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. 1999 Oct;107(Suppl 5):693–700. doi: 10.1289/ehp.99107s5693

The role of genetic factors in autoimmune disease: implications for environmental research.

G S Cooper 1, F W Miller 1, J P Pandey 1
PMCID: PMC1566257  PMID: 10502533

Abstract

Studies in both humans and in animal models of specific disorders suggest that polymorphisms of multiple genes are involved in conferring either a predisposition to or protection from autoimmune diseases. Genes encoding polymorphic proteins that regulate immune responses or the rates and extent of metabolism of certain chemical structures have been the focus of much of the research regarding genetic susceptibility. We examine the type and strength of evidence concerning genetic factors and disease etiology, drawing examples from a number of autoimmune diseases. Twin studies of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes, and multiple sclerosis (MS) indicate that disease concordance in monozygotic twins is 4 or more times higher than in dizygotic twins. Strong familial associations (odds ratio ranging from 5-10) are seen in studies of MS, type I diabetes, Graves disease, discoid lupus, and SLE. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Recent genomewide searches in RA, SLE, and MS provide evidence for multiple susceptibility genes involving major histocompatibility complex (MHC) and non-MHC loci; there is also evidence that many autoimmune diseases share a common set of susceptibility genes. The multifactorial nature of the genetic risk factors and the low penetrance of disease underscore the potential influence of environmental factors and gene-environment interactions on the etiology of autoimmune diseases.

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Selected References

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  1. Aho K., Koskenvuo M., Tuominen J., Kaprio J. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol. 1986 Oct;13(5):899–902. [PubMed] [Google Scholar]
  2. Aitman T. J., Todd J. A. Molecular genetics of diabetes mellitus. Baillieres Clin Endocrinol Metab. 1995 Jul;9(3):631–656. doi: 10.1016/s0950-351x(95)80655-5. [DOI] [PubMed] [Google Scholar]
  3. Altobelli E., Chiarelli F., Valenti M., Verrotti A., Blasetti A., Di Orio F. Family history and risk of insulin-dependent diabetes mellitus: a population-based case-control study. Acta Diabetol. 1998 Apr;35(1):57–60. doi: 10.1007/s005920050102. [DOI] [PubMed] [Google Scholar]
  4. Becker K. G., Simon R. M., Bailey-Wilson J. E., Freidlin B., Biddison W. E., McFarland H. F., Trent J. M. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9979–9984. doi: 10.1073/pnas.95.17.9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bellamy N., Duffy D., Martin N., Mathews J. Rheumatoid arthritis in twins: a study of aetiopathogenesis based on the Australian Twin Registry. Ann Rheum Dis. 1992 May;51(5):588–593. doi: 10.1136/ard.51.5.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bias W. B., Reveille J. D., Beaty T. H., Meyers D. A., Arnett F. C. Evidence that autoimmunity in man is a Mendelian dominant trait. Am J Hum Genet. 1986 Nov;39(5):584–602. [PMC free article] [PubMed] [Google Scholar]
  7. Brennan P., Hajeer A., Ong K. R., Worthington J., John S., Thomson W., Silman A., Ollier B. Allelic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles among women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 1997 Aug;40(8):1383–1386. doi: 10.1002/art.1780400804. [DOI] [PubMed] [Google Scholar]
  8. Brix T. H., Christensen K., Holm N. V., Harvald B., Hegedüs L. A population-based study of Graves' disease in Danish twins. Clin Endocrinol (Oxf) 1998 Apr;48(4):397–400. doi: 10.1046/j.1365-2265.1998.00450.x. [DOI] [PubMed] [Google Scholar]
  9. Burlingame R. W. The clinical utility of antihistone antibodies. Autoantibodies reactive with chromatin in systemic lupus erythematosus and drug-induced lupus. Clin Lab Med. 1997 Sep;17(3):367–378. [PubMed] [Google Scholar]
  10. Cederholm J., Wibell L. Familial influence on type 1 (insulin-dependent) diabetes mellitus by relatives with either insulin-treated or type 2 (non-insulin-dependent) diabetes mellitus. Diabetes Res. 1991 Nov;18(3):109–113. [PubMed] [Google Scholar]
  11. Cornélis F., Fauré S., Martinez M., Prud'homme J. F., Fritz P., Dib C., Alves H., Barrera P., de Vries N., Balsa A. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10746–10750. doi: 10.1073/pnas.95.18.10746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cribb A. E., Grant D. M., Miller M. A., Spielberg S. P. Expression of monomorphic arylamine N-acetyltransferase (NAT1) in human leukocytes. J Pharmacol Exp Ther. 1991 Dec;259(3):1241–1246. [PubMed] [Google Scholar]
  13. Dahlquist G., Blom L., Tuvemo T., Nyström L., Sandström A., Wall S. The Swedish childhood diabetes study--results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia. 1989 Jan;32(1):2–6. doi: 10.1007/BF00265396. [DOI] [PubMed] [Google Scholar]
  14. Deapen D., Escalante A., Weinrib L., Horwitz D., Bachman B., Roy-Burman P., Walker A., Mack T. M. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992 Mar;35(3):311–318. doi: 10.1002/art.1780350310. [DOI] [PubMed] [Google Scholar]
  15. Dugoujon J. M., Cambon-Thomsen A. Immunoglobulin allotypes (GM and KM) and their interactions with HLA antigens in autoimmune diseases: a review. Autoimmunity. 1995;22(4):245–260. doi: 10.3109/08916939508995322. [DOI] [PubMed] [Google Scholar]
  16. Dunckley H., Gatenby P. A., Hawkins B., Naito S., Serjeantson S. W. Deficiency of C4A is a genetic determinant of systemic lupus erythematosus in three ethnic groups. J Immunogenet. 1987 Aug-Oct;14(4-5):209–218. doi: 10.1111/j.1744-313x.1987.tb00383.x. [DOI] [PubMed] [Google Scholar]
  17. Dyment D. A., Sadovnick A. D., Ebers G. C., Sadnovich A. D. Genetics of multiple sclerosis. Hum Mol Genet. 1997;6(10):1693–1698. doi: 10.1093/hmg/6.10.1693. [DOI] [PubMed] [Google Scholar]
  18. Ebers G. C., Bulman D. E., Sadovnick A. D., Paty D. W., Warren S., Hader W., Murray T. J., Seland T. P., Duquette P., Grey T. A population-based study of multiple sclerosis in twins. N Engl J Med. 1986 Dec 25;315(26):1638–1642. doi: 10.1056/NEJM198612253152603. [DOI] [PubMed] [Google Scholar]
  19. Ebers G. C., Kukay K., Bulman D. E., Sadovnick A. D., Rice G., Anderson C., Armstrong H., Cousin K., Bell R. B., Hader W. A full genome search in multiple sclerosis. Nat Genet. 1996 Aug;13(4):472–476. doi: 10.1038/ng0896-472. [DOI] [PubMed] [Google Scholar]
  20. Elston R. C. Methods of linkage analysis--and the assumptions underlying them [see comment]. Am J Hum Genet. 1998 Oct;63(4):931–934. doi: 10.1086/302073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Folomeev M., Dougados M., Beaune J., Kouyoumdjian J. C., Nahoul K., Amor B., Alekberova Z. Plasma sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus. 1992 May;1(3):191–195. doi: 10.1177/096120339200100312. [DOI] [PubMed] [Google Scholar]
  22. Foppa I., Spiegelman D. Power and sample size calculations for case-control studies of gene-environment interactions with a polytomous exposure variable. Am J Epidemiol. 1997 Oct 1;146(7):596–604. doi: 10.1093/oxfordjournals.aje.a009320. [DOI] [PubMed] [Google Scholar]
  23. Foster H., Fay A., Kelly C., Charles P., Walker D., Griffiths I. Thyroid disease and other autoimmune phenomena in a family study of primary Sjögren's syndrome. Br J Rheumatol. 1993 Jan;32(1):36–40. doi: 10.1093/rheumatology/32.1.36. [DOI] [PubMed] [Google Scholar]
  24. Gaffney P. M., Kearns G. M., Shark K. B., Ortmann W. A., Selby S. A., Malmgren M. L., Rohlf K. E., Ockenden T. C., Messner R. P., King R. A. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14875–14879. doi: 10.1073/pnas.95.25.14875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. García-Closas M., Thompson W. D., Robins J. M. Differential misclassification and the assessment of gene-environment interactions in case-control studies. Am J Epidemiol. 1998 Mar 1;147(5):426–433. doi: 10.1093/oxfordjournals.aje.a009467. [DOI] [PubMed] [Google Scholar]
  26. Ginn L. R., Lin J. P., Plotz P. H., Bale S. J., Wilder R. L., Mbauya A., Miller F. W. Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases. Arthritis Rheum. 1998 Mar;41(3):400–405. doi: 10.1002/1529-0131(199803)41:3<400::AID-ART4>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  27. Goldstein A. M., Falk R. T., Korczak J. F., Lubin J. H. Detecting gene-environment interactions using a case-control design. Genet Epidemiol. 1997;14(6):1085–1089. doi: 10.1002/(SICI)1098-2272(1997)14:6<1085::AID-GEPI87>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  28. Goldstein R., Sengar D. P. Comparative studies of the major histocompatibility complex in French Canadian and non-French Canadian Caucasians with systemic lupus erythematosus. Arthritis Rheum. 1993 Aug;36(8):1121–1127. doi: 10.1002/art.1780360813. [DOI] [PubMed] [Google Scholar]
  29. Hajeer A. H., Worthington J., Silman A. J., Ollier W. E. Association of tumor necrosis factor microsatellite polymorphisms with HLA-DRB1*04-bearing haplotypes in rheumatoid arthritis patients. Arthritis Rheum. 1996 Jul;39(7):1109–1114. doi: 10.1002/art.1780390706. [DOI] [PubMed] [Google Scholar]
  30. Harty L. C., Caporaso N. E., Hayes R. B., Winn D. M., Bravo-Otero E., Blot W. J., Kleinman D. V., Brown L. M., Armenian H. K., Fraumeni J. F., Jr Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. J Natl Cancer Inst. 1997 Nov 19;89(22):1698–1705. doi: 10.1093/jnci/89.22.1698. [DOI] [PubMed] [Google Scholar]
  31. Howard P. F., Hochberg M. C., Bias W. B., Arnett F. C., Jr, McLean R. H. Relationship between C4 null genes, HLA-D region antigens, and genetic susceptibility to systemic lupus erythematosus in Caucasian and black Americans. Am J Med. 1986 Aug;81(2):187–193. doi: 10.1016/0002-9343(86)90250-0. [DOI] [PubMed] [Google Scholar]
  32. Huston D. P. The biology of the immune system. JAMA. 1997 Dec 10;278(22):1804–1814. [PubMed] [Google Scholar]
  33. Hwang S. J., Beaty T. H., Liang K. Y., Coresh J., Khoury M. J. Minimum sample size estimation to detect gene-environment interaction in case-control designs. Am J Epidemiol. 1994 Dec 1;140(11):1029–1037. doi: 10.1093/oxfordjournals.aje.a117193. [DOI] [PubMed] [Google Scholar]
  34. Hwang S. J., Beaty T. H., Panny S. R., Street N. A., Joseph J. M., Gordon S., McIntosh I., Francomano C. A. Association study of transforming growth factor alpha (TGF alpha) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects. Am J Epidemiol. 1995 Apr 1;141(7):629–636. doi: 10.1093/oxfordjournals.aje.a117478. [DOI] [PubMed] [Google Scholar]
  35. Jara L. J., Lavalle C., Espinoza L. R. Does prolactin have a role in the pathogenesis of systemic lupus erythematosus? J Rheumatol. 1992 Sep;19(9):1333–1336. [PubMed] [Google Scholar]
  36. Jarvik G. P. Complex segregation analyses: uses and limitations. Am J Hum Genet. 1998 Oct;63(4):942–946. doi: 10.1086/302075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Jiang X., Khursigara G., Rubin R. L. Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils. Science. 1994 Nov 4;266(5186):810–813. doi: 10.1126/science.7973636. [DOI] [PubMed] [Google Scholar]
  38. Jones M. A., Silman A. J., Whiting S., Barrett E. M., Symmons D. P. Occurrence of rheumatoid arthritis is not increased in the first degree relatives of a population based inception cohort of inflammatory polyarthritis. Ann Rheum Dis. 1996 Feb;55(2):89–93. doi: 10.1136/ard.55.2.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Järvinen P., Kaprio J., Mäkitalo R., Koskenvuo M., Aho K. Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: an increased prevalence of disease in MZ twins and concordance of disease features. J Intern Med. 1992 Jan;231(1):67–72. doi: 10.1111/j.1365-2796.1992.tb00500.x. [DOI] [PubMed] [Google Scholar]
  40. Kaprio J., Tuomilehto J., Koskenvuo M., Romanov K., Reunanen A., Eriksson J., Stengård J., Kesäniemi Y. A. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia. 1992 Nov;35(11):1060–1067. doi: 10.1007/BF02221682. [DOI] [PubMed] [Google Scholar]
  41. Kaufman L. D., Gruber B. L., Gregersen P. K. Clinical follow-up and immunogenetic studies of 32 patients with eosinophilia-myalgia syndrome. Lancet. 1991 May 4;337(8749):1071–1074. doi: 10.1016/0140-6736(91)91717-9. [DOI] [PubMed] [Google Scholar]
  42. Khoury M. J., Flanders W. D. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls! Am J Epidemiol. 1996 Aug 1;144(3):207–213. doi: 10.1093/oxfordjournals.aje.a008915. [DOI] [PubMed] [Google Scholar]
  43. Khoury M. J., James L. M. Population and familial relative risks of disease associated with environmental factors in the presence of gene-environment interaction. Am J Epidemiol. 1993 Jun 1;137(11):1241–1250. doi: 10.1093/oxfordjournals.aje.a116626. [DOI] [PubMed] [Google Scholar]
  44. Kinnunen E., Juntunen J., Ketonen L., Koskimies S., Konttinen Y. T., Salmi T., Koskenvuo M., Kaprio J. Genetic susceptibility to multiple sclerosis. A co-twin study of a nationwide series. Arch Neurol. 1988 Oct;45(10):1108–1111. doi: 10.1001/archneur.1988.00520340062013. [DOI] [PubMed] [Google Scholar]
  45. Kinnunen E., Koskenvuo M., Kaprio J., Aho K. Multiple sclerosis in a nationwide series of twins. Neurology. 1987 Oct;37(10):1627–1629. doi: 10.1212/wnl.37.10.1627. [DOI] [PubMed] [Google Scholar]
  46. Koumantaki Y., Giziaki E., Linos A., Kontomerkos A., Kaklamanis P., Vaiopoulos G., Mandas J., Kaklamani E. Family history as a risk factor for rheumatoid arthritis: a case-control study. J Rheumatol. 1997 Aug;24(8):1522–1526. [PubMed] [Google Scholar]
  47. Kumana C. R., Chan M. M., Wong K. L., Wong R. W., Kou M., Lauder I. J. Lack of association between slow acetylator status and spontaneous lupus erythematosus. Clin Pharmacol Ther. 1990 Aug;48(2):208–213. doi: 10.1038/clpt.1990.137. [DOI] [PubMed] [Google Scholar]
  48. Kumar D., Gemayel N. S., Deapen D., Kapadia D., Yamashita P. H., Lee M., Dwyer J. H., Roy-Burman P., Bray G. A., Mack T. M. North-American twins with IDDM. Genetic, etiological, and clinical significance of disease concordance according to age, zygosity, and the interval after diagnosis in first twin. Diabetes. 1993 Sep;42(9):1351–1363. doi: 10.2337/diab.42.9.1351. [DOI] [PubMed] [Google Scholar]
  49. Kwoh C. K., Venglish C., Lynn A. H., Whitley D. M., Young E., Chakravarti A. Age, sex, and the familial risk of rheumatoid arthritis. Am J Epidemiol. 1996 Jul 1;144(1):15–24. doi: 10.1093/oxfordjournals.aje.a008850. [DOI] [PubMed] [Google Scholar]
  50. Kyvik K. O., Green A., Beck-Nielsen H. Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. BMJ. 1995 Oct 7;311(7010):913–917. doi: 10.1136/bmj.311.7010.913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Lahita R. G., Bradlow L., Fishman J., Kunkel H. G. Estrogen metabolism in systemic lupus erythematosus: patients and family members. Arthritis Rheum. 1982 Jul;25(7):843–846. doi: 10.1002/art.1780250726. [DOI] [PubMed] [Google Scholar]
  52. Lawrence J. S., Martins C. L., Drake G. L. A family survey of lupus erythematosus. 1. Heritability. J Rheumatol. 1987 Oct;14(5):913–921. [PubMed] [Google Scholar]
  53. Lin J. P., Cash J. M., Doyle S. Z., Peden S., Kanik K., Amos C. I., Bale S. J., Wilder R. L. Familial clustering of rheumatoid arthritis with other autoimmune diseases. Hum Genet. 1998 Oct;103(4):475–482. doi: 10.1007/s004390050853. [DOI] [PubMed] [Google Scholar]
  54. Linet M. S., Harlow S. D., McLaughlin J. K., McCaffrey L. D. A comparison of interview data and medical records for previous medical conditions and surgery. J Clin Epidemiol. 1989;42(12):1207–1213. doi: 10.1016/0895-4356(89)90119-4. [DOI] [PubMed] [Google Scholar]
  55. Linet M. S., Mclaughlin J. K., Harlow S. D., Fraumeni J. F. Family history of autoimmune disorders and cancer in multiple myeloma. Int J Epidemiol. 1988 Sep;17(3):512–513. doi: 10.1093/ije/17.3.512. [DOI] [PubMed] [Google Scholar]
  56. Litwin A., Adams L. E., Zimmer H., Foad B., Loggie J. H., Hess E. V. Prospective study of immunologic effects of hydralazine in hypertensive patients. Clin Pharmacol Ther. 1981 Apr;29(4):447–456. doi: 10.1038/clpt.1981.62. [DOI] [PubMed] [Google Scholar]
  57. Martucci C. P., Fishman J. P450 enzymes of estrogen metabolism. Pharmacol Ther. 1993 Feb-Mar;57(2-3):237–257. doi: 10.1016/0163-7258(93)90057-k. [DOI] [PubMed] [Google Scholar]
  58. Matsuda A., Kuzuya T. Diabetic twins in Japan. Diabetes Res Clin Pract. 1994 Oct;24 (Suppl):S63–S67. doi: 10.1016/0168-8227(94)90229-1. [DOI] [PubMed] [Google Scholar]
  59. May D. G. Genetic differences in drug disposition. J Clin Pharmacol. 1994 Sep;34(9):881–897. doi: 10.1002/j.1552-4604.1994.tb04001.x. [DOI] [PubMed] [Google Scholar]
  60. Midgard R., Grønning M., Riise T., Kvåle G., Nyland H. Multiple sclerosis and chronic inflammatory diseases. A case-control study. Acta Neurol Scand. 1996 May;93(5):322–328. doi: 10.1111/j.1600-0404.1996.tb00004.x. [DOI] [PubMed] [Google Scholar]
  61. Morris R. J., Freed C. R., Kohler P. F. Drug acetylation phenotype unrelated to development of spontaneous systemic lupus erythematosus. Arthritis Rheum. 1979 Jul;22(7):777–780. doi: 10.1002/art.1780220714. [DOI] [PubMed] [Google Scholar]
  62. Moser K. L., Neas B. R., Salmon J. E., Yu H., Gray-McGuire C., Asundi N., Bruner G. R., Fox J., Kelly J., Henshall S. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14869–14874. doi: 10.1073/pnas.95.25.14869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Mulcahy B., Waldron-Lynch F., McDermott M. F., Adams C., Amos C. I., Zhu D. K., Ward R. H., Clegg D. O., Shanahan F., Molloy M. G. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet. 1996 Sep;59(3):676–683. [PMC free article] [PubMed] [Google Scholar]
  64. Mumford C. J., Wood N. W., Kellar-Wood H., Thorpe J. W., Miller D. H., Compston D. A. The British Isles survey of multiple sclerosis in twins. Neurology. 1994 Jan;44(1):11–15. doi: 10.1212/wnl.44.1.11. [DOI] [PubMed] [Google Scholar]
  65. Nagata C., Fujita S., Iwata H., Kurosawa Y., Kobayashi K., Kobayashi M., Motegi K., Omura T., Yamamoto M., Nose T. Systemic lupus erythematosus: a case-control epidemiologic study in Japan. Int J Dermatol. 1995 May;34(5):333–337. doi: 10.1111/j.1365-4362.1995.tb03614.x. [DOI] [PubMed] [Google Scholar]
  66. Nebert D. W. Elevated estrogen 16 alpha-hydroxylase activity: is this a genotoxic or nongenotoxic biomarker in human breast cancer risk? J Natl Cancer Inst. 1993 Dec 1;85(23):1888–1891. doi: 10.1093/jnci/85.23.1888. [DOI] [PubMed] [Google Scholar]
  67. Nebert D. W., McKinnon R. A., Puga A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol. 1996 Apr;15(4):273–280. doi: 10.1089/dna.1996.15.273. [DOI] [PubMed] [Google Scholar]
  68. Olmos P., A'Hern R., Heaton D. A., Millward B. A., Risley D., Pyke D. A., Leslie R. D. The significance of the concordance rate for type 1 (insulin-dependent) diabetes in identical twins. Diabetologia. 1988 Oct;31(10):747–750. doi: 10.1007/BF00274777. [DOI] [PubMed] [Google Scholar]
  69. Ong M. L., Mant T. G., Veerapen K., Fitzgerald D., Wang F., Manivasagar M., Bosco J. J. The lack of relationship between acetylator phenotype and idiopathic systemic lupus erythematosus in a South-east Asian population: a study of Indians, Malays and Malaysian Chinese. Br J Rheumatol. 1990 Dec;29(6):462–464. doi: 10.1093/rheumatology/29.6.462. [DOI] [PubMed] [Google Scholar]
  70. Ottman R. Gene-environment interaction: definitions and study designs. Prev Med. 1996 Nov-Dec;25(6):764–770. doi: 10.1006/pmed.1996.0117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Ou D., Mitchell L. A., Tingle A. J. A new categorization of HLA DR alleles on a functional basis. Hum Immunol. 1998 Oct;59(10):665–676. doi: 10.1016/s0198-8859(98)00067-6. [DOI] [PubMed] [Google Scholar]
  72. Oursler J. R., Farmer E. R., Roubenoff R., Mogavero H. S., Watson R. M. Cutaneous manifestations of the eosinophilia-myalgia syndrome. Br J Dermatol. 1992 Aug;127(2):138–146. doi: 10.1111/j.1365-2133.1992.tb08046.x. [DOI] [PubMed] [Google Scholar]
  73. Pandey J. P., Fudenberg H. H. Immunogenetic markers in autoimmune disease. Ann Intern Med. 1984 Dec;101(6):868–869. doi: 10.7326/0003-4819-101-6-868. [DOI] [PubMed] [Google Scholar]
  74. Perera F. P. Environment and cancer: who are susceptible? Science. 1997 Nov 7;278(5340):1068–1073. doi: 10.1126/science.278.5340.1068. [DOI] [PubMed] [Google Scholar]
  75. Price E. J., Venables P. J. Drug-induced lupus. Drug Saf. 1995 Apr;12(4):283–290. doi: 10.2165/00002018-199512040-00008. [DOI] [PubMed] [Google Scholar]
  76. Reidenberg M. M., Drayer D. E., Lorenzo B., Strom B. L., West S. L., Snyder E. S., Freundlich B., Stolley P. D. Acetylation phenotypes and environmental chemical exposure of people with idiopathic systemic lupus erythematosus. Arthritis Rheum. 1993 Jul;36(7):971–973. doi: 10.1002/art.1780360714. [DOI] [PubMed] [Google Scholar]
  77. Reidenberg M. M. The chemical induction of systemic lupus erythematosus and lupus-like illnesses. Arthritis Rheum. 1981 Aug;24(8):1004–1009. doi: 10.1002/art.1780240805. [DOI] [PubMed] [Google Scholar]
  78. Remmers E. F., Longman R. E., Du Y., O'Hare A., Cannon G. W., Griffiths M. M., Wilder R. L. A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats. Nat Genet. 1996 Sep;14(1):82–85. doi: 10.1038/ng0996-82. [DOI] [PubMed] [Google Scholar]
  79. Reveille J. D., Moulds J. M., Ahn C., Friedman A. W., Baethge B., Roseman J., Straaton K. V., Alarcón G. S. Systemic lupus erythematosus in three ethnic groups: I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. LUMINA Study Group. Lupus in minority populations, nature versus nurture. Arthritis Rheum. 1998 Jul;41(7):1161–1172. doi: 10.1002/1529-0131(199807)41:7<1161::AID-ART4>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  80. Reveille J. D. The genetic contribution to the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol. 1998 May;10(3):187–200. doi: 10.1097/00002281-199805000-00007. [DOI] [PubMed] [Google Scholar]
  81. Reveille J. D., Wilson R. W., Provost T. T., Bias W. B., Arnett F. C. Primary Sjögren's syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984 Dec;101(6):748–756. doi: 10.7326/0003-4819-101-6-748. [DOI] [PubMed] [Google Scholar]
  82. Richeldi L., Kreiss K., Mroz M. M., Zhen B., Tartoni P., Saltini C. Interaction of genetic and exposure factors in the prevalence of berylliosis. Am J Ind Med. 1997 Oct;32(4):337–340. doi: 10.1002/(sici)1097-0274(199710)32:4<337::aid-ajim3>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  83. Richeldi L., Sorrentino R., Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. 1993 Oct 8;262(5131):242–244. doi: 10.1126/science.8105536. [DOI] [PubMed] [Google Scholar]
  84. Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
  85. Robertson N. P., Fraser M., Deans J., Clayton D., Walker N., Compston D. A. Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. Brain. 1996 Apr;119(Pt 2):449–455. doi: 10.1093/brain/119.2.449. [DOI] [PubMed] [Google Scholar]
  86. Ruberti G., Begovich A. B., Steere A. C., Klitz W., Erlich H. A., Fathman C. G. Molecular analysis of the role of the HLA class II genes DRB1, DQA1, DQB1, and DPB1 in susceptibility to Lyme arthritis. Hum Immunol. 1991 May;31(1):20–27. doi: 10.1016/0198-8859(91)90044-a. [DOI] [PubMed] [Google Scholar]
  87. Rudwaleit M., Tikly M., Khamashta M., Gibson K., Klinke J., Hughes G., Wordsworth P. Interethnic differences in the association of tumor necrosis factor promoter polymorphisms with systemic lupus erythematosus. J Rheumatol. 1996 Oct;23(10):1725–1728. [PubMed] [Google Scholar]
  88. Russell G. I., Bing R. F., Jones J. A., Thurston H., Swales J. D. Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. Q J Med. 1987 Oct;65(246):845–852. [PubMed] [Google Scholar]
  89. Sadovnick A. D., Armstrong H., Rice G. P., Bulman D., Hashimoto L., Paty D. W., Hashimoto S. A., Warren S., Hader W., Murray T. J. A population-based study of multiple sclerosis in twins: update. Ann Neurol. 1993 Mar;33(3):281–285. doi: 10.1002/ana.410330309. [DOI] [PubMed] [Google Scholar]
  90. Sadovnick A. D., Baird P. A., Ward R. H. Multiple sclerosis: updated risks for relatives. Am J Med Genet. 1988 Mar;29(3):533–541. doi: 10.1002/ajmg.1320290310. [DOI] [PubMed] [Google Scholar]
  91. Sakkas L. I., Moore D. F., Akritidis N. C. Cancer in families with systemic sclerosis. Am J Med Sci. 1995 Dec;310(6):223–225. [PubMed] [Google Scholar]
  92. Sawcer S., Jones H. B., Feakes R., Gray J., Smaldon N., Chataway J., Robertson N., Clayton D., Goodfellow P. N., Compston A. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet. 1996 Aug;13(4):464–468. doi: 10.1038/ng0896-464. [DOI] [PubMed] [Google Scholar]
  93. Schaid D. J. Transmission disequilibrium, family controls, and great expectations. Am J Hum Genet. 1998 Oct;63(4):935–941. doi: 10.1086/302077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Schur P. H. Genetics of systemic lupus erythematosus. Lupus. 1995 Dec;4(6):425–437. doi: 10.1177/096120339500400603. [DOI] [PubMed] [Google Scholar]
  95. Schur P. H., Marcus-Bagley D., Awdeh Z., Yunis E. J., Alper C. A. The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus. Arthritis Rheum. 1990 Jul;33(7):985–992. doi: 10.1002/art.1780330710. [DOI] [PubMed] [Google Scholar]
  96. Shou M., Korzekwa K. R., Brooks E. N., Krausz K. W., Gonzalez F. J., Gelboin H. V. Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone. Carcinogenesis. 1997 Jan;18(1):207–214. doi: 10.1093/carcin/18.1.207. [DOI] [PubMed] [Google Scholar]
  97. Silman A. J., MacGregor A. J., Thomson W., Holligan S., Carthy D., Farhan A., Ollier W. E. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993 Oct;32(10):903–907. doi: 10.1093/rheumatology/32.10.903. [DOI] [PubMed] [Google Scholar]
  98. Speirs C., Fielder A. H., Chapel H., Davey N. J., Batchelor J. R. Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus. Lancet. 1989 Apr 29;1(8644):922–924. doi: 10.1016/s0140-6736(89)92506-3. [DOI] [PubMed] [Google Scholar]
  99. Spielman R. S., Ewens W. J. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet. 1996 Nov;59(5):983–989. [PMC free article] [PubMed] [Google Scholar]
  100. Steere A. C., Dwyer E., Winchester R. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med. 1990 Jul 26;323(4):219–223. doi: 10.1056/NEJM199007263230402. [DOI] [PubMed] [Google Scholar]
  101. Strom B. L., Reidenberg M. M., West S., Snyder E. S., Freundlich B., Stolley P. D. Shingles, allergies, family medical history, oral contraceptives, and other potential risk factors for systemic lupus erythematosus. Am J Epidemiol. 1994 Oct 1;140(7):632–642. doi: 10.1093/oxfordjournals.aje.a117302. [DOI] [PubMed] [Google Scholar]
  102. Taylor J. A., Umbach D. M., Stephens E., Castranio T., Paulson D., Robertson C., Mohler J. L., Bell D. A. The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res. 1998 Aug 15;58(16):3603–3610. [PubMed] [Google Scholar]
  103. Thomson G. HLA disease associations: models for the study of complex human genetic disorders. Crit Rev Clin Lab Sci. 1995;32(2):183–219. doi: 10.3109/10408369509084684. [DOI] [PubMed] [Google Scholar]
  104. Uetrecht J. P. Mechanism of drug-induced lupus. Chem Res Toxicol. 1988 May-Jun;1(3):133–143. doi: 10.1021/tx00003a001. [DOI] [PubMed] [Google Scholar]
  105. Varga J., Heiman-Patterson T. D., Emery D. L., Griffin R., Lally E. V., Uitto J. J., Jimenez S. A. Clinical spectrum of the systemic manifestations of the eosinophilia-myalgia syndrome. Semin Arthritis Rheum. 1990 Jun;19(6):313–328. doi: 10.1016/0049-0172(90)90069-r. [DOI] [PubMed] [Google Scholar]
  106. Vicario J. L., Serrano-Rios M., San Andrés F., Arnaiz-Villena A. HLA-DR3, DR4 increase in chronic stage of Spanish oil disease. Lancet. 1982 Jan 30;1(8266):276–276. doi: 10.1016/s0140-6736(82)90994-1. [DOI] [PubMed] [Google Scholar]
  107. Vinasco J., Beraún Y., Nieto A., Fraile A., Mataran L., Pareja E., Martín J. Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens. 1997 Jan;49(1):74–78. doi: 10.1111/j.1399-0039.1997.tb02715.x. [DOI] [PubMed] [Google Scholar]
  108. Weeks D. E., Lathrop G. M. Polygenic disease: methods for mapping complex disease traits. Trends Genet. 1995 Dec;11(12):513–519. doi: 10.1016/s0168-9525(00)89163-5. [DOI] [PubMed] [Google Scholar]
  109. White P. C. Genetic diseases of steroid metabolism. Vitam Horm. 1994;49:131–195. doi: 10.1016/s0083-6729(08)61147-4. [DOI] [PubMed] [Google Scholar]
  110. Wilson A. G., de Vries N., van de Putte L. B., Duff G. W. A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann Rheum Dis. 1995 Jul;54(7):601–603. doi: 10.1136/ard.54.7.601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Yang Q., Khoury M. J. Evolving methods in genetic epidemiology. III. Gene-environment interaction in epidemiologic research. Epidemiol Rev. 1997;19(1):33–43. doi: 10.1093/oxfordjournals.epirev.a017944. [DOI] [PubMed] [Google Scholar]
  112. del Junco D., Luthra H. S., Annegers J. F., Worthington J. W., Kurland L. T. The familial aggregation of rheumatoid arthritis and its relationship to the HLA-DR4 association. Am J Epidemiol. 1984 May;119(5):813–829. doi: 10.1093/oxfordjournals.aje.a113802. [DOI] [PubMed] [Google Scholar]

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