Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1

PLOS ONE, Nov 2011

Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.

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Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1

et al. (2011) Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1. PLoS ONE 6(11): e26949. doi:10.1371/journal.pone.0026949 Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA )-DRB1*01:01 Allele and Ancestral Haplotype 8.1 Sophia S. Wang 0 Yani Lu 0 Nathaniel Rothman 0 Amr M. Abdou 0 James R. Cerhan 0 Anneclaire De Roos 0 Scott Davis 0 Richard K. Severson 0 Wendy Cozen 0 Stephen J. Chanock 0 Leslie Bernstein 0 Lindsay M. Morton 0 Patricia Hartge 0 Franca Fraternali, Kings College, London, United Kingdom 0 1 Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute and City of Hope, Duarte, California, United States of America, 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), United States Department of Human Health Services (DHHS), Rockville, Maryland, United States of America, 3 Department of Microbiology and Immunology, National Research Center, Cairo, Egypt, 4 Division of Epidemiology, College of Medicine, Mayo Clinic , Rochester , Minnesota, United States of America, 5 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States of America, 6 Department of Family Medicine and Public Health Sciences, Karmanos Cancer Institute, Wayne State University , Detroit, Michigan , United States of America, 7 Norris Comprehensive Cancer Center, University of Southern California , Los Angeles, California , United States of America Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk. - Introduction HLA-DRB1*0101 OR (95% CI) AH 8.1 OR (95% CI) 1.00 (reference) 1.11 (0.711.774) 1.00 (reference) 0.52 (0.221.19) 1.00 (reference) 0.88 (0.441.73) 1.12 (0.572.19) 1.00 (reference) 1.44 (0.633.29) 1.19 (0.492.90) 1.00 (reference) 2.29 (1.134.66) 1.23 (0.712.14) 1.04 (0.512.12) 1.00 (reference) 2.81 (1.127.05) 1.00 (reference) 0.88 (0.312.5) 1.00 (reference) 1.29 (0.672.47) 1.00 (reference) 0.72 (0.281.87) 1.00 (reference) 0.44 (0.220.88) 1.00 (reference) 1.75 (0.793.89) 1.00 (reference) 0.83 (0.491.41) 1.00 (reference) 1.32 (0.602.92) 0.88 (0.382.02) 1.00 (reference) 0.77 (0.321.88) 0.69 (0.261.81) 1.00 (reference) 0.92 (0.382.23) 0.75 (0.411.37) 0.44 (0.181.08) 1.00 (reference) 2.35 (0.816.82) 1.00 (reference) 1.62 (0.584.50) 1.00 (reference) 1.27 (0.463.52) 1.00 (reference) 0.50 (0.201.22) 1.00 (reference) 1.44 (0.484.30) 1.00 (reference) 0.69 (0.321.48) 1.00 (reference) 0.98 (0.392.42) HLA-DRB1*0101 OR (95% CI) AH 8.1 OR (95% CI) 1.00 (reference) 1.01 (0.521.96) 1.00 (reference) 1.40 (0.672.92) 1.00 (reference) 1.50 (0.753.00) 1.00 (reference) 0.57 (0.261.26) 1.00 (reference) 0.37 (0.180.75) 1.00 (reference) 0.39 (0.141.06) 1.00 (reference) 1.02 (0.492.16) 1.00 (reference) 0.98 (0.422.31) 1.00 (reference) 2.54 (0.986.59) 1.00 (reference) 0.39 (0.160.97) 1.00 (reference) 1.54 (0.633.81) 1.00 (reference) 2.25 (0.855.91) 1.00 (reference) 1.93 (0.824.41) Total furans (blood; mol/g) HLA-DRB1*0101 OR (95% CI) 1.00 (reference) AH 8.1 OR (95% CI) 1.00 (reference) NC Materials and Methods o h .r t p e L n t C e m n B s ly e L b c D A N 0 3 0 7 6 .0 .9 C .0 .7 .7 1 1 N 1 0 1 6 3 8 3 8 8 4 6 1 3 5 3 ) ) ) ) ) e 4 e 8 e c .6 c .8 c ren 2 ren 1 ren fee .94 fee .55 fee (r (0 (r (0 (r ) ) ) ) e 6 e 3 c .4 c .7 n 2 n 3 re re fee .91 fee .93 (r (0 (r (0 ) ) ) ) ) ) e 0 3 e 4 0 c .1 .1 c .0 .2 n 1 2 n 2 6 re re fee .30 .26 fee .40 .64 (r (0 (0 (r (0 (0 0 7 4 0 1 9 .0 .5 .7 .0 .9 .9 1 0 0 1 0 1 0 1 3 9 4 2 2 5 1 1 1 ) ) ) ) ) ) e 0 8 e 4 8 c .4 .0 c .6 .1 n 1 1 n 2 3 re re fee .57 .15 fee .83 .66 (r (0 (0 (r (0 (0 0 9 0 0 8 5 .0 .8 .4 .0 .4 .4 1 0 0 1 1 1 ) ) ) ) ) ) e 3 4 e 2 7 c .1 .6 c .7 .8 n 1 2 n 1 2 re re fee .47 .73 fee .58 .68 (r (0 (0 (r (0 (0 0 3 9 0 9 9 .0 .7 .3 .0 .9 .3 1 0 1 1 0 1 ) ) ) ) ) ) e 4 5 e 8 0 c .1 .8 c .8 .8 n 1 1 n 1 3 re re fee .74 .34 fee .06 .38 (r (0 (0 (r (0 (0 0 3 9 0 6 8 .0 .7 .8 .0 .0 .7 1 0 0 1 1 1 2 2 2 7 1 8 4 6 1 2 5 3 ) ) ) ) ) ) e 3 7 e 9 6 c .1 .5 c .3 .5 n 1 1 n 1 1 re re fee .65 .64 fee .70 .62 (r (0 (0 (r (0 (0 0 6 0 0 8 9 .0 .8 .0 .0 .9 .9 1 0 1 1 0 0 9 4 3 9 6 3 6 5 2 5 2 Questionnaire Risk Factor Data Statistical Analysis ) ) ) ) e 8 e 4 c .1 c .6 n 3 n 2 re re fee .54 fee .44 (r (0 (r (0 ) ) ) ) ) e 6 e 8 e c .9 c .4 c ren 1 ren 4 ren fee .66 fee .56 fee (r (0 (r (0 (r 0 1 0 7 .0 C .0 .3 .0 C .0 1 N 1 1 1 N 1 2 4 1 5 1 3 8 1 8 H 9 2 9 4 5 2 7 2 1 7 2 1 5 1 5 1 2 1 3 1 n o n , L .00 .24 .74 .00 .18 .00 .11 .00 .61 .00 A tye 1 1 1 1 1 1 1 1 1 1 N c o k u e l ) ) 2 ) ) ) e 9 . e 7 .6 c .0 8 c .6 4 n 1 n 6 1 re 5 re (free .(510 .(01 (free .(350 .(460 0 1 6 0 7 5 .0 .4 .9 .0 .8 .0 1 0 2 1 1 3 ) ) ) ) ) ) e 3 2 e 7 6 c .5 .3 c .5 .8 n 1 2 n 1 2 re re (free .(640 .(540 (free .(520 .(067 0 9 2 0 0 8 .0 .9 .1 .0 .9 .3 1 0 1 1 0 1 ) ) ) ) ) 7 e 6 2 e 1 . c .3 .8 c .3 6 n 1 3 n 4 re re 4 (free .(460 .(084 (free .(970 .(01 0 9 9 0 5 4 .0 .7 .7 .0 .0 .6 1 0 1 1 2 2 ) ) ) ) ) ) e 1 0 e 0 3 c .1 .4 c .4 .6 n 1 1 n 1 1 re re fee .64 .54 fee .70 .65 (r (0 (0 (r (0 (0 0 4 7 0 9 3 .0 .8 .8 .0 .9 .0 1 0 0 1 0 1 0 3 7 .0 .8 C .0 .7 .1 1 0 N 1 1 4 ) ) ) ) ) ) e 2 2 e 5 1 c .2 .3 c .2 .9 n 1 1 n 2 2 re re (free .(502 .(205 (free .(706 .(607 0 0 8 0 1 9 .0 .8 .5 .0 .3 .3 1 0 0 1 1 1 8 9 9 5 1 4 6 8 2 6 3 ) ) ) ) e 5 e 5 c .4 c .5 n 2 n 3 re re fee .78 fee .73 (r (0 (r (0 l()t/kaEonhgw ,6101 $169 ii)(ta6BngVmm ,.009713 $.09772 Results Discussion ) ) ) ) ) e 4 )e ) e 0 6 (frrceeen ..(44061 (frrceeen ..860215 (frrceeen ..(52062 ..(68032 ( 0 5 0 1 0 6 6 .0 .8 .0 .2 .0 .1 .2 1 0 1 1 1 1 1 ) ) ) ) ) e 9 e 5 e c .6 c .2 c ren 6 ren 5 ren fee .82 fee .26 fee (r (0 (r (0 (r 6 ) ) ) 5 ) ) ) e 6 e . e 3 9 c .5 c 4 c .1 .0 ren 2 ren 0 ren 4 4 (free .(150 (free .(01 (free .(250 .(670 e s u f 3 0 1 5 7 9 3 4 5 if 6 1 1 3 1 3 1 4 1 3 1 d , L Acknowledgments 1. 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Sophia S. Wang, Yani Lu, Nathaniel Rothman, Amr M. Abdou, James R. Cerhan, Anneclaire De Roos, Scott Davis, Richard K. Severson, Wendy Cozen, Stephen J. Chanock, Leslie Bernstein, Lindsay M. Morton, Patricia Hartge. Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1, PLOS ONE, 2011, DOI: 10.1371/journal.pone.0026949