and IL-4 production in the Japanese population. Genes Immun. 2002;3:107–9.View ArticlePubMedGoogle Scholar
- Ahirwar D, Kesarwani P, Manchanda PK, Mandhani A, Mittal RD. Anti- and proinflammatory cytokine gene polymorphism and genetic predisposition: association with smoking, tumor stage and grade, and bacillus Calmette-Guérin immunotherapy in bladder cancer. Cancer Genet Cytogenet. 2008;184:1–8.View ArticlePubMedGoogle Scholar
- Yang CM, Chen HC, Hou YY, Lee MC, Liou HH, Huang SJ, Yen LM, Eng DM, Hsieh YD, Ger LP. A high IL-4 production diplotype is associated with an increased risk but better prognosis of oral and pharyngeal carcinomas. Arch Oral Biol. 2014;59:35–46.View ArticlePubMedGoogle Scholar
- Yang X, Li P, Tao J, Qin C, Cao Q, Gu J, Deng X, Wang J, Liu X, Wang Z, Wu B, Gu M, Lu Q, Yin C. Association between NFKB1 -94ins/del ATTG promoter polymorphism and cancer susceptibility: an updated meta-analysis. Int J Genomics. 2014;2014:1–9.View ArticleGoogle Scholar
- Li P, Gu J, Yang X, Cai H, Tao J, Yang X, Lu Q, Wang Z, Yin C, Gu M. Functional promoter -94 ins/del ATTG polymorphism in NFKB1 gene is associated with bladder cancer risk in a Chinese population. PLoS One. 2013;8:1–7.Google Scholar
- Duan W, Wang E, Zhang F, Wang T, You X, Qiao B. Association between the NFKB1-94 ins/del ATTG polymorphism and cancer risk: an updated meta-analysis. Cancer Invest. 2014;32:311–20.View ArticlePubMedGoogle Scholar
- Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. Association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of esophageal squamous cell carcinoma. PLoS One. 2013;8:1–12.View ArticleGoogle Scholar
- Xu L, Huang S, Chen W, Song Z, Cai S. NFKB1 -94 insertion/deletion polymorphism and cancer risk: a meta-analysis. Tumor Biol. 2014;35:5181–7.View ArticleGoogle Scholar
- Fujimoto D, Hirono Y, Goi T, Katayama K, Matsukawa S, Yamaguchi A. The activation of proteinase-activated receptor-1 (PAR1) promotes gastric cancer cell alteration of cellular morphology related to cell motility and invasion. Int J Oncol. 2013;42:565–73.PubMedGoogle Scholar
- Mercer PF, Williams AE, Scotton CJ, José RJ, Sulikowski M, Moffatt JD, Murray LA, Chambers RC. Proteinase-activated receptor-1, CCL2, and CCL7 regulate acute neutrophilic lung inflammation. Am J Respir. Cell Mol Biol. 2014;50:144–57.PubMed CentralPubMedGoogle Scholar
- Arnaud E, Nicaud V, Poirier O, Rendu F, Alhenc-Gelas M, Fiessinger J-N, Emmerich J, Aiach M. Protective effect of a thrombin receptor (protease-activated receptor 1) gene polymorphism toward venous thromboembolism. Arterioscler Thromb Vasc Biol. 2000;20:585–92.View ArticlePubMedGoogle Scholar
- Lurje G, Husain H, Power DG, Yang D, Groshen S, Pohl A, Zhang W, Ning Y, Manegold PC, El-Khoueiry A, et al. Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma. Ann Oncol. 2010;21:78–86.PubMed CentralView ArticlePubMedGoogle Scholar
- Lurje G, Leers JM, Pohl A, Oezcelik A, Zhang W, Ayazi S, Winder T, Ning Y, Yang D, Klipfel NE, et al. Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus. Ann Surg. 2010;251:857–64.View ArticlePubMedGoogle Scholar
- Eroğlu A, Karabıyık A, Akar N. The association of protease activated receptor 1 gene—506 I/D polymorphism with disease-free survival in breast cancer patients. Ann Surg Oncol. 2012;19:1365–9.View ArticlePubMedGoogle Scholar
- Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11 [internet]. International Agency for Research on Cancer, Lyon, France. 2013. http://globocan.iarc.fr. Accessed on 6 Jan 2016.
- The 1000 Genomes Project Consortium. An integrated map of genetic variation from 1092 human genomes. Nature. 2012;491:56–65.PubMed CentralView ArticleGoogle Scholar
- Cardena MMSG, Ribeiro-dos-Santos AKC, Santos SEB, Mansura AJ, Bernardez-Pereira S, Santos PCJL, Pereira AC, Fridman C. Mitochondrial and genomic ancestry are associated with etiology of heart failure in Brazilian patients. J Hum Hypertens. 2015;5:1.Google Scholar
- Leite FPN, Callegari-Jacques SM, Carvalho BA, Kommers T, Matte CHF, Raimann PE, Schwengber SP, Sortica VA, Tsuneto LT, Petzl-Erler ML, Salzano FM, Hutz MH. Y-STR analysis in Brazilian and South Amerindian populations. Am J Hum Biol. 2008;20:359–63.View ArticlePubMedGoogle Scholar
- Manta FSN, Pereira R, Vianna R, De Araújo ARB, Gitaí DLG, Da Silva DA, Gusmão L. Revisiting the genetic ancestry of Brazilians using autosomal AIM-indels. PLoS One. 2013;8:1–11.Google Scholar
- Palha T, Gusmão L, Ribeiro-Rodrigues E, Guerreiro JF, Ribeiro-dos-Santos Â, Santos S. Disclosing the genetic structure of Brazil through analysis of male lineages with highly discriminating haplotypes. PLoS One. 2012;7:1–8.View ArticleGoogle Scholar
- Pena SDJ, di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy FDSG, Kohlrausch F, Magno LAV, Montenegro RC, Moraes MO, de Moraes MEA, de Moraes MR, Ojopi ÉB, Perini JA, Racciopi C, Ribeiro-dos-Santos ÂKC, Rios-Santos F, Romano-Silva MA, Sortica VA, Suarez-Kurtz G. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One 2011;6(2):e17063PubMed CentralView ArticlePubMedGoogle Scholar
- Santos NPC, Ribeiro-Rodrigues EM, Ribeiro-dos-Santos AKC, Pereira R, Gusmão L, Amorim A, Guerreiro JF, Zago MA, Matte C, Hutz MH, Santos SEB. Assessing individual interethnic admixture and population substructure using a 48-Insertion-Deletion (INSEL) Ancestry-Informative Marker (AIM) Panel. Hum Mutat. 2010;31:184–90.View ArticlePubMedGoogle Scholar
- Cavalcante GC, Freitas NSC, Ribeiro-dosSantos AM, Carvalho DC, Silva EM, Assumpção PP, Ribeiro-dos-Santos AKC, Santos SEB, Santos NPC. Investigation of potentially deleterious alleles for response to cancer treatment with 5-Fluorouracil. Anticancer Res. 2015;35(12):6971–7.PubMedGoogle Scholar
- Callegari-Jacques SM. Bioestatística: princípios e aplicações. Porto Alegre: Artmed; 2003Google Scholar
- Freitas NSC, Resque RL, Ribeiro-Rodrigues EM, Guerreiro JF, Santos NPC, Ribeiro-dos-Santos AKC, Santos SEB. X-linked insertion/deletion polymorphisms: forensic applications of a 33-markers panel. Int J Legal Med. 2010;124:589–93.View ArticlePubMedGoogle Scholar
- Pena SDJ, Pimenta JR, Bydlowski SP. DNA tests probe the genomic ancestry of Brazilians DNA tests probe the genomic ancestry of Brazilians. Braz J Med Biol Res. 2009;42:870–6.View ArticlePubMedGoogle Scholar
- Carvalho DC, Wanderley AV, Amador MAT, Fernandes MR, Cavalcante GC, Pantoja KB, Mello FA, de Assumpção PP, Khayat AS, Ribeiro-dos-Santos Â, Santos S, dos Santos NP. Amerindian genetic ancestry and INDEL polymorphisms associated with susceptibility of childhood B-cell Leukemia in an admixed population from the Brazilian Amazon. Leuk Res. 2015;39:1239–45.View ArticleGoogle Scholar
- Vieira PC, Burbano RM, Fernandes DC, Montenegro RC, dos Santos SE, Sortica VA, Assumpção PP, Ribeiro-dos-Santos ÂK, Carvalho AA, Santos NP. Population stratification effect on cancer susceptibility in an admixed population from Brazilian Amazon. Anticancer Res. 2015;35(4):2009–14.PubMedGoogle Scholar
- Pereira L, Zamudio R, Soares-Souza G, et al. Socioeconomic and nutritional factors account for the association of gastric cancer with Amerindian ancestry in a Latin American admixed population. PLoS One. 2012;7:e41200.PubMed CentralView ArticlePubMedGoogle Scholar
- Zamudio R, Pereira L, Rocha CD, Berg DE, et al. Population, epidemiological, and functional genetics of gastric cancer candidate genes in peruvians with predominant amerindian ancestry. Dig Dis Sci. 2016;61:107–16.View ArticlePubMedGoogle Scholar
- Ribeiro-Rodrigues EM, Palha TJBF, Bittencourt EA, Ribeiro-dos-Santos AKC, Santos S. Extensive survey of 12 X-STRs reveals genetic heterogeneity among Brazilian populations. Int J Legal Med. 2011;125:445–52.View ArticlePubMedGoogle Scholar
- Santos SEB, Ribeiro-Rodrigues EM, Ribeiro-dos-Santos AKC, Hutz MH, Tovo-Rodrigues L, Salzano FM, Callegari-Jacques SM. Autosomal STR analyses in native Amazonian tribes suggest a population structure driven by isolation by distance. Hum Biol. 2009;81:71–88.View ArticlePubMedGoogle Scholar
- Silva WA, Bortolini MC, Schneider MP, Marrero A, Elion J, Krishnamoorthy R, Zago MA. MtDNA haplogroup analysis of black Brazilian and sub-Saharan populations: implications for the Atlantic slave trade. Hum Biol. 2006;78:29–41.View ArticlePubMedGoogle Scholar
- Excoffier L, Lischer HEL. Arlequin suite version 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10:564–7.View ArticlePubMedGoogle Scholar
- Ayres M, Ayres JRM, Ayres DL, Santos AS. BioEstat version 5.0. Sociedade Civil Mamirauá, MCT—CNPq, Belém, Pará, Brasil, 2007.Google Scholar
- Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.Google Scholar