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Genetics and Molecular Biology

Print version ISSN 1415-4757

Genet. Mol. Biol. vol.34 no.3 São Paulo  2011

https://doi.org/10.1590/S1415-47572011000300003 

RESEARCH ARTICLE

 

Population analysis of vitamin D receptor polymorphisms and the role of genetic ancestry in an admixed population

 

 

Tulio C. LinsI; Rodrigo G. VieiraI; Dario GrattapagliaI,II; Rinaldo W. PereiraI

IPrograma de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil
IIHereditas Tecnologia em Análise de DNA, Brasília, DF, Brazil

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ABSTRACT

The vitamin D receptor (VDR) is an essential protein related to bone metabolism. Some VDR alleles are differentially distributed among ethnic populations and display variable patterns of linkage disequilibrium (LD). In this study, 200 unrelated Brazilians were genotyped using 21 VDR single nucleotide polymorphisms (SNPs) and 28 ancestry informative markers. The patterns of LD and haplotype distribution were compared among Brazilian and the HapMap populations of African (YRI), European (CEU) and Asian (JPT+CHB) origins. Conditional regression and haplotype-specific analysis were performed using estimates of individual genetic ancestry in Brazilians as a quantitative trait. Similar patterns of LD were observed in the 5' and 3' gene regions. However, the frequency distribution of haplotype blocks varied among populations. Conditional regression analysis identified haplotypes associated with European and Amerindian ancestry, but not with the proportion of African ancestry. Individual ancestry estimates were associated with VDR haplotypes. These findings reinforce the need to correct for population stratification when performing genetic association studies in admixed populations.

Key words: Brazilian population, HapMap, haplotype, population diversity, VDR.


 

 

Introduction

The vitamin D receptor (VDR) is a member of the superfamily of nuclear receptors for steroid hormones that functions as a ligand-activated transcription factor (Dusso et al., 2005). The VDR associated with the secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2 Vitamin D3) and heterodimerized with the retinoid X receptor (RXR) binds to vitamin D3 response elements in the promoter region of responsive genes (Dusso et al., 2005). The genes that are up- or down-regulated by the complex of vitamin D3, VDR, RXR and other recruited proteins are associated with calcium homeostasis, bone metabolism, cell cycle, immunomodulation and other hormonal systems (Dusso et al., 2005; Lips, 2007). The broad range of vitamin D functions has focused attention on the VDR gene as an important candidate gene that could explain variations in specific phenotypes possibly connected with vitamin D metabolism (Valdivielso and Fernandez, 2006).

Much information has been generated since the first description of VDR polymorphism (Morrison et al., 1994) and has led to intense investigation of the allelic variation in the VDR gene in different ethnic populations (Nejentsev et al., 2004; Thakkinstian et al., 2004; Fang et al., 2005). The conflicting data on the association of VDR polymorphisms with specific phenotypes is sometimes confusing. The reasons commonly given to explain the difficulty in reproducing many results include uncontrolled environmental factors, population stratification, locus heterogeneity and different linkage disequilibrium (LD) patterns (Nejentsev et al., 2004; Thakkinstian et al., 2004; Fang et al., 2005). The VDR region consists essentially of three haplotype blocks located in the intergenic region of the VDR and COL1A1 gene, the 5' promoter region and the 3' region encompassing the untranslated region, with the frequency distributions of LD and haplotypes varying among European, African and Asian populations (Nejentsev et al., 2004; Fang et al., 2005).

Specific variations in the allelic frequencies of VDR polymorphisms among Europeans, Africans, Amerindians and Asians could increase the risk of spurious associations in studies of recently admixed populations such as Brazilians (Rosenberg and Nordborg, 2006). The current Brazilian population is one of the most heterogeneous in the world, descending from an admixture of Europeans, Amerindians and Africans during the last five centuries. The use of ancestry informative markers (AIMs) has revealed ample genetic heterogeneity in the Brazilian population (Callegari-Jacques et al., 2003; Parra et al., 2003; Marrero et al., 2005; Lins et al., 2010) and this characteristic may be used to control population stratification in association studies (Suarez-Kurtz et al., 2007).

Association studies in admixed populations relying only on self-reported ancestry or physical features to arrange volunteers in homogenous groups may produce spurious associations because of stratification generated by admixture (Cardon and Palmer, 2003; Ziv and Burchard, 2003; Suarez-Kurtz et al., 2007). This is particularly important when DNA markers used to conduct association studies and the phenotype investigated display different frequency distributions among the reference groups that gave rise to the admixed population (Pritchard and Donnelly, 2001; Rosenberg and Nordborg, 2006). Bone phenotypes differ among Africans and Europeans (Gilsanz et al., 1998; Jones et al., 2004) and several polymorphisms, including those of the VDR gene, have been investigated as candidates to explain its quantitative variation. The purpose of this study was to perform a greater in-depth analysis of variability in the VDR gene in admixed Brazilians and correlate this variability with individual genetic ancestry estimates in order to identify possible pitfalls when performing association studies in an admixed population.

 

Material and Methods

Population sample

The Brazilian population sample (BRZ) consisted of 200 unrelated healthy subjects randomly chosen from individuals involved in no-cost paternity investigations from 2003 to 2005. All subjects signed an informed consent form that allowed the use of their DNA samples for paternity testing and further population genetics research. To avoid bias during analysis no attempt was made to classify the subjects according to morphological or social traits. The subjects were allocated to one of five groups (n = 40 each) based on their birthplace in one of the five geopolitical regions (Midwest, Northeast, North, Southeast and South) of Brazil. The research protocol was approved by the university Ethics Committee.

HapMap data and genotyping

The VDR genotypes of the HapMap population samples were retrieved from an online database (Data Rel 21a/phaseII Jan07, on NCBI B35 assembly, dbSNP b125). The total sample consisted of 89 unrelated East-Asian individuals (ASN) comprising 45 Han Chinese from Beijing (CHB) and 44 Japanese from Tokyo (JPT), 60 unrelated individuals from northern and western European origin (CEU) and 60 unrelated Yoruba individuals (YRI) from Ibadan, Nigeria.

The choice of VDR SNPs was based on markers of HapMap phase I and phase II data that were polymorphic in at least one population and dispersed with average intervening distances of 5 kb; Haploview software (Barrett et al., 2005) was used to establish the LD patterns. Subsequently, a minimum set of SNPs representing the original LD blocks was selected with a 90% prediction coverage (Lins et al., 2009). Sixteen SNPs were selected in addition to the five most studied VDR polymorphisms (rs11568820-Cdx2, rs10735810-FokI, rs1544410-BsmI, rs7975232-ApaI and rs731236-TaqI) used in our previous studies (Gentil et al., 2007, 2009; Lins et al., 2007, 2009; Moreno Lima et al., 2007).

Estimates of genetic admixture in the Brazilian samples were calculated using a set of 28 autosomal ancestry informative markers (AIMs) selected from previous studies that reported large differences in allele frequency among European, African and Native American populations. Detailed procedures for calculating the ancestry estimates are described by Lins et al. (2010) who used the same population as the present study.

PCR primers and single base extension primers were designed using Primer3 based on recommendations of the SNaPshot Multiplex Kit protocol (Applied Biosystems). The SNPs were assembled into three multiplex panels and then genotyped by a modified single base extension methodology described elsewhere (Lins et al., 2007).

Statistical analysis

Estimates of allele frequency, deviations from Hardy-Weinberg equilibrium and pairwise genetic distance estimates based on Wright's Fst statistics were calculated using Arlequin v. 3.01 (Excoffier et al., 2005).

The linkage disequilibrium analyses were done by estimating the parameters D' and r2. The structure of haplotype blocks in each population was defined by solid spine of LD algorithm in Haploview version 3.32 (Barrett et al., 2005). This criterion defines a block when the first and last markers are in strong LD with all intermediate markers, thereby providing more robust block boundaries. After block definition, the haplotypes of the HapMap population samples were estimated for the blocks established in BRZ in order to compare the haplotype distributions. Haplotype estimates were then calculated using Whap software (Purcell et al., 2007) which is based on the expectation-maximization algorithm and uses the estimates of posterior probabilities to account for the ambiguity of haplotype phase in subsequent association tests. This package was developed to handle quantitative traits and covariates for regression analysis. In this case, the individual ancestry estimated for each ethnic group was set as a quantitative trait in BRZ. Initially, a likelihood ratio test (LRT) on the omnibus conditional regression test indicated whether there was a significant influence of haplotypes on the trait. Then, a haplotype-specific regression-based test comparing the haplotype effect against all other haplotypes indicated whether the effect observed on a specific haplotype was significant (Purcell et al., 2007). For quantitative traits, the conditional analysis approach is more robust and was chosen to model genotype conditional on trait, instead of trait conditional on genotype (the usual approach in such analyses) (Purcell et al., 2007). In addition, a standard approach run in Phase version 2.0.2 software (Stephens and Donnelly, 2003) was used to estimate recombination hotspots by comparing the median of recombination parameters among SNP pairs with the background rate assumed for the general human population (Crawford et al., 2004).

 

Results

The allele frequency distribution for the VDR gene was similar in the five geopolitical regions (Table 1) and a pairwise Fst test identified no significant difference among them (all p-values were > 0.050). However, a significant difference was found when the Brazilian subgroups were combined to form one group (BRZ) and compared with the HapMap populations in a pairwise Fst test. In this case, the Brazilian population was genetically more distant from the HapMap African derived population (BRZ-YRI Fst = 0.154; p < 0.001) than from the HapMap population with European background (BRZ-CEU Fst = 0.012; p = 0.009). The analysis of individual loci showed that only four out of 19 loci were significantly different (p < 0.05) in the pair BRZ-CEU (Table 2). In contrast, in the other population pairs, only a few loci did not differ significantly in their allele frequencies (Table 2).

Information on the VDR haplotype structure in the HapMap data showed that haplotype extension was greater in CEU, followed by ASN and YRI, which had more blocks of lower extension, compared to the others (Figure 1). The CEU and ASN populations had similar LD patterns, with two blocks in the 5' region, one of them identical, and one block in the 3' region. A difference was observed only in the length of the first 5' and 3' haplotype blocks.

 

 

For a comparative inter-population analysis of haplotype block diversity, four SNPs were excluded from the BRZ dataset either because they lacked genotypes in HapMap (e.g., rs4077869 and rs2239185 missing in the CEU population and rs7302235 missing in the ASN population) or deviated from Hardy-Weinberg expectations in BRZ (rs4516035 p = 0.001). Overall, two blocks were observed in the Brazilian population, one in the 5' gene region and another at the end of the transcription region and the 3' UTR region of the VDR gene (Figure 1). The 5' haplotype block contained the Cdx2, rs10783219 and rs3890734 SNPs and extended 13 kb, with mean linkage disequilibrium measures of D' = 0.924 and r2 = 0.175. The 3' haplotype block consisted of rs2248098, BsmI, ApaI, TaqI, rs9729, rs7968585 SNPs and spanned 21 kb, with mean linkage disequilibrium measures of D' = 0.849 and r2 = 0.475. The estimated haplotypes for each block identified five haplotypes in the 5' region (Table 3) and 19 in the 3' region of the gene (Table 4) when all populations were considered.

Regions with no haplotype blocks and a low LD were found between SNPs rs3890734 and rs2853559 and between SNPs rs2254210, FokI and rs886441, for which no block structure was found in any of the populations studied (Figure 1). The test to identify possible recombination hotspots showed two regions of greater intensity relative to the background recombination rate. In Brazilians, the region at FokI and rs886441 had a recombination rate 60 times higher than the background rate, whereas between rs3890734 and rs2853559 the rate was 18 times higher (Figure 1).

The test for population structure in the Brazilian population using autosomal AIMs identified a higher probability for a three-hybrid population, and assigned estimates of contributions as 0.771 ± 0.044 for European, 0.143 ± 0.019 for African and 0.085 ± 0.015 for Amerindian. The individual estimates of ancestry proportion showed that most individuals had a widely distributed three-hybrid pattern of variation with a trend towards a higher contribution by European ancestry. The individual estimates were later used as a quantitative trait in conditional regression tests.

The conditional regression omnibus test indicated a significant correlation with the 5' haplotypes only when estimates of European ancestry were used (p = 0.027) and for 3' haplotypes there was a significant correlation when using estimates of Amerindian and European ancestry (p = .018 and 0.041, respectively); there was no significance when using African ancestry proportions (p > 0.111). Haplotype-specific tests in the 5' region identified two haplotypes with opposing raw regression coefficients (B) indicating that the first haplotype (5'H01) was positively related to European ancestry while the second (5'H02) had a negative correlation (Table 3). In the 3' region, haplotypes with opposing raw regression coefficient signs (B) were significant for Amerindian ancestry (3'H02 and 3'H03) and two haplotypes (3'H02 and 3'H04) were significant for European ancestry (Table 4). When the 3' haplotype block was reduced to only the Bsm-Apa-Taq haplotype, a similar effect of ancestry was observed, but in this case the haplotype with a positive regression in Amerindian ancestry had a negative regression in European ancestry and vice-versa (Table 5).

 

Discussion

In this work, a panel of allelic diversity at the VDR gene locus was generated and the effect of genetic ancestry on haplotype distribution in an admixed population was evaluated. The results described here extend the information about VDR genotypes and provide the first map of VDR haplotypes for a Brazilian population.

The measures of population admixture evaluated with AIMs revealed that the biogeographical ancestral structure of the Brazilian population was European, African and Amerindian (in this order), as previously described (Lins et al., 2010). However, Fst analysis of VDR SNPs revealed a greater distinction between the Brazilian population and the HapMap population of African origin than with the HapMap population of European origin. These results indicate that, in an admixed population, recent admixture cannot always eliminate ancestral LD block structures along chromosomes (Sawyer et al., 2005; Tang et al., 2006). Consequently, complex levels of population admixture can create analytical risks in research involving loci associated with susceptibility to disease and in populations with different profiles, especially in those undergoing admixture. This is likely the case of the VDR gene and bone metabolism phenotypes, such as bone mineral density and osteoporosis (Thakkinstian et al., 2004; Uitterlinden et al., 2004).

Some studies have clearly demonstrated significant associations between European ancestry and body composition traits in admixed populations (Bonilla et al., 2004; Shaffer et al., 2007), while others have shown the relationship between VDR haplotypes and fracture risk in Whites or osteoporosis in European and Asian populations (Thakkinstian et al., 2004; Fang et al., 2005). The present work improves our understanding of the effect of genetic ancestry on the distribution of VDR gene haplotypes in admixed populations and reinforces the importance of correcting for population admixture in genetic association studies that encompass bone-related phenotypes.

The comparative analysis of VDR revealed genetic heterogeneity involving different haplotype blocks in the four populations studied. Considering the recent admixture of Latin American people, especially Brazilians, the variation in the patterns of LD seen here is not surprising in view of demographic events and genetic factors such as drift and recombination during the process of admixture (Gabriel et al., 2002; Liu et al., 2004; Sawyer et al., 2005). Haplotype structure analysis in other admixed populations has also revealed the importance of genetic heterogeneity since linkage disequilibrium increases or breaks down differently in different populations (Moraes et al., 2003; Boldt et al., 2006; Lohmueller et al., 2006; Nakamoto et al., 2006).

Random genetic drift generates large diversity among populations with the same continental origin, e.g., African, European, Amerindian or Asian (Rosenberg et al., 2002). In the present case, the HapMap populations used for comparison were not the most representative sources for the Brazilian parental population studied here and differed from those used to estimate individual autossomic ancestry (which also do not represent the Brazilian parental populations). This limitation is extremely important since the groups used here represent more general continental populations and their characteristics should therefore not be extrapolated to specific populations such as the many that constituted the admixture in current Brazilians, particularly when studying disease-related polymorphisms. As with considerations about genetic ancestry and disease-associated SNPs, the patterns of LD and identification of genetic ancestry blocks should also be addressed prior to the selection of tagSNPs for association studies in admixed populations (Lins et al., 2009).

The distribution of the 5' haplotype for the VDR gene in BRZ was similar to that of the CEU population. The regression coefficient confirmed this relationship. In this case, the haplotype that showed a positive association with European ancestry in Brazilians (5'H01) was absent in the ASN population and had a low frequency in YRI (Table 3). In contrast, the haplotype that correlated negatively with European ancestry (5'H02) had a higher frequency in YRI and ASN than in CEU. These results indicate that both European and non-European ancestries contributed to haplotype variation in our admixed population. Notably, this same phenomenon occurred in the 3' region haplotypes, but in this case there was also a significant association with the Amerindian contribution (Table 4).

The African ancestry showed no correlation with any of the haplotypes examined. Indeed, variation in the extent and amount of LD in the VDR gene is lower in African populations than in European or East-Asians (Nejentsev et al., 2004; Fang et al., 2005), suggesting that extensive recombination precluded the extension of LD in African populations. In agreement with this, the 3' haplotypes defined by the BRZ population exhibited high diversity and low frequencies in YRI (Table 4) when compared to Bsm-Apa-Taq haplotypes, which had a higher LD (Table 5). Moreover, the FokI SNP was not in linkage disequilibrium with any of the SNPs in the populations tested. This observation corroborates previous findings (Nejentsev et al., 2004; Fang et al., 2005) and suggests a major site of haplotype breakage and recombination in the VDR gene that is independent of ethnicity.

Previous studies of the VDR gene in Brazilians only sampled a few loci but some complex phenotypes (Lazaretti-Castro et al., 1997; Hauache et al., 1998; de Brito Junior et al., 2004; Maistro et al., 2004; Goulart et al., 2006; Gentil et al., 2007, 2009; Moreno Lima et al., 2007; Rezende et al., 2007). Some studies have tried to correct the genetic heterogeneity of the Brazilian population by using self-reported ancestry or physical traits as proxy for different ethnic groups. For instance, Rezende et al. (2007) reported no difference in the distribution of VDR haplotypes in Brazilian self-reported Blacks and Whites. This may be explained by the fact that dissociation between physical appearance and genetic ancestry in Brazilians (Parra et al., 2003; Marrero et al., 2005) may have created spurious similarity in genotype and haplotype frequencies among these groups because of the population substructure. As shown here, admixture in the Brazilian population provides the opportunity to segregate the contribution of individual ancestry from genetic ancestry blocks at the VDR gene locus.

In conclusion, the results of this investigation provide a large map of haplotypes for the entire VDR gene and intragenic regions in a carefully sampled Brazilian population. Comparison with the HapMap data was essential for understanding the patterns of LD and haplotype variation among populations and for elucidating the effects of admixture on this diversity. Our findings also support studies that involve tagSNP selection between different ethnic populations (Nejentsev et al., 2004; Lins et al., 2009). Genetic polymorphisms such as those observed here may partly explain ethnic differences in vitamin D3 status and their relationship to bone phenotype and hormonal homeostasis, particularly in elderly women, as well as the role of environmental factors such as diet, lifestyle and sun exposure (Uitterlinden et al., 2004; Dusso et al., 2005; Valdivielso and Fernandez, 2006).

 

Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Pró-Reitoria de Pós-Graduação e Pesquisa da Universidade Católica de Brasília (PRPGP-UCB). TCL was supported by a CAPES scholarship. We thank Luciana Rollemberg Nogueira and Meiriele Luisa da Silva (both undergraduate students) for their valuable help in this work during their academic training.

 

References

Barrett JC, Fry B, Maller J and Daly MJ (2005) Haploview: Analysis and visualization of LD and haplotype maps. Bio-informatics 21:263-265.         [ Links ]

Boldt AB, Culpi L, Tsuneto LT, de Souza IR, Kun JF and Petzl-Erler ML (2006) Diversity of the MBL2 gene in various Brazilian populations and the case of selection at the mannose-binding lectin locus. Hum Immunol 67:722-734.         [ Links ]

Bonilla C, Parra EJ, Pfaff CL, Dios S, Marshall JA, Hamman RF, Ferrell RE, Hoggart CL, McKeigue PM and Shriver MD (2004) Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 68:139-153.         [ Links ]

Callegari-Jacques SM, Grattapaglia D, Salzano FM, Salamoni SP, Crossetti SG, Ferreira ME and Hutz MH (2003) Historical genetics: Spatiotemporal analysis of the formation of the Brazilian population. Am J Hum Biol 15:824-834.         [ Links ]

Cardon LR and Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598-604.         [ Links ]

Crawford DC, Bhangale T, Li N, Hellenthal G, Rieder MJ, Nickerson DA and Stephens M (2004) Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet 36:700-706.         [ Links ]

de Brito Junior RB, Scarel-Caminaga RM, Trevilatto PC, de Souza AP and Barros SP (2004) Polymorphisms in the vitamin D receptor gene are associated with periodontal disease. J Periodontol 75:1090-1095.         [ Links ]

Dusso AS, Brown AJ and Slatopolsky E (2005) Vitamin D. Am J Physiol Renal Physiol 289:F8-F28.         [ Links ]

Excoffier L, Laval G and Schneider S (2005) Arlequin v. 3.0: An integrated software package for population genetics data analysis. Evol Bioinform Online 1:47-50.         [ Links ]

Fang Y, van Meurs JB, d'Alesio A, Jhamai M, Zhao H, Rivadeneira F, Hofman A, van Leeuwen JP, Jehan F, Pols HA et al. (2005) Promoter and 3'-untranslated-region haplotypes in the vitamin D receptor gene predispose to osteoporotic fracture: The Rotterdam Study. Am J Hum Genet 77:807-823.         [ Links ]

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M et al. (2002) The structure of haplotype blocks in the human genome. Science 296:2225-2229.         [ Links ]

Gentil P, de Lima Lins TC, Lima RM, de Abreu BS, Grattapaglia D, Bottaro M, de Oliveira RJ and Pereira RW (2009) Vitamin-D-receptor genotypes and bone-mineral density in postmenopausal women: Interaction with physical activity. J Aging Phys Act 17:31-45.         [ Links ]

Gentil P, Lima RM, Lins TC, Abreu BS, Pereira RW and Oliveira RJ (2007) Physical activity, Cdx-2 genotype, and BMD. Int J Sports Med 28:1065-1069.         [ Links ]

Gilsanz V, Skaggs DL, Kovanlikaya A, Sayre J, Loro ML, Kaufman F and Korenman SG (1998) Differential effect of race on the axial and appendicular skeletons of children. J Clin Endocrinol Metab 83:1420-1427.         [ Links ]

Goulart LR, Ferreira FR and Goulart IMB (2006) Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy. FEMS Immunol Med Microbiol 48:91-98.         [ Links ]

Hauache OM, Lazaretti-Castro M, Andreoni S, Gimeno SG, Brandão C, Ramalho AC, Kasamatsu TS, Kunii I, Hayashi LF, Dib SA et al. (1998) Vitamin D receptor gene polymorphism: Correlation with bone mineral density in a Brazilian population with insulin-dependent diabetes mellitus. Osteoporos Int 8:204-210.         [ Links ]

Jones Jr A, Shen W, St-Onge MP, Gallagher D, Heshka S, Wang Z and Heymsfield SB (2004) Body-composition differences between African American and white women: Relation to resting energy requirements. Am J Clin Nutr 79:780-786.         [ Links ]

Lazaretti-Castro M, Duarte-de-Oliveira MA, Russo EM and Vieira JG (1997) Vitamin D receptor alleles and bone mineral density in a normal premenopausal Brazilian female population. Braz J Med Biol Res 30:929-932.         [ Links ]

Lins TC, Nogueira LR, Lima RM, Gentil P, Oliveira RJ and Pereira RW (2007) A multiplex single-base extension protocol for genotyping Cdx2, FokI, BsmI, ApaI, and TaqI polymorphisms of the vitamin D receptor gene. Genet Mol Res 6:316-324.         [ Links ]

Lins TC, Abreu BS and Pereira RW (2009) TagSNP transferability and relative loss of variability prediction from HapMap to an admixed population. J Biomed Sci 16:73.         [ Links ]

Lins TC, Vieira RG, Abreu BS, Grattapaglia D and Pereira RW (2010) Genetic composition of Brazilian population samples based on a set of twenty-eight ancestry informative SNPs. Am J Hum Biol 22:187-192.         [ Links ]

Lips P (2007) Vitamin D status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol 103:620-625.         [ Links ]

Liu N, Sawyer SL, Mukherjee N, Pakstis AJ, Kidd JR, Kidd KK, Brookes AJ and Zhao H (2004) Haplotype block structures show significant variation among populations. Genet Epidemiol 27:385-400.         [ Links ]

Lohmueller KE, Wong LJ, Mauney MM, Jiang L, Felder RA, Jose PA and Williams SM (2006) Patterns of genetic variation in the hypertension candidate gene GRK4: Ethnic variation and haplotype structure. Ann Hum Genet 70:27-41.         [ Links ]

Maistro S, Snitcovsky I, Sarkis AS, da Silva IA and Brentani MM (2004) Vitamin D receptor polymorphisms and prostate cancer risk in Brazilian men. Int J Biol Markers 19:245-249.         [ Links ]

Marrero AR, Das Neves Leite FP, De Almeida Carvalho B, Peres LM, Kommers TC, Da Cruz IM, Salzano FM, Ruiz-Linares A, Da Silva Junior WA and Bortolini MC (2005) Heterogeneity of the genome ancestry of individuals classified as White in the state of Rio Grande do Sul, Brazil. Am J Hum Biol 17:496-506.         [ Links ]

Moraes MO, Santos AR, Schonkeren JJ, Vanderborght PR, Ottenhoff TH, Moraes ME, Moraes JR, Sampaio EP, Sarno EN and Huizinga TW (2003) Interleukin-10 promoter haplotypes are differently distributed in the Brazilian versus the Dutch population. Immunogenetics 54:896-899.         [ Links ]

Moreno Lima R, de Abreu BS, Gentil P, de Lima Lins TC, Grattapaglia D, Pereira RW and de Oliveira RJ (2007) Lack of association between vitamin D receptor genotypes and haplotypes with fat-free mass in postmenopausal Brazilian women. J Gerontol A Biol Sci Med Sci 62:966-972.         [ Links ]

Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN and Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284-287.         [ Links ]

Nakamoto K, Wang S, Jenison RD, Guo GL, Klaassen CD, Wan YJ and Zhong XB (2006) Linkage disequilibrium blocks, haplotype structure, and htSNPs of human CYP7A1 gene. BMC Genetics 7:29.         [ Links ]

Nejentsev S, Godfrey L, Snook H, Rance H, Nutland S, Walker NM, Lam AC, Guja C, Ionescu-Tirgoviste C, Undlien DE et al. (2004) Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene. Hum Mol Genet 13:1633-1639.         [ Links ]

Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM and Pena SD (2003) Color and genomic ancestry in Brazilians. Proc Natl Acad Sci USA 100:177-182.         [ Links ]

Pritchard JK and Donnelly P (2001) Case-control studies of association in structured or admixed populations. Theor Popul Biol 60:227-237.         [ Links ]

Purcell S, Daly MJ and Sham PC (2007) WHAP: Haplotype-based association analysis. Bioinformatics 23:255-256.         [ Links ]

Rezende VB, Barbosa Jr F, Montenegro MF, Sandrim VC, Gerlach RF and Tanus-Santos JE (2007) An interethnic comparison of the distribution of vitamin D receptor genotypes and haplotypes. Clin Chim Acta 384:155-159.         [ Links ]

Rosenberg NA and Nordborg M (2006) A general population-genetic model for the production by population structure of spurious genotype-phenotype associations in discrete, admixed or spatially distributed populations. Genetics 173:1665-1678.         [ Links ]

Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA and Feldman MW (2002) Genetic structure of human populations. Science 298:2381-2385.         [ Links ]

Sawyer SL, Mukherjee N, Pakstis AJ, Feuk L, Kidd JR, Brookes AJ and Kidd KK (2005) Linkage disequilibrium patterns vary substantially among populations. Eur J Hum Genet 13:677-686.         [ Links ]

Shaffer JR, Kammerer CM, Reich D, McDonald G, Patterson N, Goodpaster B, Bauer DC, Li J, Newman AB, Cauley JA et al. (2007) Genetic markers for ancestry are correlated with body composition traits in older African Americans. Osteoporos Int 18:733-741.         [ Links ]

Stephens M and Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162-1169.         [ Links ]

Suarez-Kurtz G, Perini JA, Bastos-Rodrigues L, Pena SD and Struchiner C (2007) Impact of population admixture on the distribution of the CYP3A5*3 polymorphism. Pharmacogenomics 8:1299-1306.         [ Links ]

Tang H, Coram M, Wang P, Zhu X and Risch N (2006) Reconstructing genetic ancestry blocks in admixed individuals. Am J Hum Genet 79:1-12.         [ Links ]

Thakkinstian A, D'Este C and Attia J (2004) Haplotype analysis of VDR gene polymorphisms: A meta-analysis. Osteoporos Int 15:729-734.         [ Links ]

Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA and Van Leeuwen JP (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338:143-156.         [ Links ]

Valdivielso JM and Fernandez E (2006) Vitamin D receptor polymorphisms and diseases. Clin Chim Acta 371:1-12.         [ Links ]

Ziv E and Burchard EG (2003) Human population structure and genetic association studies. Pharmacogenomics 4:431-441.         [ Links ]

 

Internet Resources

Primer3, http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www. cgi.         [ Links ]

 

 

Send correspondence to:
Rinaldo Wellerson Pereira
Universidade Católica de Brasília
SGAN 916, módulo B, bloco C, 2° andar, sala S-220, Asa Norte
70790-160 Brasília, DF, Brazil
E-mail: rinaldo@pos.ucb.br

Received: February 7, 2011; Accepted: April 27, 2011.

 

 

Associate Editor: Francisco Mauro Salzano
License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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