- Research article
- Open Access
- Open Peer Review
The genetic variants at the HLA-DRB1 gene are associated with primary IgA nephropathy in Han Chinese
© Jiyun et al.; licensee BioMed Central Ltd. 2012
- Received: 23 September 2011
- Accepted: 14 May 2012
- Published: 14 May 2012
Immunoglobulin A nephropathy (IgAN), an immune-complex-mediated glomerulonephritis defined immunohistologically by the presence of glomerular IgA deposits, is the most common primary glomerular disease worldwide and a significant cause of end-stage renal disease. Familial clustering of patients with IgAN suggests a genetic predisposition.
In this study, 192 patients with IgAN and 192 normal controls in the Sichuan cohort and 935 patients with IgAN and 2,103 normal controls in the Beijing cohort were investigated. HLA-DRB1*01–DRB1*10 specificities were genotyped by the PCR–SSP technique in both cohorts. Based on the HLA-DRB1*04-positive results, the subtypes of HLA-DRB1*04 were analyzed using sequencing-based typing (SBT) in 291 IgAN cases and 420 matched controls.
The frequency of HLA-DRB1*04 in the IgAN group was significantly higher than that in the control group (0.129 vs. 0.092, P = 8.29 × 10-5, odds ratio (OR) =1.381, 95% confidence interval (CI) 1.178–1.619). Other alleles at the HLA-DRB1 locus were observed with no significant differences between the case and control groups. The dominant alleles of the HLA-DRB1*04 subtypes were DRB1*0405 in both cohorts. The frequencies of HLA-DRB1*0405 and 0403 were significantly increased in the patients compared to healthy subjects.
HLA-DRB1*04 was significantly associated with primary IgAN in Chinese population. This result implies that HLA-DRB1 gene plays a major role in primary IgAN.
- IgA nephropathy
- Association study
Immunoglobulin A nephropathy (IgAN), an immune-complex-mediated glomerulonephritis defined immunohistologically by the presence of glomerular IgA deposits, is the most common primary glomerular disease worldwide and a significant cause of end-stage renal disease . The pathogenesis of IgAN remains poorly understood, and its treatment is limited. No consistent infectious or environmental agent has been identified as responsible for the IgA-antibody response. However, familial aggregation of patients with IgAN suggests that genetic factors contribute to the development of this disease . Previous genome-wide linkage studies of multiplex families with IgAN have identified four loci with significant linkage on 6q22, 2q36, 4q26–31, and 17q12–22 [3–5]. Unfortunately, to date, no disease-specific genes linked to the loci have been identified within the linkage intervals. However, susceptibility to primary IgAN has been associated with single-nucleotide polymorphisms (SNPs) in the E-selectin and L-selectin genes, HLA-DRA, C1GalT1, and ST6GALNAC2, as well as in the PIGR gene [6–12]. Moreover, polymorphisms of the ACE and AGT genes have been associated with progression to chronic renal failure in patients with primary IgAN [13, 14].
The primary function of the human leukocyte antigen (HLA) system is to regulate the immune response. MHC Class II molecules are important determinants of the IgA-mediated immune response, and the susceptibility alleles for several autoimmune diseases have now been located in the Class II region. In Caucasian patients with primary IgAN, a significant increase in the HLA-DQw7 allele frequency has been observed . However, DQ alleles showed no consistent association with IgAN in different populations. In British patients, a decreased frequency of DQBI*0201 was observed, in Finnish patients a decreased frequency of DQB1*0602 was observed, and in Italian patients, no association between DQ markers and IgAN was found . Earlier studies have shown that HLA-DR4 might be associated with IgAN in Japanese [17–19]. However, no association between IgAN and HLA-A, B, C, DR, and DQ was found in a Chinese Taiwanese population .
On the other hand, in the Italian population with a family history of primary IgAN, there was an increased incidence of HLA-DRB1*08 compared to those with sporadic primary IgAN . In the present study, we investigated the association between the genetic variants at the HLA-DRB1 gene and primary IgAN in Han Chinese population.
Patients and controls
Characteristics of primary IgAN cases and controls matched for age and ethnicity
32.07 ± 9.77
63.19 ± 9.14
31.18 ± 10.98
49.21 ± 16.02
HLA-DRB1 genotyping using PCR–SSP
The genotyping for HLA-DRB1 was performed using PCR–SSP as described previously . The PCR amplifications were performed at 94°C or 1 min followed by 30 cycles, and the amplification conditions were different depending on HLA-DRB1*01–DRB1*10 specificities . The β-actin gene was used as an internal control to ensure that the enzymatic in vitro DNA amplification process had worked in each tube.
HLA-DRB1*04 subtypes detected by DNA sequencing-based typing (SBT)
The HLA-DRB1*04-positive samples, composed of 291 cases and 420 controls, were selected from the Sichuan cohort and the Beijing cohort by HLA-DRB1*01–DRB1*10 specificities. The subtypes of HLA-DRB1*04 were further analyzed in the HLA-DRB1*04-positive samples, as described previously . The following primers were used to amplify exon 2 of the HLA-DRB1 gene: forward, 5′- CAggAAACAgCTATgACCTgAgACgCACgTTTCTTggAgCAggTTAAAC-3′; and reverse, 5′- TgTAAAACgACggCCAgTgCTYACCTCgCCKCTgCAC -3′. The PCR amplification protocols for exon 2 of the HLA-DRB1 gene were identical and consisted of an initial denaturation at 95°C for 15 min, followed by 30 cycles at 95°C for 20 s, 62°Cfor 10 s, and 72°C for 90 s. The PCR products were purified with the ExoSAP-IT® (USB Corporation) and sequenced employing ABI BigDye chemistry (Applied Biosystems). The following primers were used as sequencing primers: M13F, 5′- CAggAAACAgCTATgACC-3′; and M13R, 5′- TgTAAAACgACggCCAgT-3′. The samples were sequenced using the ABI PRISM 310 Genetic Analyzer (Applied Biosystems). uTYPETM SBT software was used to process the DNA sequence files for analysis and HLA-DRB1*04 alleles’ assignment.
The frequency distribution of the HLA-DRB1 and HLA-DRB1*04 subtype alleles in the patient and normal control groups was compared using a Fisher’s exact test. Stratified analysis was performed using Cochran-Mantel-Haenszel method. The IgAN patients were classified into different subgroups for the purpose of studying the association of HLA-DRB1*04 alleles with clinical factors of patients by gender, blood pressure (according to the standard of hypertension of WHO-ISH in 1999), 24-h content of urine protein (≥3.5 or <3.5 g/24 h), serum creatinine level (≤120 or >120 μmol/l), hematuria (positive or negative), eGFR (≥60 or <60 ml/min/1.73 m2), and glomeruloscerosis (positive or negative). The strength of an association with alleles and genotypes was indicated by an odds ratio (OR) with a 95% confidence interval (CI) and P value. P value <0.05 was defined as statistically significant. SPSS version 13.0 for Windows was used for all statistical analyses.
The frequencies of HLA-DRB1 alleles in primary IgAN patients and healthy controls
A comparison of the frequencies of HLA-DRB1 alleles in primary IgAN patients and healthy controls from the Sichuan cohort
Case (n = 192)
(n = 192)
2.35 × 10-3
A comparison of the frequencies of HLA-DRB1*04 in primary IgAN patients and healthy controls of different cohorts
Han Chinese in the Sichuan cohorta
2.35 × 10-3
Han Chinese in the Beijing cohorta
2.67 × 10-3
Both cohorts combinedb
8.29 × 10-5
Frequency of HLA-DRB1*04 subtypes in primary IgAN patients and healthy controls
A comparison of the frequencies of HLA-DRB1*04 subtypes in primary IgAN patients and healthy controls of Han Chinese descent
Case (n = 935 × 2)
(n = 2088 × 2)
2.088 × 10-4
5.225 × 10-7
The association of HLA-DRB1*04 alleles and its subtypes with clinical factors in primary IgAN patients
The association of HLA-DRB1*04 alleles with clinical and pathological parameters of primary IgAN patients
(n = 1104)
(n = 1079)
(n = 1061)
Upro (g/24Hr) (n = 1056)
Blood pressure (n = 1076)
eGFR, ml/min/1.73 m2 (n = 1079)
Glomeruloscerosis (n = 1079)
Previous studies have demonstrated that the HLA loci are associated with IgAN in different populations but not consistent with any alleles [1, 15–20, 24]. A family-based and case–control association study using the genome-wide association study (GWAS) approach suggested that the HLA region contains the strongest common susceptibility alleles of primary IgAN in a small European cohort . HLA Imputation Analysis shows that the HLA-B, DRB1, DQA, and DQB loci are associated with IgAN, and the strongest association was observed at the HLA-DQ locus in the study . Recently, a GWAS for primary IgAN identified three independent loci in the major histocompatibility complex in a cohort of 3,144 primary IgAN cases of Chinese and European ancestry. The study showed that 27 SNPs exceeding genome-wide thresholds for significance were located in a 0.54-Mb interval within the MHC. Imputation of classical HLA alleles showed that the strongest association was located within a ~170-kb interval that includes HLA-DRB1, HLA-DQA1, and HLA-DQB1 . This further indicated that the HLA-DRB1 region is one of the major primary IgAN susceptibility loci.
The HLA-DRB1 locus is, by far, the most polymorphic MHC class II locus and has more than 540 alleles . Previous studies have found a significant association between IgAN and the HLA-DRB1 alleles in a Japanese population [17, 19, 28]. Recently, a study showed that HLA-DRB1 polymorphisms were related to the occurrence and disease progression of Han Chinese patients with primary IgAN. HLA-DRB1*140501 was reported to be a susceptible allele, and HLA-DRB1*070101 was reported to be a resistant allele. HLA-DRB1*030101 may serve as a predictor of disease progression and renal damage of primary IgAN in Han Chinese . However, previous studies did not substantiate the conclusion that HLA-DRB1 was significantly associated with IgAN because a small number of samples were included in these studies and there was no association between the HLA-DR antigen and primary IgAN in Taiwanese Chinese . In our studies, all of these samples were pre-typed at a low resolution using PCR –SSP, which provided information on the HLA-DRB1 alleles at serological recognition. Then, we typed the HLA-DRB1*04 subtype alleles using a high resolution sequence-based HLA-DRB1 typing of Exon 2. Compared with HLA-DRB1 typing using the SBT approach for these samples, it took less time and money to determine the allele frequencies of HLA-DRB1 using a two-stage typing approach combined with PCR-SSP and SBT. We further confirmed that the genetic variants at the HLA-DRB1 gene were significantly associated with IgAN in a large Han Chinese cohort composed of 1,127 cases and 2,295 controls. However, since our approach does not distinguish between the alleles DRB1*11 and *12, DRB1*13 and *14 and DRB1*15 and *16, it could be missing the true associations between other HLA-DRB1 alleles as well. In addition, the IgAN GWAS study demonstrated a strong protective effect of the DRB1*15 allele (OR=0.61, P=10-6) and potentially of other DRB1 alleles .
As for diseases of polygenic inheritance, there are different disease susceptibility genes in different populations. Primary IgAN, defined as predominant IgA mesangial deposits in the absence of clinical or laboratory evidence of other associated systemic diseases, has also been proposed to include at least two distinct clinical entities (those with and without macroscopic hematuria) [1, 30, 31], which may be determined by different susceptibility genes. Therefore, heterogeneity between populations may account for some of the controversy in HLA associations with IgAN.
The allelic frequency and diversity of HLA-DRB1 among different populations emphasizes the need for research using matched patient and control groups in genetic association studies. Some reports indicate that the population of Metropolitan Beijing, in the northern part of China, includes a mixture of individuals from both the northern and central provinces. However, these reports have also found that there are few people from the southern region. In addition, the reports indicate that the population mix of the Sichuan province, considered representative of southern China, could in fact have been affected by the mass migrations during the late Ming and early Qing dynasties. At those times, people came to Sichuan from both the southern and the central regions, such as Hunan and Hubei. As a result, the cases and controls for our studies have been recruited through geographic matching, to eliminate the adverse impact of stratification. We evaluated the allelic frequency of HLA-DRB1 in the Sichuan cohort (192 cases and 192 controls) and the Beijing cohort (935 cases and 2,103 controls). Subsequently, we analyzed the Sichuan and Beijing cohorts together and confirmed a strong association with primary IgAN susceptibility, that the allele frequency of HLA-DRB1*04 was significantly associated with primary IgAN susceptibility. HLA-DRB1*0405 and 0403 were the susceptible allele of pIgAN patients in Han Chinese population. However, there is no significant association between clinical factors and the frequency of the HLA-DRB1*04 alleles and its subtype in primary IgAN patients.
In summary, this study showed that the HLA-DRB1*04 had a strong association with primary IgAN in a Chinese population. In our disease association studies, all of these samples were pre-typed at a low resolution using PCR –SSP, which may limit our ability to detect rare alleles of HLA DRB1. The primary technology used to detect rare alleles of HLA-DRB1 is the high resolution SBT, which could contribute to the proper identification of susceptible or resistant alleles of IgAN. HLA-DRB1 has been shown to be associated with many autoimmune diseases, however, the mechanism of the HLA-DRB1 causing IgAN is poorly understood. Thus further research exploring the pathogenesis of HLA-DRB1 with IgAN is needed.
HLA-DRB1*04 was significantly associated with primary IgAN in Chinese population. HLA-DRB1*0405 and 0403 were the susceptible allele of pIgAN patients in Han Chinese population. However, there is no significant association between clinical factors and the frequency of the HLA-DRB1*04 alleles and its subtype in primary IgAN patients.
We thank the patients with IgAN and their families for participating. The authors acknowledge the following grant support (to Z. Yang): the Department of Science and Technology of Sichuan Province (04JY029-045, 05ZQ026-018), the Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital; and (to J. Yang) the Sichuan Province Science and Technology Foundation for Youth (No. 09ZQ026-034).
- Hsu SI, Ramirez SB, Winn MP, Bonventre JV, Owen WF: Evidence for genetic factors in the development and progression of IgA nephropathy. Kidney Int. 2000, 57 (5): 1818-1835. 10.1046/j.1523-1755.2000.00032.x.View ArticlePubMedGoogle Scholar
- Karnib HH, Sanna-Cherchi S, Zalloua PA, Medawar W, D’Agati VD, Lifton RP, Badr K, Gharavi AG: Characterization of a large Lebanese family segregating IgA nephropathy. Nephrol Dial Transplant. 2007, 22 (3): 772-777. 10.1093/ndt/gfl677.View ArticlePubMedGoogle Scholar
- Bisceglia L, Cerullo G, Forabosco P, Torres DD, Scolari F, Di Perna M, Foramitti M, Amoroso A, Bertok S, Floege J, et al: Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci. Am J Hum Genet. 2006, 79 (6): 1130-1134. 10.1086/510135.View ArticlePubMedPubMed CentralGoogle Scholar
- Gharavi AG, Yan Y, Scolari F, Schena FP, Frasca GM, Ghiggeri GM, Cooper K, Amoroso A, Viola BF, Battini G, et al: IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet. 2000, 26 (3): 354-357. 10.1038/81677.View ArticlePubMedGoogle Scholar
- Paterson AD, Liu XQ, Wang K, Magistroni R, Song X, Kappel J, Klassen J, Cattran D, St George-Hyslop P, Pei Y: Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36. J Am Soc Nephrol. 2007, 18 (8): 2408-2415. 10.1681/ASN.2007020241.View ArticlePubMedGoogle Scholar
- Akiyama F, Tanaka T, Yamada R, Ohnishi Y, Tsunoda T, Maeda S, Takei T, Obara W, Ito K, Honda K, et al: Single-nucleotide polymorphisms in the class II region of the major histocompatibility complex in Japanese patients with immunoglobulin A nephropathy. J Hum Genet. 2002, 47 (10): 532-538. 10.1007/s100380200080.View ArticlePubMedGoogle Scholar
- Obara W, Iida A, Suzuki Y, Tanaka T, Akiyama F, Maeda S, Ohnishi Y, Yamada R, Tsunoda T, Takei T, et al: Association of single-nucleotide polymorphisms in the polymeric immunoglobulin receptor gene with immunoglobulin A nephropathy (IgAN) in Japanese patients. J Hum Genet. 2003, 48 (6): 293-299.PubMedGoogle Scholar
- Takei T, Iida A, Nitta K, Tanaka T, Ohnishi Y, Yamada R, Maeda S, Tsunoda T, Takeoka S, Ito K, et al: Association between single-nucleotide polymorphisms in selectin genes and immunoglobulin A nephropathy. Am J Hum Genet. 2002, 70 (3): 781-786. 10.1086/339077.View ArticlePubMedPubMed CentralGoogle Scholar
- Pirulli D, Crovella S, Ulivi S, Zadro C, Bertok S, Rendine S, Scolari F, Foramitti M, Ravani P, Roccatello D, et al: Genetic variant of C1GalT1 contributes to the susceptibility to IgA nephropathy. J Nephrol. 2009, 22 (1): 152-159.PubMedGoogle Scholar
- Li GS, Zhu L, Zhang H, Lv JC, Ding JX, Zhao MH, Shen Y, Wang HY: Variants of the ST6GALNAC2 promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy. Hum Mutat. 2007, 28 (10): 950-957. 10.1002/humu.20543.View ArticlePubMedGoogle Scholar
- Liu XQ, Paterson AD, He N, St George-Hyslop P, Rauta V, Gronhagen-Riska C, Laakso M, Thibaudin L, Berthoux F, Cattran D: IL5RA and TNFRSF6B gene variants are associated with sporadic IgA nephropathy. J Am Soc Nephrol. 2008, 19 (5): 1025-1033. 10.1681/ASN.2007091013.View ArticlePubMedPubMed CentralGoogle Scholar
- Li GS, Zhang H, Lv JC, Shen Y, Wang HY: Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy. Kidney Int. 2007, 71 (5): 448-453. 10.1038/sj.ki.5002088.View ArticlePubMedGoogle Scholar
- Rodriguez-Perez JC, Macias-Reyes A, Jimenez-Sosa A, Companioni O, Rodriguez-Esparragon FJ, Cobo MA, Checa-Andres MD, Palop-Cubillo L, Alonso A, Torres A: A synergistic association of ACE I/D and eNOS G894T gene variants with the progression of immunoglobulin A nephropathy - a pilot study. Am J Nephrol. 2009, 30 (3): 303-309. 10.1159/000225938.View ArticlePubMedGoogle Scholar
- Yoon HJ, Chin HJ, Na KY, Chae DW, Kim S, Jeon US, Chung WK, Lee HH, Yang J, Kim S, et al: Association of angiotensin II type 2 receptor gene A1818T polymorphism with progression of immunoglobulin A nephropathy in Korean patients. J Korean Med Sci. 2009, 24 (Suppl): S38-S43. 10.3346/jkms.2009.24.S1.S38.View ArticlePubMedPubMed CentralGoogle Scholar
- Li PK, Burns AP, So AK, Pusey CD, Feehally J, Rees AJ: The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians. Kidney Int. 1991, 39 (5): 961-965. 10.1038/ki.1991.121.View ArticlePubMedGoogle Scholar
- Fennessy M, Hitman GA, Moore RH, Metcalfe K, Medcraft J, Sinico RA, Mustonen JT, D’Amico G: HLA-DQ gene polymorphism in primary IgA nephropathy in three European populations. Kidney Int. 1996, 49 (2): 477-480. 10.1038/ki.1996.67.View ArticlePubMedGoogle Scholar
- Hiki Y, Kobayashi Y, Ookubo M, Kashiwagi N: The role of HLA-DR4 in the long-term prognosis of IgA nephropathy. Nephron. 1990, 54 (3): 264-265. 10.1159/000185867.View ArticlePubMedGoogle Scholar
- Nomoto Y, Endoh M, Miura M, Suga T, Tomino Y, Sakai H, Nose Y, Tsuji K: IgA nephropathy associated with HLA-DR4 antigen. Am J Nephrol. 1984, 4 (3): 184-187. 10.1159/000166803.View ArticlePubMedGoogle Scholar
- Kohara M, Naito S, Arakawa K, Miyata J, Chihara J, Taguchi T, Takebayashi S: The strong association of HLA-DR4 with spherical mesangial dense deposits in IgA nephropathy. J Clin Lab Immunol. 1985, 18 (4): 157-160.PubMedGoogle Scholar
- Huang CC, Hu SA, Lin JL, Wu JH: HLA and Chinese IgA nephropathy in Taiwan. Tissue Antigens. 1989, 33 (1): 45-47. 10.1111/j.1399-0039.1989.tb01677.x.View ArticlePubMedGoogle Scholar
- Scolari F, Amoroso A, Savoldi S, Mazzola G, Prati E, Valzorio B, Viola BF, Nicola B, Movilli E, Sandrini M, et al: Familial clustering of IgA nephropathy: further evidence in an Italian population. Am J Kidney Dis. 1999, 33 (5): 857-865. 10.1016/S0272-6386(99)70417-8.View ArticlePubMedGoogle Scholar
- Lin L, Chen Y, Xiao Z, Huang S, Yang Z: The association of HLA-DRB1 alleles with rheumatoid arthritis in the Chinese Shantou population: a follow-up study. Biochem Cell Biol. 2007, 85 (2): 227-238. 10.1139/o06-204.View ArticlePubMedGoogle Scholar
- Sayer DC, Whidborne R, De Santis D, Rozemuller EH, Christiansen FT, Tilanus MG: A multicenter international evaluation of single-tube amplification protocols for sequencing-based typing of HLA-DRB1 and HLA-DRB3,4,5. Tissue Antigens. 2004, 63 (5): 412-423. 10.1111/j.0001-2815.2004.00214.x.View ArticlePubMedGoogle Scholar
- Doxiadis II, De Lange P, De Vries E, Persijn GG, Claas FH: Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure. Tissue Antigens. 2001, 57 (4): 344-347. 10.1034/j.1399-0039.2001.057004344.x.View ArticlePubMedGoogle Scholar
- Feehally J, Farrall M, Boland A, Gale DP, Gut I, Heath S, Kumar A, Peden JF, Maxwell PH, Morris DL: HLA Has Strongest Association with IgA Nephropathy in Genome-Wide Analysis. J Am Soc Nephrol. 2010Google Scholar
- Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, Sanna-Cherchi S, Men CJ, Julian BA, Wyatt RJ, et al: Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011, 43 (4): 321-327. 10.1038/ng.787.View ArticlePubMedPubMed CentralGoogle Scholar
- Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SG: IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res. 2003, 31 (1): 311-314. 10.1093/nar/gkg070.View ArticlePubMedPubMed CentralGoogle Scholar
- Kashiwabara H, Shishido H, Tomura S, Tuchida H, Miyajima T: Strong association between IgA nephropathy and HLA-DR4 antigen. Kidney Int. 1982, 22 (4): 377-382. 10.1038/ki.1982.185.View ArticlePubMedGoogle Scholar
- Cao HX, Li M, Nie J, Wang W, Zhou SF, Yu XQ: Human leukocyte antigen DRB1 alleles predict risk and disease progression of immunoglobulin A nephropathy in Han Chinese. Am J Nephrol. 2008, 28 (4): 684-691. 10.1159/000122111.View ArticlePubMedPubMed CentralGoogle Scholar
- Beukhof JR, Kardaun O, Ockhuizen T, van der Hem GK: Kidney survival in IgA nephropathy: multiple regression analysis of genetically differing subpopulations–is IgA nephropathy a real disease entity?. Semin Nephrol. 1987, 7 (4): 367-369.PubMedGoogle Scholar
- Beukhof JR, Ockhuizen T, Halie LM, Westra J, Beelen JM, Donker AJ, Hoedemaeker PJ, van der Hem GK: Subentities within adult primary IgA-nephropathy. Clin Nephrol. 1984, 22 (4): 195-199.PubMedGoogle Scholar
- Chen J, Zheng H, Bei JX, Sun L, Jia WH, Li T, Zhang F, Seielstad M, Zeng YX, Zhang X, et al: Genetic structure of the Han Chinese population revealed by genome-wide SNP variation. Am J Hum Genet. 2009, 85 (6): 775-785. 10.1016/j.ajhg.2009.10.016.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/33/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.