Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: Immunogenetics. 2013 Apr 12;65(7):543–552. doi: 10.1007/s00251-013-0700-2

Structure of tumor necrosis factor-alpha haploblocks in European populations

Aimee M Merino 3, Kui Zhang 2, Richard A Kaslow 1,3, Brahim Aissani 1,*
PMCID: PMC3985396  NIHMSID: NIHMS467254  PMID: 23579626

Abstract

DNA variants in the tumor necrosis factor-α (TNF) and linked lymphotoxin-α genes, and specific alleles of the highly polymorphic human leukocyte antigen B (HLA-B) gene have been implicated in a plethora of immune and infectious diseases. However, the tight linkage disequilibrium characterizing the central region of the human major histocompatibility complex (MHC) containing these gene loci has made difficult the unequivocal interpretation of genetic association data.

To alleviate these difficulties and facilitate the design of more focused follow-up studies, we investigated the structure and distribution of HLA-B-specific MHC haplotypes reconstructed in a European population from unphased genotypes at a set of 25 single nucleotide polymorphism sites spanning a 66 kilobase-long region across TNF.

Consistent with the published data, we found limited genetic diversity across the so-called TNF block, with the emergence of seven common MHC haplotypes, termed TNF block super-haplotypes. We also found that the ancestral haplotype 8.1 shares a TNF block haplotype with HLA-B*4402. HLA-B*5701, a known protective allele in HIV-1 pathogenesis, occurred in a unique TNF block haplotype.

Keywords: SNPs, TNF, LTA, HLA-B

Allelic diversity at the HLA genes on chromosome 6p21.3 has been associated with a myriad of disease mechanisms underlying autoimmunity, infection and malignancy. Current data indicate that single nucleotide polymorphisms (SNPs) in immunoregulatory genes such as TNF and lymphotoxin A (LTA) are associated with the development of chronic diseases, cancer, and autoimmune conditions (Allcock et al. 1999; Cheong et al. 2001). For example, the ‘G’ allele at nucleotide position +252 (rs909253 A>G) of LTA alone or in combination with the ‘A’ allele at position −308 (rs1800629 G>A) of TNF have been repeatedly associated with increased risk for both classical and HIV-related non-Hodgkin’s lymphoma (NHL) (Juszczynski et al. 2002; Nowak et al. 2007; Nowak et al. 2008; Aissani et al. 2009) however, it remains uncertain whether variants in LTA and TNF or markers in adjacent loci represent true causal variants.

While the −308A variant has been associated with high levels of TNF production, attempts to relate sequence variation in this gene to functional variation as measured by biologic activity of the molecules have been controversial (Bouma et al. 1996; He et al. 1995; Huizinga et al. 1997; Louis et al. 1998; Turner et al. 1995; Wilson et al. 1997). Finally, the SNPs in the two genes repeatedly associated with NHL most often occur on one of the most conserved extended haplotypes found in the human genome—the Caucasian HLA-B*0801-containing ancestral haplotype (8.1AH) (Degli-Esposti et al. 1992; Price et al. 1999) that spans more than 2 Mb across MHC. Understanding the structure of the joint HLA and MHC SNP haplotypes across the TNF locus is important for the correct interpretation of association data because the pattern of linkage disequilibrium (LD) across the MHC is HLA-specific (de Bakker et al. 2006).

In the present study, we have analyzed the genetic diversity across the TNF block in a collection of 660 participants enrolled in the Multicenter AIDS Cohort Study (MACS), a prospective study of HIV infection and AIDS (Kaslow et al. 1987). To validate our observations, two study groups from published studies of MHC haplotypes served as reference healthy populations. These were the CEU population (n=92) from the International HapMap project (de Bakker et al., 2006) and a study group (n=398) from the populations of Busselton and Perth, Australia (Valente et al. 2009).

Informed consent was obtained and the Institutional Review Board at each center approved the MACS study. We restricted the analysis to subjects of non-Hispanic European ancestry because of insufficient numbers of subjects from other ethnic groups. All of the 660 sampled individuals were HIV seropositive and half of them (n=330) had Kaposi’s sarcoma; these two groups were cases (henceforth group #1) and matched controls (group # 2) selected from ongoing studies of HIV-related Kaposi’s sarcoma. To prevent possible distortions of our estimate of population distribution of MHC haplotypes, we conducted separate analyses of these two study groups.

Extended MHC haplotypes were reconstructed for a set of 25 SNPs spanning a 66 Kb interval across the TNF locus and including 12 SNPs shared with the CEU and Australian population studies. This genomic interval is flanked by telomeric HLA-B and encompasses seven other genes in the following telomere-to-centromere order; mitochondrial coiled coil domain 1 (MCCD1), HLA-B associated transcript 1 (BAT1), ATPase G2 isoform (ATP6V1G2), nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-like 1 (NFKBIL1), LTA, TNF, and leukocyte specific transcript 1 (LST1). We reconstructed haplotypes formed by these 25 tagging SNPs alone and jointly with HLA-B. With the joint haplotypes of HLA-B and MHC SNP being available only from the study of the HapMap sample, we compared our estimates of the joint HLA-B and SNP haplotype (henceforth joint MHC haplotypes) frequencies to those of the HapMap sample and of the SNP only haplotypes to both reference samples (Table 1).

Table 1.

Distribution of joint HLA-B and MHC SNP Haplotypes in European populations

graphic file with name nihms467254t1.jpg
Open in a new tab

There were 24 subjects in group 1 and 22 in group 2 that were present in the population at ≥ 1.0 %. Frequencies were defined by the HAPLORE program (Zhang et al. 2005) using the expectation maximization algorithm. Only the minor allele is listed. NA represents ‘not found’ in the samples tested. (?) is a potentially distinct HLA-B*5701-containing haplotype. SNPs in bold were typed in all three study populations.

SNPs were chosen by a systematic search of populations of Western European ancestry in public databases (HapMap I and SNP500 cancer database) and private databases (Illumina Technologies, San Diego, CA and Applied Biosystems Inc., Foster City, CA). The primary criteria for SNP selection included an aggressive (r2 > 0.80) haplotype tagging potential (htSNP) across gene loci, minor allele frequency (MAF) > 5%, and predicted functionality (identified in PupaSuite (Conde et al. 2006)) Additionally we selected two-hit SNPs (or Illumina-validated) with a “designability” score of 1 (anticipated success rate > 80%).

HLA-B typing was performed to four-digit resolution by reference-strand conformation polymorphism and DNA sequencing-based typing methods. SNP typing was performed on a commercially available genotyping platform (BeadArray®, Illumina Inc., San Diego, CA). Reliability in SNP typing was assessed by duplicate typing of a random set of 44 samples. SNP markers were examined separately in the two study groups for adherence to HWE using Pearson’s chi-squared test

The expectation-maximization based haplotype inference program HAPLORE (Zhang et al. 2005) was used to estimate haplotype frequencies separately in the two study groups. All of the typed SNPs were in HWE (p>0.05) and were included in the reconstruction of haplotypes from the unphased genotype data. Comparison of genotype frequencies showed no significant difference (p>0.05) between the two study groups, indicating that disease status introduced no significant bias in our estimate of haplotype frequencies (data not shown).

We identified a total of 38 joint haplotypes, with 24 of them present in group 1 and 22 present in group 2 at a frequency ≥1% (Table 1). The cumulative frequencies of the joint haplotypes present at a frequency greater than 0.5% were 69.0% and 69.8% in study groups 1 and 2, respectively. The frequency of joint haplotypes did not differ significantly (α=5%) between group 1, group 2, and the CEU population of HapMap. Of the haplotypes found at ≥0.5% in group 1 or group 2, 18 of them were not found in the HapMap sample likely due to the smaller number of subjects.

Approximately 30% of the joint haplotypes in the study population were rare (<0.5%), with several private haplotypes (not shown). A higher number of rare haplotypes (approximately 40%) were seen in the HapMap sample because of the small size of this sample. Another non-exclusive explanation is a lower genetic diversity in the CEU population compared to that in the multicenter MACS population, The large proportion of rare and private haplotypes is undoubtedly due to the high heterozygosity at HLA-B; indeed, compared to the joint haplotypes, only 14–18% of the SNP-only haplotypes (henceforth SNP haplotypes) were rare or private.

The overall distributions of SNP haplotypes in the two study groups were not statistically different from one another, and are comparable to those obtained in the HapMap and Australian general populations. Haplotype 148 was seen in our samples and the Australians but not in the HapMap sample, probably due to the small number of subjects in that group. The remarkable similarity of the distributions between these three groups indicates that our results are generalizable to healthy populations of European descent. Reconstruction of SNP haplotypes identified 15 haplotypes in group 1 and 13 in group 2, present at frequencies greater than ≥0.5%. The number of reconstructed haplotypes was similar in groups 1 and 2 (11 and 14 haplotypes respectively) as well as to the smaller population from the HapMap project (12 haplotypes) (de Bakker et al.). In the Australian subjects from Busselton and Perth, there were 18 and 15 haplotypes respectively, possibly due to the inclusion of a larger number of test SNPs (n=38) in that study (Valente et al. 2009).

The present study identified several HLA-specific patterns of haplotype sequences across the TNF block in the European populations. First, consistent with the published data [(Belfer et al. 2004; Valente et al. 2009), we show that genetic diversity across TNF is very limited across the TNF block, which appears to span at least a 66 Kb-long region flanked by MMCD1 and LST1, the telomeric and centromeric gene loci, respectively. Second and for the first time, we show that haplotype sequence diversity across the TNF block differentiates in seven common haplotypes (frequency greater than 2%) defined by a small number of SNP sites. We propose to name these common joint haplotypes “TNF block super-haplotype” (highlighted as alternate gray and white bands in column 1 of Table 1). Third, about one third of the joint haplotypes occurs at a frequency of less than 0.5%, reflecting the remarkable genetic diversity at the HLA-B locus.

The first TNF block super-haplotype accounts for 12.4–14.8% of the total haplotypes and is essentially made up of two HLA-B*0702-containing haplotypes differing by a unique tagging SNP (rs3130062) A>G in NFKBIL1, and a single haplotype carrying HLA-B*4001.

The second TNF block super-haplotype, is defined by 4 SNP sites; rs2071594 (ATP6V1G2), rs2071592 (NFKBIL1), rs1800683 (LTA) and TNF −308 SNP rs1800629. Super-haplotype II, accounts for 12.3–12.5% and comprises the known 8.1AH, which invariably carries the A allele at TNF −308 (G>A) (Aissani et al. 2009). The other member of super-haplotype II carries HLA-B*4402, accounting for about 2% and carrying also TNF −308A; this study is the first to show that this allele also occurs on a HLA background other than 8.1AH. The implication of this finding for association studies of 8.1AH- and TNF −308A-associated diseases is important. In effect, when both B*4402 and B*0801 alleles are associated with the outcome under study; this would exclude HLA-B and provide a means to focus the follow-up study on the carriers of B*4402 because the extent of the B*4402 haplotype is much limited compared to 8.1AH. Inversely, if B*4402 is not associated in the presence of an association with B*0801, then HLA-B or a gene outside the TNF block carried on 8.1AH is the most likely causal gene. Accounting for this observation in planning follow-up association studies of 8.1AH-associated diseases such as type 1 diabetes (T1D) may speed and lower the cost of follow-up studies.

The third TNF block super-haplotype occurs at a frequency of 8.7–11.8% and is defined by 3 SNP sites; rs2071594 (ATP6V1G2), rs2071592 (NFKBIL1), and rs1800683 (LTA). SNP haplotype 31 containing B*4001, does not carry the minor allele at rs2071592, but is more closely related to super-haplotype III than any of the other super-haplotypes.

The fourth super-haplotype is the least common (2.0–3.9%) and comprises one HLA-B*5701, and another putative B*5701 haplotype (highlighted by a question mark) that has emerged in the reconstruction of SNP haplotypes and not in that of the joint haplotypes at our cut-off frequency of 0.5%. It appears to be most closely related to the B*5701-bearing haplotype, differing only in a C>G transversion in TNF (rs3093668) and an A>C in the intergenic region between MICB and MCCD1. Although rare, if confirmed, the second putative B*5701 haplotype is of great interest in HIV association studies as it may help clarify the causal relationship of this allele to HIV infection and progression as discussed above for B*4402 and B*0801 alleles. An observation that deserves a comment is the lower estimates of the joint B*5701 haplotype frequency in our HIV study population compared to that of the general European population, which is about 5%. This clear difference is expected because B*5701 has consistently been shown to be protective for HIV infection and progression (Fellay et al. 2009; Fellay et al. 2007; Goulder et al. 1996; Liu et al. 2003).

Super-haplotype V is defined by variant A at SNP rs2256965 (LST1). B*3501, an allele consistently associated with a rapid progression of HIV infection, occurs on 4 MHC haplotypes, three of which are members of super-haplotype V and one of super-haplotype VI.

Super-haplotype VI is defined by 2 SNPs; one in LTA (rs2009658) and the other in NFKBIL1 (rs2255798). It occurs at a frequency of 11.2–12.8%. One of the B*3501 carrying haplotypes occurs in this group. Two of the haplotypes in this group contain B*1501 but differ in two SNPs in NFKBIL1 (rs2239707 and rs2230365).

The seventh super-haplotype is defined by two SNPs, one occurring in BAT1 (rs2239528) and the other in LTA (rs928815). Only three haplotypes fall into this group, occurring at 1.8–2.9%. HLA-B*4901 occurs in both super-haplotype VII and III. Our categorization of TNF block haplotypes into super-haplotypes allows convenient grouping of similar haplotypes by tag SNPs for analysis in association studies.

Several tag SNPs used here to reconstruct haplotypes have been reported in association studies. For example, the minor allele (C allele) of the intergenic polymorphism rs3093993, occuring between MICB and MCCD1, was shown to be associated with decreased HIV-1 cellular DNA and viral control in HIV infected individuals through genome wide association (GWA) studies (Dalmasso et al. 2008). Our data shows that that the minor allele of rs3093993 occurs on the haplotype carrying the HIV-protective allele B*5701 (SNP haplotype 79), in addition to haplotypes with B*0702, *4001, *5701, and *4901. HLA-B*57 molecules have been shown in numerous studies to be protective in HIV infection (Fellay et al. 2009; Fellay et al. 2007; Goulder et al. 1996; Liu et al. 2003) and also to be associated with lower viral load (Kloverpris et al. 2012). Whether the protection seen in these studies is due to the sole effect of HLA-B or to its joint effect with the gene tagged by rs3093993 or by another polymorphism in LD with these polymorphisms is difficult to ascertain. However, comparisons of haplotype sequence conservation and divergence across super-haplotypes of interest may be informative for the delineation of the most likely candidate region.

The minor alleles of SNPs rs2857605, rs2239707, and rs2230365; all intronic in NFKBIL1, comprise a haplotype that has been associated with increased risk of NHL (Wang et al. 2009). SNPs rs2857605 and rs2239707 occurred in super-haplotype I and SNPs rs2239707 and rs2230365 occurred in super-haplotype VI. All three SNPs were found in super-haplotype VII except with B*4901.

SNPs rs2071592 and rs2071594, located in NFKBIL1 and the 3’ flanking region of ATP6V1G2 respectively, are associated with an increased incidence of rheumatoid arthritis (RA) (Okamoto et al. 2003). Most commonly (>50% of haplotypes) the minor alleles of these two SNPs occurred on HLA-B*0801, *4402, or *2705; all of which have been associated with adult or juvenile RA in previous studies (Avila-Portillo et al. 1994; Berntson et al. 2008; Raychaudhuri et al. 2012). These haplotypes are of super-haplotype II and III. Another NFKBIL1 SNP (rs4947324) associated with RA (Jung et al. 2009) occurs in both super-haplotype IV and two B*3501-carrying members of super-haplotype V.

The minor allele of rs2009658 has been associated with an increased risk of breast cancer (Madeleine et al. 2011). This SNP only occurred in super-haplotype VI and frequently (>30% of the time) was found with either HLA-B* 1501 or *1402, both of which have been associated with an increased incidence of breast cancer (Biswal et al. 1998; Cantu de Leon et al. 2009). B*1501 alleles from super-haplotype III lack the C>G transversion, allowing for discrimination between these polymorphisms in association studies.

The minor allele of rs1800683, found in LTA, has been associated with protection from myocardial infarction (Koch et al. 2007) and decreased antibody response to measles (Dhiman et al. 2008) as part of an extended haplotype with other SNPs in TNF and LTA. Allele A of this SNP occurred in super-haplotype II and III. Another SNP located in LTA, rs2229094 (previously known as rs2857713) encodes a missense mutation (Cys13Arg) in the encoded peptide. This polymorphism has been associated with several disparate conditions including gastric cancer in Japanese men (Takei et al. 2008), preeclampsia in pregnant women (Parimi et al. 2008), proliferative vitreoretinopathy (Rojas et al. 2010), and cancer-related mortality (Gallicchio et al. 2008). In a study of an Indian population, the minor allele of rs2229094 was found to be negatively associated with Type 2 diabetes mellitus (Mahajan et al. 2010). SNP rs2229094 occurred on super-haplotype IV, the B*3501-containing super-haplotype V, and super-haplotype VI.

SNP rs1799964 is located at position T-1031C of TNF. Modeling with MFOLD indicates that the C allele of this polymorphism prevents the binding of several transcription factors by altering the accessibility of the DNA (Basu et al. 2012). In studies of malaria, this SNP has been associated with increased parasitemia, heightened severity of disease, and incidence of cerebral involvement (Basu et al. 2012; Hananantachai et al. 2007; Sinha et al. 2008). Case studies have found the minor allele G of this SNP to be associated with Crohn’s disease, asthma, decreased immunity after natural infection or vaccination against measles, and cancer-associated mortality (Dhiman et al. 2008; Gallicchio et al. 2008; Puthothu et al. 2009; Sanchez et al. 2009). Interestingly, this is the only allele shared by all members of super-haplotypes IV and VI, suggesting that within the TNF block, TNF is the sole candidate gene for these diseases.

Experimental evidence suggests that haplotypic differences in the promoter region of TNF alter the transcription level of this important cytokine (Basu et al. 2012). Occurring with rs1799964 in this study was rs3093668, a SNP in the 3’ UTR of TNF. A family-based study identified this SNP with type 1 diabetes mellitus (Boraska et al. 2009). Both of these TNF SNPs occurred on super-haplotype IV and rs1799964 also occurred on super-haplotype VI.

The most studied TNF promoter −308 (G>A) SNP, rs1800629, has been implicated in the development of multiple diseases. The minor allele (A) has been associated with cerebral malaria (McGuire et al. 1994) and susceptibility to septic shock (Mira et al. 1999). Case studies have found an increased frequency of the A allele in lung (Shih et al. 2006) and hepatocellular cancers (Akkiz et al. 2009) but the G allele has been found with increased frequency in basal cell carcinoma (Rizzato et al. 2011) and renal cell cancer (Basturk et al. 2005). The differential findings related to this potent cytokine in malignancy may highlight the delicate balance between immune surveillance and inflammation in cancer development. Other diseases that have been associated with the A allele include type 1 diabetes mellitus (Noble et al. 2006), type 2 diabetes mellitus (Kubaszek et al. 2003), and asthma (Wang et al. 2004; Witte et al. 2002). Amongst healthy volunteers, individuals homozygous for AA at −308 exhibited decreased gray matter in the hippocampus (Baune et al. 2012), possibly indicating that this polymorphism plays a role in neurodegenerative disease. This SNP was only found on super-haplotype II, with the ancestral HLA-B*0801 and also B*4402. Because the B*0801 haplotype is so common, the minor allele frequency (MAF) of rs1800629 was 12.3–12.5%.

SNP rs3093662 is located in an intron of TNF. Previously this SNP was shown to be overrepresented in HIV controllers, individuals with low viral load and no disease symptoms after ten years of treatment-naïve HIV infection (Dalmasso et al. 2008; Kloverpris et al. 2012). Occurring on super-haplotype IV and one B*3501-containing super-haplotype V, rs3093662 was most commonly (>70% of extended haplotypes) found in LD with HLA-B*5701. This particular B allele is strongly protective in HIV infection (Kamya et al. 2011; Kloverpris et al. 2012; Miura et al. 2009; Nou et al. 2009) whereas B*3501 is rather at risk; in the light of our data, this observation indicated that HLA-B and not TNF is the most likely causally-related gene.

The distribution patterns of the TNF block super-haplotypes revealed in the present study will likely undergo refinements and updates in future studies of larger samples, higher SNP coverage and diverse European and other Caucasian populations. However, it is quite possible that the TNF block super-haplotypes are the local structure of much longer MHC haplotypes, plausibly the conserved extended haplotypes or ancestral haplotypes (Dawkins et al. 1999).

Acknowledgment

Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at The Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick, Lisa Jacobson), Howard Brown Health Center and Northwestern University Medical School (John Phair), University of California, Los Angeles (Roger Detels), and University of Pittsburgh (Charles Rinaldo). Website located at http://www.statepi.jhsph.edu/macs/macs.html.

Sources of support

Funding was provided by R01-CA106168 (RAK) and partially by the Department of Epidemiology (BA). The Multicenter AIDS Cohort Study (MACS) is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041.

References

  1. Aissani B, Ogwaro KM, Shrestha S, Tang J, Breen EC, Wong HL, Jacobson LP, Rabkin CS, Ambinder RF, Martinez-Maza O, Kaslow RA. The major histocompatibility complex conserved extended haplotype 8.1 in AIDS-related non-Hodgkin lymphoma. J Acquir Immune Defic Syndr. 2009;52:170–179. doi: 10.1097/QAI.0b013e3181b017d5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akkiz H, Bayram S, Bekar A, Ozdil B, Akgollu E, Sumbul AT, Demiryurek H, Doran F. G-308A TNF-alpha polymorphism is associated with an increased risk of hepatocellular carcinoma in the Turkish population: case-control study. Cancer Epidemiol. 2009;33:261–264. doi: 10.1016/j.canep.2009.06.001. [DOI] [PubMed] [Google Scholar]
  3. Allcock RJ, de la Concha EG, Fernandez-Arquero M, Vigil P, Conejero L, Arroyo R, Price P. Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster. Hum Immunol. 1999;60:1266–1273. doi: 10.1016/s0198-8859(99)00127-5. [DOI] [PubMed] [Google Scholar]
  4. Avila-Portillo LM, Vargas-Alarcon G, Andrade F, Alarcon-Segovia D, Granados J. Linkage disequilibrium of HLA-DR3 and HLA-DR4 with HLA-B alleles in Mexican patients with rheumatoid arthritis. Clin Exp Rheumatol. 1994;12:497–502. [PubMed] [Google Scholar]
  5. Basturk B, Yavascaoglu I, Vuruskan H, Goral G, Oktay B, Oral HB. Cytokine gene polymorphisms as potential risk and protective factors in renal cell carcinoma. Cytokine. 2005;30:41–45. doi: 10.1016/j.cyto.2004.10.016. [DOI] [PubMed] [Google Scholar]
  6. Basu M, Das T, Ghosh A, Majumder S, Maji AK, Kanjilal SD, Mukhopadhyay I, Roychowdhury S, Banerjee S, Sengupta S. Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level. PLoS One. 2012;7:e46441. doi: 10.1371/journal.pone.0046441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Baune BT, Konrad C, Grotegerd D, Suslow T, Ohrmann P, Bauer J, Arolt V, Heindel W, Domschke K, Schoning S, Rauch AV, Sehlmeyer C, Kugel H, Dannlowski U. Tumor necrosis factor gene variation predicts hippocampus volume in healthy individuals. Biol Psychiatry. 2012;72:655–662. doi: 10.1016/j.biopsych.2012.04.002. [DOI] [PubMed] [Google Scholar]
  8. Belfer I, Buzas B, Hipp H, Dean M, Evans C, Lorincz I, Max MB, Goldman D. Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans. Genes Immun. 2004;5:505–512. doi: 10.1038/sj.gene.6364118. [DOI] [PubMed] [Google Scholar]
  9. Berntson L, Damgard M, Andersson-Gare B, Herlin T, Nielsen S, Nordal E, Rygg M, Zak M, Fasth A. HLA-B27 predicts a more extended disease with increasing age at onset in boys with juvenile idiopathic arthritis. J Rheumatol. 2008;35:2055–2061. [PubMed] [Google Scholar]
  10. Biswal BM, Kumar R, Julka PK, Sharma U, Vaidya MC. Human leucocytic antigens (HLA) in breast cancer. Indian J Med Sci. 1998;52:177–183. [PubMed] [Google Scholar]
  11. Boraska V, Zeggini E, Groves CJ, Rayner NW, Skrabic V, Diakite M, Rockett KA, Kwiatkowski D, McCarthy MI, Zemunik T. Family-based analysis of tumor necrosis factor and lymphotoxin-alpha tag polymorphisms with type 1 diabetes in the population of South Croatia. Hum Immunol. 2009;70:195–199. doi: 10.1016/j.humimm.2008.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bouma G, Xia B, Crusius JB, Bioque G, Koutroubakis I, Von Blomberg BM, Meuwissen SG, Pena AS. Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD) Clin Exp Immunol. 1996;103:391–396. doi: 10.1111/j.1365-2249.1996.tb08292.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cantu de Leon D, Perez-Montiel D, Villavicencio V, Garcia Carranca A, Mohar Betancourt A, Acuna-Alonzo V, Lopez-Tello A, Vargas-Alarcon G, Barquera R, Yu N, Yunis EJ, Granados J. High resolution human leukocyte antigen (HLA) class I and class II allele typing in Mexican mestizo women with sporadic breast cancer: case-control study. BMC Cancer. 2009;9:48. doi: 10.1186/1471-2407-9-48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cheong KY, Allcock RJ, Eerligh P, Witt CS, Christiansen FT, McCann V, Price P. Localization of central MHC genes influencing type I diabetes. Hum Immunol. 2001;62:1363–1370. doi: 10.1016/s0198-8859(01)00351-2. [DOI] [PubMed] [Google Scholar]
  15. Conde L, Vaquerizas JM, Dopazo H, Arbiza L, Reumers J, Rousseau F, Schymkowitz J, Dopazo J. PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes. Nucleic Acids Res. 2006;34:W621–W625. doi: 10.1093/nar/gkl071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dalmasso C, Carpentier W, Meyer L, Rouzioux C, Goujard C, Chaix ML, Lambotte O, Avettand-Fenoel V, Le Clerc S, de Senneville LD, Deveau C, Boufassa F, Debre P, Delfraissy JF, Broet P, Theodorou I. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study. PLoS One. 2008;3:e3907. doi: 10.1371/journal.pone.0003907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dawkins R, Leelayuwat C, Gaudieri S, Tay G, Hui J, Cattley S, Martinez P, Kulski J. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunol Rev. 1999;167:275–304. doi: 10.1111/j.1600-065x.1999.tb01399.x. [DOI] [PubMed] [Google Scholar]
  18. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, Ke X, Monsuur AJ, Whittaker P, Delgado M, Morrison J, Richardson A, Walsh EC, Gao X, Galver L, Hart J, Hafler DA, Pericak-Vance M, Todd JA, Daly MJ, Trowsdale J, Wijmenga C, Vyse TJ, Beck S, Murray SS, Carrington M, Gregory S, Deloukas P, Rioux JD. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38:1166–1172. doi: 10.1038/ng1885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Degli-Esposti MA, Leaver AL, Christiansen FT, Witt CS, Abraham LJ, Dawkins RL. Ancestral haplotypes: conserved population MHC haplotypes. Hum Immunol. 1992;34:242–252. doi: 10.1016/0198-8859(92)90023-g. [DOI] [PubMed] [Google Scholar]
  20. Dhiman N, Ovsyannikova IG, Vierkant RA, Pankratz VS, Jacobson RM, Poland GA. Associations between cytokine/cytokine receptor single nucleotide polymorphisms and humoral immunity to measles, mumps and rubella in a Somali population. Tissue Antigens. 2008;72:211–220. doi: 10.1111/j.1399-0039.2008.01097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, Urban TJ, Zhang K, Gumbs CE, Smith JP, Castagna A, Cozzi-Lepri A, De Luca A, Easterbrook P, Gunthard HF, Mallal S, Mussini C, Dalmau J, Martinez-Picado J, Miro JM, Obel N, Wolinsky SM, Martinson JJ, Detels R, Margolick JB, Jacobson LP, Descombes P, Antonarakis SE, Beckmann JS, O'Brien SJ, Letvin NL, McMichael AJ, Haynes BF, Carrington M, Feng S, Telenti A, Goldstein DB. Common genetic variation and the control of HIV-1 in humans. PLoS Genet. 2009;5 doi: 10.1371/journal.pgen.1000791. e1000791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB. A whole-genome association study of major determinants for host control of HIV-1. Science. 2007;317:944–947. doi: 10.1126/science.1143767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gallicchio L, Chang H, Christo DK, Thuita L, Huang HY, Strickland P, Ruczinski I, Hoffman SC, Helzlsouer KJ. Single nucleotide polymorphisms in inflammation-related genes and mortality in a community-based cohort in Washington County, Maryland. Am J Epidemiol. 2008;167:807–813. doi: 10.1093/aje/kwm378. [DOI] [PubMed] [Google Scholar]
  24. Goulder PJ, Bunce M, Krausa P, McIntyre K, Crowley S, Morgan B, Edwards A, Giangrande P, Phillips RE, McMichael AJ. Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection. AIDS Res Hum Retroviruses. 1996;12:1691–1698. doi: 10.1089/aid.1996.12.1691. [DOI] [PubMed] [Google Scholar]
  25. Hananantachai H, Patarapotikul J, Ohashi J, Naka I, Krudsood S, Looareesuwan S, Tokunaga K. Significant association between TNF-alpha (TNF) promoter allele (−1031C, −863C, and −857C) and cerebral malaria in Thailand. Tissue Antigens. 2007;69:277–280. doi: 10.1111/j.1399-0039.2006.00756.x. [DOI] [PubMed] [Google Scholar]
  26. He B, Navikas V, Lundahl J, Soderstrom M, Hillert J. Tumor necrosis factor alpha-308 alleles in multiple sclerosis and optic neuritis. J Neuroimmunol. 1995;63:143–147. doi: 10.1016/0165-5728(95)00138-7. [DOI] [PubMed] [Google Scholar]
  27. Huizinga TW, Westendorp RG, Bollen EL, Keijsers V, Brinkman BM, Langermans JA, Breedveld FC, Verweij CL, van de Gaer L, Dams L, Crusius JB, Garcia-Gonzalez A, van Oosten BW, Polman CH, Pena AS. TNF-alpha promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. J Neuroimmunol. 1997;72:149–153. doi: 10.1016/s0165-5728(96)00182-8. [DOI] [PubMed] [Google Scholar]
  28. Jung J, Song JJ, Kwon D. Allelic based gene-gene interactions in rheumatoid arthritis. BMC Proc. 2009;3(Suppl 7):S76. doi: 10.1186/1753-6561-3-S7-S76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Juszczynski P, Kalinka E, Bienvenu J, Woszczek G, Borowiec M, Robak T, Kowalski M, Lech-Maranda E, Baseggio L, Coiffier B, Salles G, Warzocha K. Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome. Blood. 2002;100:3037–3040. doi: 10.1182/blood-2002-02-0654. [DOI] [PubMed] [Google Scholar]
  30. Kamya P, Boulet S, Tsoukas CM, Routy JP, Thomas R, Cote P, Boulassel MR, Baril JG, Kovacs C, Migueles SA, Connors M, Suscovich TJ, Brander C, Tremblay CL, Bernard N. Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57. J Virol. 2011;85:5949–5960. doi: 10.1128/JVI.02652-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kaslow RA, Ostrow DG, Detels R, Phair JP, Polk BF, Rinaldo CR., Jr The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants. Am J Epidemiol. 1987;126:310–318. doi: 10.1093/aje/126.2.310. [DOI] [PubMed] [Google Scholar]
  32. Kloverpris HN, Stryhn A, Harndahl M, van der Stok M, Payne RP, Matthews PC, Chen F, Riddell L, Walker BD, Ndung'u T, Buus S, Goulder P. HLA-B*57 Micropolymorphism shapes HLA allele-specific epitope immunogenicity, selection pressure, and HIV immune control. J Virol. 2012;86:919–929. doi: 10.1128/JVI.06150-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Koch W, Hoppmann P, Michou E, Jung V, Pfeufer A, Mueller JC, Gieger C, Wichmann HE, Meitinger T, Schomig A, Kastrati A. Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans. Hum Mol Genet. 2007;16:1821–1827. doi: 10.1093/hmg/ddm130. [DOI] [PubMed] [Google Scholar]
  34. Kubaszek A, Pihlajamaki J, Komarovski V, Lindi V, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M. Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes. 2003;52:1872–1876. doi: 10.2337/diabetes.52.7.1872. [DOI] [PubMed] [Google Scholar]
  35. Liu C, Carrington M, Kaslow RA, Gao X, Rinaldo CR, Jacobson LP, Margolick JB, Phair J, O'Brien SJ, Detels R. Association of polymorphisms in human leukocyte antigen class I and transporter associated with antigen processing genes with resistance to human immunodeficiency virus type 1 infection. J Infect Dis. 2003;187:1404–1410. doi: 10.1086/374394. [DOI] [PubMed] [Google Scholar]
  36. Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S, Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998;113:401–406. doi: 10.1046/j.1365-2249.1998.00662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Madeleine MM, Johnson LG, Malkki M, Resler AJ, Petersdorf EW, McKnight B, Malone KE. Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer. Breast Cancer Res Treat. 2011;129:887–899. doi: 10.1007/s10549-011-1520-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mahajan A, Tabassum R, Chavali S, Dwivedi OP, Chauhan G, Tandon N, Bharadwaj D. Obesity-dependent association of TNF-LTA locus with type 2 diabetes in North Indians. J Mol Med (Berl) 2010;88:515–522. doi: 10.1007/s00109-010-0594-5. [DOI] [PubMed] [Google Scholar]
  39. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994;371:508–510. doi: 10.1038/371508a0. [DOI] [PubMed] [Google Scholar]
  40. Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riche F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282:561–568. doi: 10.1001/jama.282.6.561. [DOI] [PubMed] [Google Scholar]
  41. Miura T, Brockman MA, Schneidewind A, Lobritz M, Pereyra F, Rathod A, Block BL, Brumme ZL, Brumme CJ, Baker B, Rothchild AC, Li B, Trocha A, Cutrell E, Frahm N, Brander C, Toth I, Arts EJ, Allen TM, Walker BD. HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition. J Virol. 2009;83:2743–2755. doi: 10.1128/JVI.02265-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Noble JA, Valdes AM, Lane JA, Green AE, Erlich HA. Linkage disequilibrium with predisposing DR3 haplotypes accounts for apparent effects of tumor necrosis factor and lymphotoxin-alpha polymorphisms on type 1 diabetes susceptibility. Hum Immunol. 2006;67:999–1004. doi: 10.1016/j.humimm.2006.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Nou E, Zhou Y, Nou DD, Blankson JN. Effective downregulation of HLA-A*2 and HLA-B*57 by primary human immunodeficiency virus type 1 isolates cultured from elite suppressors. J Virol. 2009;83:6941–6946. doi: 10.1128/JVI.00306-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Nowak J, Kalinka-Warzocha E, Juszczynski P, Bilinski P, Mika-Witkowska R, Zajko M, Bienvenu J, Coiffier B, Salles G, Warzocha K. Association of human leukocyte antigen ancestral haplotype 8.1 with adverse outcome of non-Hodgkin's lymphoma. Genes Chromosomes Cancer. 2007;46:500–507. doi: 10.1002/gcc.20436. [DOI] [PubMed] [Google Scholar]
  45. Nowak J, Kalinka-Warzocha E, Juszczynski P, Mika-Witkowska R, Zajko M, Graczyk-Pol E, Coiffier B, Salles G, Warzocha K. Haplotype-specific pattern of association of human major histocompatibility complex with non-Hodgkin's lymphoma outcome. Tissue Antigens. 2008;71:16–26. doi: 10.1111/j.1399-0039.2007.00954.x. [DOI] [PubMed] [Google Scholar]
  46. Okamoto K, Makino S, Yoshikawa Y, Takaki A, Nagatsuka Y, Ota M, Tamiya G, Kimura A, Bahram S, Inoko H. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet. 2003;72:303–312. doi: 10.1086/346067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Parimi N, Tromp G, Kuivaniemi H, Nien JK, Gomez R, Romero R, Goddard KA. Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia. BMC Med Genet. 2008;9:60. doi: 10.1186/1471-2350-9-60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, French M, Mallal S, Christiansen F. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. 1999;167:257–274. doi: 10.1111/j.1600-065x.1999.tb01398.x. [DOI] [PubMed] [Google Scholar]
  49. Puthothu B, Bierbaum S, Kopp MV, Forster J, Heinze J, Weckmann M, Krueger M, Heinzmann A. Association of TNF-alpha with severe respiratory syncytial virus infection and bronchial asthma. Pediatr Allergy Immunol. 2009;20:157–163. doi: 10.1111/j.1399-3038.2008.00751.x. [DOI] [PubMed] [Google Scholar]
  50. Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, Alfredsson L, Padyukov L, Klareskog L, Worthington J, Siminovitch KA, Bae SC, Plenge RM, Gregersen PK, de Bakker PI. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44:291–296. doi: 10.1038/ng.1076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Rizzato C, Canzian F, Rudnai P, Gurzau E, Stein A, Koppova K, Hemminki K, Kumar R, Campa D. Interaction between functional polymorphic variants in cytokine genes, established risk factors and susceptibility to basal cell carcinoma of skin. Carcinogenesis. 2011;32:1849–1854. doi: 10.1093/carcin/bgr197. [DOI] [PubMed] [Google Scholar]
  52. Rojas J, Fernandez I, Pastor JC, Garcia-Gutierrez MT, Sanabria MR, Brion M, Coco RM, Ruiz-Moreno JM, Garcia-Arumi J, Elizalde J, Ruiz-Miguel M, Gallardo JM, Corrales RM, Carracedo A. A strong genetic association between the tumor necrosis factor locus and proliferative vitreoretinopathy: the retina 4 project. Ophthalmology. 2010;117:2417–2423. doi: 10.1016/j.ophtha.2010.03.059. e1–2. [DOI] [PubMed] [Google Scholar]
  53. Sanchez R, Levy E, Costea F, Sinnett D. IL-10 and TNF-alpha promoter haplotypes are associated with childhood Crohn's disease location. World J Gastroenterol. 2009;15:3776–3782. doi: 10.3748/wjg.15.3776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Shih CM, Lee YL, Chiou HL, Chen W, Chang GC, Chou MC, Lin LY. Association of TNF-alpha polymorphism with susceptibility to and severity of non-small cell lung cancer. Lung Cancer. 2006;52:15–20. doi: 10.1016/j.lungcan.2005.11.011. [DOI] [PubMed] [Google Scholar]
  55. Sinha S, Mishra SK, Sharma S, Patibandla PK, Mallick PK, Sharma SK, Mohanty S, Pati SS, Ramteke BK, Bhatt R, Joshi H, Dash AP, Ahuja RC, Awasthi S, Venkatesh V, Habib S. Polymorphisms of TNF-enhancer and gene for FcgammaRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population. Malar J. 2008;7:13. doi: 10.1186/1475-2875-7-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Takei K, Ikeda S, Arai T, Tanaka N, Muramatsu M, Sawabe M. Lymphotoxin-alpha polymorphisms and presence of cancer in 1,536 consecutive autopsy cases. BMC Cancer. 2008;8:235. doi: 10.1186/1471-2407-8-235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Turner DM, Grant SC, Lamb WR, Brenchley PE, Dyer PA, Sinnott PJ, Hutchinson IV. A genetic marker of high TNF-alpha production in heart transplant recipients. Transplantation. 1995;60:1113–1117. doi: 10.1097/00007890-199511270-00010. [DOI] [PubMed] [Google Scholar]
  58. Valente FP, Tan C, Phipps M, Witt CS, Kaur G, Gut I, Allcock R, Price P. TNF block haplotypes associated with conserved MHC haplotypes in European, Asian and Australian Aboriginal donors. Tissue Antigens. 2009;74:57–61. doi: 10.1111/j.1399-0039.2009.01258.x. [DOI] [PubMed] [Google Scholar]
  59. Wang SS, Purdue MP, Cerhan JR, Zheng T, Menashe I, Armstrong BK, Lan Q, Hartge P, Kricker A, Zhang Y, Morton LM, Vajdic CM, Holford TR, Severson RK, Grulich A, Leaderer BP, Davis S, Cozen W, Yeager M, Chanock SJ, Chatterjee N, Rothman N. Common gene variants in the tumor necrosis factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk. PLoS One. 2009;4:e5360. doi: 10.1371/journal.pone.0005360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wang TN, Chen WY, Wang TH, Chen CJ, Huang LY, Ko YC. Gene-gene synergistic effect on atopic asthma: tumour necrosis factor-alpha-308 and lymphotoxin-alpha-NcoI in Taiwan's children. Clin Exp Allergy. 2004;34:184–188. doi: 10.1111/j.1365-2222.2004.01867.x. [DOI] [PubMed] [Google Scholar]
  61. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997;94:3195–3199. doi: 10.1073/pnas.94.7.3195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Witte JS, Palmer LJ, O'Connor RD, Hopkins PJ, Hall JM. Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma. Eur J Hum Genet. 2002;10:82–85. doi: 10.1038/sj.ejhg.5200746. [DOI] [PubMed] [Google Scholar]
  63. Zhang K, Sun F, Zhao H. HAPLORE: a program for haplotype reconstruction in general pedigrees without recombination. Bioinformatics. 2005;21:90–103. doi: 10.1093/bioinformatics/bth388. [DOI] [PubMed] [Google Scholar]

RESOURCES