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Vitamin D receptor gene polymorphisms and susceptibility for primary osteoarthritis of the knee in a Latin American population

Advances in Rheumatology volume 58, Article number: 6 (2018) Cite this article

Abstract

Background

Primary Osteoarthritis (OA) of the knee is a multifactorial disease that has an important genetic component, and several genes have been associated with its development. The vitamin D receptor has a role in skeletal metabolism that suggests a relationship with OA. The aim of this study was to analyze the association of Vitamin D receptor gene (VDR) polymorphisms in Mexican Mestizo patients.

Methods

A case-control study was conducted in which 107 cases with primary OA of the knee and 114 controls were included. Cases were patients > 40 years of age with a Body mass index (BMI) of ≤27 and a radiological score for OA of the knee of ≥2. Controls were subjects > 40 years of age with a radiological score of < 2. VDR polymorphisms rs1544410, rs7975232, and rs731236 were analyzed by means of restriction endonucleases, and logistic regression was developed to evaluate risk magnitude.

Results

A significantly increased risk was found of nearly two-fold for the allele T and TT genotypes of rs731236, independently of other well recognized risk factors.

Conclusions

The rs731236 polymorphism is associated with the risk of primary OA of the knee in Mexican Mestizo population.

Background

Osteoarthritis (OA) is the most frequent form of arthritis and is a leading cause of musculoskeletal disability worldwide. The World Health Organization (WHO) estimates that approximately 10% of the world’s population aged ≥60 years have symptomatic OA and that it is the fourth leading cause of Years lived with disability (YLD) [1, 2]. OA can occur in any joint, but the knee is the most common site involved; in fact, it is considered that 6% of adults can be affected and that this is one of the most common reasons for total joint replacement [3,4,5]. OA is characterized by progressive degeneration of articular cartilage in synovial joints, resulting in joint space narrowing, osteophyte formation, and subchondral sclerosis, which is clinically translated as pain and joint stiffness [4, 5].

OA is a multifactorial disease in which genetics and environmental factors, such as aging, gender, obesity, significant trauma, occupation, and sports activities, among others, are strongly related with its development [4, 5]. It is classified as primary when no discernible cause is evident and secondary when a triggering factor is apparent. Primary OA possess a strong genetic component, as demonstrated by several twin and family studies, which have demonstrated 39–65% heritability (h2) and an increased risk for OA of up to 14-fold in first-degree relatives of probands with OA [6, 7]. On the other hand, genetic association studies have demonstrated that primary OA is associated with several genes related to different molecular pathways or classes of molecules such as inflammation, Extracellular matrix (ECM) molecules, Wnt signaling, Bone morphogenetic proteins, proteases or their inhibitors, and genes related with modulation of osteocyte or chondrocyte differentiation [6, 7].

The Vitamin D receptor plays an important role in skeletal metabolism because this acts as an important regulator of calcium metabolism and bone cell function; therefore, its abnormalities are probably related with OA [8]. The vitamin D receptor gene (VDR) is located on chromosome 12q13.11, contains 11 exons, and spans approximately 75 kb. The gene contains several polymorphisms, and three have been frequently studied for determining an association in OA: rs1544410 and rs7975232 in intron 8, and the synonymous variant rs731236 in exon 9 [9,10,11]. With regard to primary OA of the knee, some reports have shown an association in the presence of these VDR polymorphisms [12,13,14], however, this has not always been confirmed [15,16,17,18]. A meta-analysis on the three most frequently studied VDR polymorphisms in OA analyzed Asian and European studies; however, the results showed no association in all study subjects, as well as by stratification by ethnicity [19]. An updated meta-analysis, showed a significant association between the A allele and AA genotype of the rs7975232 with OA in Asian population, but not in the whole population [20]. Because genetic associations could vary among populations and because there are no association studies on VDR and OA in Latin-American populations, our aim was to analyze the association of the three VDR polymorphisms in Mexican Mestizo patients.

Methods

Subjects

We conducted a case-control study whose protocol was approved by the Ethics and Investigation Committee of the National Rehabilitation Institute, a tertiary-care referral center in Mexico City. All of the participants were recruited at the Articular Rehabilitation Clinic and were of Mexican Mestizo origin, the latter defined as a person born in Mexico, with a Spanish-derived last name, and with a family of Mexican ancestors back to the third generation [21]. Cases included persons aged > 40 years with a clinical diagnosis of OA and a radiologic score of ≥2 for OA of the knee, with a Body mass index (BMI, kg/m2) of ≤27, with no history of serious injuries or knee surgeries, and with no other articular diseases. Controls were subjects aged > 40 years without a clinical diagnosis of OA of the knee, with a radiologic score of < 2, and with no history of serious knee injuries or diseases of the joints. All controls arrived at the clinic mainly due to orthopedic problems, such as shoulder lesions or fractures, or orthopedic problems not involving serious knee damage. Radiological evaluation of all participants was performed by a sole trained observer who was blinded to the patients’ diagnosis. Grading of OA was assessed using a 5-point scale according to the Kellgren-Lawrence radiographic-classification grading method in anteroposterior weight-bearing and lateral x-rays of the knees [22]. To perform a more efficient classification of cases and controls and to identify possible co-variables or confounders, all study subjects were interviewed by application of a questionnaire designed specifically for this study in order to collect information regarding general, occupational, and sports activities, possible knee injuries, and clinical manifestations of OA, among others.

Genotyping

After obtaining signed informed consent, a 5-ml blood sample was drawn from each patient into tubes containing EDTA. Peripheral blood mononuclear cells were isolated, and DNA was extracted utilizing a salting out method. The genotype for three polymorphisms of the VDR was determined by Polymerase-chain-reaction (PCR) amplification and enzymatic digestion of the products using the primer pair listed previously [23]. The forward primer was the same for all three polymorphisms: 5´-CAACCAAGACTACAAGTACCGCGTCAGTGA-3′. For rs7975232 and rs731236 polymorphisms, the reverse primer was 5´-CACTTCGAGCACAAGGGGCGTTAGC-3′; and for rs1544410 was 5´-AACCAGCGGGAAGAGGTCAAGGG-3′. PCR was performed with a Gene Amp PCR system 9700 PE Applied Biosystems under standard conditions. Briefly, for fragment amplification 1X buffer solution was used (KCl 50 mM, Tris-HCl 20 mM pH 8.4), 0.6 mM DNTP, 0.5 μM of each primer, 4 mM MgCl2, 2.5 U Taq polymerase, and 250 ng genomic DNA, for a final volume reaction of 50 μL. A thermal profile was optimized as follows: 94 °C for 5 min for initial denaturation, followed by 28 cycles at 94 °C for 1 min, at 65 °C for 1 min, at 72 °C for 1 min, and 5 min at 72 °C for final extension. Subsequently, one microgram of the PCR product was digested with an excess of the endonucleases under conditions specified by the supplier (New England Biolabs, Inc., Beverly, MA, USA) and was electrophoresed on 1.5% ethidium- stained agarose gels. Information of Single Nucleotide Polymorphism (SNP) and product size after digestion with endonucleases is shown in Table 1.

Table 1 Information of the three single nucleotide polymorphisms of VDR gene
Full size table

Statistical analysis

Comparisons of continuous variables were tested by the Student t test, and corrected chi-squared statistics (x2) were applied for categorical variables. Uni- and multivariate non-conditional logistic regression analyses were conducted to estimate probability for developing OA, comparing genotypes as main effect; Odds ratios and 95% Confidence intervals [OR (95% CI)] were reported. Alpha level was 0.05. Hardy-Weinberg equilibrium (HWE) was assessed for VDR polymorphisms by means of the chi-squared test, and the STATA ver.10.0 statistical software package and Haplo View 4.0 were utilized for calculations.

Results

The characteristics of the study population are shown in Table 2. We observed statistically significant differences in mean age and in previous sport-activity frequency (p = 0.00001 and 0.004; respectively).

Table 2 General characteristics of the study population
Full size table

The SNPs rs1544410 and rs7975232 were not in HWE (Table 1) and their allelic and genotypic frequencies did not showed significant differences between the study groups (Tables 1 and 3). Only rs731236 was in HWE, and its C and T alleles showed statistically significant differences [OR (95% CI) = 0.6 (0.4–1.0) and 1.6 (1.0–2.6); respectively]. In regard to its genotypes, CT genotype suggested a protective factor [OR (95%CI) = 0.5 (0.3–0.9)], and TT genotype exhibited an increased risk with an OR (95%CI) of 1.96 (1.1–3.4) (Table 3). For multivariate analysis two models were constructed, and the risk trends for CT and TT genotypes were maintained when these results were adjusted for gender, age, BMI, and previous sport activity (Table 4).

Table 3 Allelic and genotype association testing results of rs1544410, rs7975232, and rs731236 in VDR for Mexican cases with osteoarthritis of the knee and controls
Full size table
Table 4 Multivariate analysis results of rs731236 for Mexican cases with osteoarthritis of the knee and controls
Full size table

Discussion

VDR polymorphisms are probably among those most studied for a genetic association in OA; however, there is no consistency in the results [12,13,14,15,16,17,18]. Even in the meta-analyses, there is no agreement in their findings [19, 20]. Those studies could entertain some limitations, because of the absence of analysis by OA site, since it is important to consider that associations in OA appear to be joint-specific, as suggested by association studies [6, 24] and supported by functional analyses [25]. Therefore, the genetic associations in OA of the knee should be analyzed independently of other anatomic sites. Our findings suggest that there is an association between the rs731236 polymorphism and knee OA in this Mexican Mestizo population, conferring an increased risk of nearly two-fold in the presence of T allele and TT genotype independently of other well recognized risk factors such as age, gender, BMI, and sport activities.

The rs731236 is a synonymous polymorphism located in the coding sequence and exerts no effect in the encoded protein [10, 11]. However, a functional effect of this polymorphism is suggested by studies in which homozygous TT were associated with low VDR messenger RNA (mRNA) levels, and with low serum vitamin D level in some types of cancer [26, 27]. Interestingly, Subjects with low serum levels of vitamin D had a 3-fold increased risk for progression of OA of the knee [28]. Moreover, the activity of Matrix metalloproteinases (MMP) in the growth plate chondrocyte is regulated by vitamin D [29], and low levels of vitamin D increase MMP activities [30], which contributes to cartilage degradation, the hallmark in OA [4, 5].

On the other hand, it is possible that the rs731236 reflects a real association with other genes located in the same chromosomal region, such as Collagen type II alpha 1 chain (COL2A1), which is localized at a distance of 20 kb upstream [31]. Indeed, previously an association of COL2A1 polymorphisms with knee OA was observed [32]. Or Histone deacetylase 7 (HADC7), at 10 kb downstream, which although there are not association studies with HDAC7 polymorphisms, its increased expression in the cartilage of patients with OA suggests that it may contribute to cartilage degradation [33].

VDR polymorphisms have been analyzed in different ethnic groups and differences in allele frequencies have been noted [11]; this could be due to population stratification and could explain the inconsistency in the results. For case-control genetic-association studies, this is a matter of concern because it has been suggested that the existence of genetic subgroups in a population may lead to spurious associations [34]. To control this genetic confounder, ancestry informative markers are suggested to be analyzed to avoid bias [35]. Mexican Mestizos are an admixed population [36], therefore, a possible weakness in this work is that ethnicity was determined only by self-reported family ancestry and by family history. However, the degree to which population stratification has caused confounding remains controversial [37, 38], and it has been suggested that this should not be a major confounder and that self-reported ethnicity may be sufficient to resolve that bias [38, 39]. In fact, it have been demonstrated that self-identified ethnicity correlate well with ancestral markers [40, 41]. Additionally, it is also important to consider that our controls were originated from the same geographic regions of the country as that of cases, and that the allele associated with primary OA of the knee follows HWE. This may indicate that allele frequency is not affected by inbreeding, mutation, natural selection, migration, or even population stratification [42]. Thus, spurious associations resulting from the presence of genetically different strata in our study sample are unlikely.

We are aware that being a hospital-based case-control study, it is exposed to incurring in selection bias. Therefore, to assess cases with primary OA of the knee as close as possible, the variables considerably associated with the development of secondary OA were strictly controlled during study-subject recruitment. Therefore, we think that the possibility of selection bias in our sample is low. Additionally, other potential confounders were controlled during statistical analyses, through multivariate analysis because this protects against population structure and limits the number of false positives [43]. In that sense, variables with significant differences during univariate analysis did not exhibit an effect on risk magnitude during multivariate analysis.

We recognize that our main limitation comprises sample size. However, we attempted to increase our internal validity by strictly controlling possible confounder variables through selection criteria and multivariate analysis, and we consider that our cases are truly primary OA of the knees. Finally, it is important to consider that association studies in diverse ethnic groups worldwide, especially those with a complex admixture of ancestral populations such as Latin-American populations, are a powerful resource for analyzing the genetic bases of complex diseases [44]; therefore, genetic association studies in Latino Americans would provide a better appreciation of the genetic contributions to primary OA.

Conclusions

According to the findings of this study, the rs731236 polymorphism is associated with the risk of primary OA of the knee in Mexican Mestizo population.

Abbreviations

BMI:

Body mass index

COL2A1 :

Collagen type II alpha 1 chain gene

ECM:

Extracellular matrix

HADC7 :

Histone deacetylase 7 gene

HWE:

Hardy-Weinberg equilibrium

MMP:

Matrix metalloproteinases

mRNA:

messenger RNA

OA:

Osteoarthritis

OR (95% CI):

Odds ratios (95% Confidence intervals)

PCR:

Polymerase-chain-reaction

SNP:

Single Nucleotide Polymorphism

VDR :

Vitamin D receptor gene

WHO:

World Health Organization

YLD:

Years lived with disability

References

  1. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81:646–56.

    PubMed  PubMed Central  Google Scholar 

  2. Haq SA, Davatchi F. Osteoarthritis of the knees in the COPCORD world. Int J Rheum Dis. 2011;14:122–9.

    Article  PubMed  Google Scholar 

  3. Weinstein AM, Rome BN, Reichmann WM, Collins JE, Burbine SA, Thornhill TS, et al. Estimating the burden of total knee replacement in the United States. J Bone Joint Surg Am. 2013;95:385–92.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Michael JW, Schlüter-Brust KU, Eysel P. The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee. Dtsch Arztebl Int. 2010;107:152–62.

    PubMed  PubMed Central  Google Scholar 

  5. Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol. 2014;28:5–15.

    Article  PubMed  Google Scholar 

  6. Valdes AM, Spector TD. Genetic epidemiology of hip and knee osteoarthritis. Nat Rev Rheumatol. 2011;7:23–32.

    Article  PubMed  Google Scholar 

  7. Loughlin J. Genetic contribution to osteoarthritis development: current state of evidence. Curr Opin Rheumatol. 2015;27:284–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Colombini A, Cauci S, Lombardi G, Lanteri P, Croiset S, Brayda-Bruno M, et al. Relationship between vitamin D receptor gene (VDR) polymorphisms, vitamin D status, osteoarthritis and intervertebral disc degeneration. J Steroid Biochem Mol Biol. 2013;138:24–40.

    Article  PubMed  CAS  Google Scholar 

  9. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A. 1988;85:3294–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, et al. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol. 1997;11:1165–79.

    Article  PubMed  CAS  Google Scholar 

  11. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338:143–56.

    Article  PubMed  CAS  Google Scholar 

  12. Uitterlinden AG, Burger H, Huang Q, Odding E, Duijn CM, Hofman A, et al. Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee. J Clin Invest. 1997;100:259–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Keen RW, Hart DJ, Lanchbury JS, Spector TD. Association of early osteoarthritis of the knee with a Taq I polymorphism of the vitamin D receptor gene. Arthritis Rheum. 1997;40:1444–9.

    Article  PubMed  CAS  Google Scholar 

  14. Uitterlinden AG, Burger H, van Duijn CM, Huang Q, Hofman A, Birkenhäger JC, et al. Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee. Arthritis Rheum. 2000;43:1456–64.

    Article  PubMed  CAS  Google Scholar 

  15. Loughlin J, Sinsheimer JS, Mustafa Z, Carr AJ, Clipsham K, Bloomfield VA, et al. Association analysis of the vitamin D receptor gene, the type I collagen gene COL1A1, and the estrogen receptor gene in idiopathic osteoarthritis. J Rheumatol. 2000;27:779–84.

    PubMed  CAS  Google Scholar 

  16. Huang J, Ushiyama T, Inoue K, Kawasaki T, Hukuda S. Vitamin D receptor gene polymorphisms and osteoarthritis of the hand, hip, and knee: a case-control study in Japan. Rheumatology. 2000;39:79–84.

    Article  PubMed  CAS  Google Scholar 

  17. Baldwin CT, Cupples LA, Joost O, Demissie S, Chaisson C, Mcalindon T, et al. Absence of linkage or association for osteoarthritis with the vitamin D receptor/type II collagen locus: the Framingham Osteoarthritis Study. J Rheumatol. 2002;29:161–5.

    PubMed  CAS  Google Scholar 

  18. Muraki S, Dennison E, Jameson K, Boucher BJ, Akune T, Yoshimura N, et al. Association of vitamin D status with knee pain and radiographic knee osteoarthritis. Osteoarthr Cartil. 2011;19:1301–6.

    Article  PubMed  CAS  Google Scholar 

  19. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Vitamin D receptor TaqI, BsmI and ApaI polymorphisms and osteoarthritis susceptibility: a meta-analysis. Joint Bone Spine. 2009;76:156–61.

    Article  PubMed  CAS  Google Scholar 

  20. Zhu ZH, Jin XZ, Zhang W, Chen M, Ye DQ, Zhai Y, et al. Associations between vitamin D receptor gene polymorphisms and osteoarthritis: an updated meta-analysis. Rheumatology. 2014;53:998–1008.

    Article  PubMed  CAS  Google Scholar 

  21. Gorodezky C, Aláez C, Vázquez-García MN, de la Rosa G, Infante E, Balladares S, et al. The genetic structure of Mexican Mestizos of different locations: tracking back their origins through MHC genes, blood group systems, and microsatellites. Hum Immunol. 2001;62:979–91.

    Article  PubMed  CAS  Google Scholar 

  22. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16:494–502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yokoyama K, Shigematsu T, Tsukada T, Ogura Y, Takemoto F, Hara S, et al. Apa I polymorphism in the vitamin D receptor gene may affect the parathyroid response in Japanese with end-stage renal disease. Kidney Int. 1998;53:454–8.

    Article  PubMed  CAS  Google Scholar 

  24. Reynard LN, Loughlin J. The genetics and functional analysis of primary osteoarthritis susceptibility. Expert Rev Mol Med. 2013;15:e2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Xu Y, Barter MJ, Swan DC, Rankin KS, Rowan AD, Santibanez-Koref M, et al. Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA. Osteoarthr Cartilage. 2012;20:1029–38.

    Article  CAS  Google Scholar 

  26. Carling T, Rastad J, Åkerström G, Westin G. Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors. J Clin Endocrinol Metab. 1998;83:2255–9.

    PubMed  CAS  Google Scholar 

  27. Yaylim-Eraltan I, Arzu Ergen H, Arikan S, Okay E, Oztürk O, Bayrak S, et al. Investigation of the VDR gene polymorphisms association with susceptibility to colorectal cancer. Cell Biochem Funct. 2007;25:731–7.

    Article  PubMed  CAS  Google Scholar 

  28. McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham study. Ann Intern Med. 1996;125:353–9.

    Article  PubMed  CAS  Google Scholar 

  29. Boyan BD, Schwartz Z. 1,25-Dihydroxy vitamin D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60-activated matrix vesicle matrix metalloproteinases. Cells Tissues Organs. 2009;189:70–4.

    Article  PubMed  CAS  Google Scholar 

  30. Dean DD, Schwartz Z, Schmitz J, Muniz OE, Lu Y, Calderon F, et al. Vitamin D regulation of metalloproteinase activity in matrix vesicles. Connect Tissue Res. 1996;35:331–6.

    Article  PubMed  CAS  Google Scholar 

  31. Fang Y, van Meurs JB, d’Alesio A, et al. Promoter and 3′-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the Rotterdam study. Am J Hum Genet. 2005;77:807–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Gálvez-Rosas A, González-Huerta C, Borgonio-Cuadra VM, Duarte-Salazár C, Lara-Alvarado L, de los Angeles Soria-Bastida M, et al. A COL2A1 gene polymorphism is related with advanced stages of osteoarthritis of the knee in Mexican Mestizo population. Rheumatol Int. 2010;30:1035–9.

    Article  PubMed  CAS  Google Scholar 

  33. Higashiyama R, Miyaki S, Yamashita S, Yoshitaka T, Lindman G, Ito Y, et al. Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod Rheumatol. 2010;20:11–7.

    Article  PubMed  CAS  Google Scholar 

  34. Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:2037–48.

    Article  PubMed  CAS  Google Scholar 

  35. Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet. 2003;361:598–604.

    Article  PubMed  Google Scholar 

  36. Moreno-Estrada A, Gignoux CR, Fernández-López JC, Zakharia F, Sikora M, Contreras AV, et al. Human genetics. The genetics of Mexico recapitulates native American substructure and affects biomedical traits. Science. 2014;344:1280–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Thomas DC, Witte JS. Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomark Prev. 2002;11:505–12.

    Google Scholar 

  38. Wacholder S, Rothman N, Caporaso N. Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomark Prev. 2002;11:513–20.

    Google Scholar 

  39. Barnholtz-Sloan JS, McEvoy B, Shriver MD, Rebbeck TR. Ancestry estimation and correction for population stratification in molecular epidemiologic association studies. Cancer Epidemiol Biomark Prev. 2008;17:471–7.

    Article  CAS  Google Scholar 

  40. Tang H, Quertermous T, Rodríguez B, Kardia SL, Zhu X, Brown A, et al. Genetic structure, self identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet. 2005;76:268–75.

    Article  PubMed  CAS  Google Scholar 

  41. Yaeger R, Ávila-Bront A, Abdul K, Nolan PC, Grann VR, Birchette MG, et al. Comparing genetic ancestry and self-described race in African Americans born in the United States and in Africa. Cancer Epidemiol Biomark Prev. 2008;17:1329–38.

    Article  CAS  Google Scholar 

  42. Rodríguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–14.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Setakis E, Stirnadel H, Balding DJ. Logistic regression protects against population structure in genetic association studies. Genome Res. 2006;16:290–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. González-Burchard E, Borrell LN, Choudhry S, Naqvi M, Tsai HJ, Rodriguez-Santana JR, et al. Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research. Am J Public Health. 2005;95:2161–8.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Departments of Genetics, Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”, Calzada México-Xochimilco No. 289, Arenal Guadalupe, Tlalpan, CP 14389, México City, Mexico

    Norma Celia González-Huerta, Verónica Marusa Borgonio-Cuadra & Antonio Miranda-Duarte

  2. Departments of Radiology, Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”, Calzada México-Xochimilco No. 289, Arenal Guadalupe, Tlalpan, CP 14389, México City, Mexico

    Eugenio Morales-Hernández

  3. Departments of Rheumatology, Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”, Calzada México-Xochimilco No. 289, Arenal Guadalupe, Tlalpan, CP 14389, México City, Mexico

    Carolina Duarte-Salazar

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Contributions

Concept and Study design: NCG-H, VMB-C and AM-D. Data acquisition: NCG-H, VMB-C, EM-H, CD-S. Data analysis, manuscript preparation: AM-D. All authors read and approved the final manuscript.

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Correspondence to Antonio Miranda-Duarte.

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González-Huerta, N.C., Borgonio-Cuadra, V.M., Morales-Hernández, E. et al. Vitamin D receptor gene polymorphisms and susceptibility for primary osteoarthritis of the knee in a Latin American population. Adv Rheumatol 58, 6 (2018). https://doi.org/10.1186/s42358-018-0002-3

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Advances in Rheumatology

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