Serum immunoglobulin A (IgA) concentrations were determined in 12 600 adult Swedish twins, applying a high-throughput reverse-phase protein microarray technique. The prevalence of IgA deficiency (IgAD) was found to be 1:241 in monozygotic (MZ) twins and 1:198 in dizygotic (DZ) twins. Hence, the prevalence in twins is markedly elevated as compared with the normal Swedish adult population (1:600). The twins did not show a difference in the frequency of HLA haplotypes in comparison with almost 40 000 healthy Swedish controls. As expected, the risk-conveying HLA alleles A*01, B*08 and DRB1*01 were overrepresented among the IgAD twins and were also associated with significantly lower mean serum IgA concentrations in the twin cohort. In contrast, significantly higher mean IgA concentrations were found among individuals carrying the protective HLA alleles B*07 and DRB1*15. Exome sequencing data from two MZ twin pairs discordant for the deficiency showed no differences between the siblings. Model fitting analyses derived a heritability of 35% and indicate that genetic influences are modestly important for IgAD. The probandwise concordance rates for IgAD were found to be 31% for MZ and 13% for DZ twins.
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Macpherson AJ, McCoy KD, Johansen F-E, Brandtzaeg P . The immune geography of IgA induction and function. Mucosal Immunol 2008; 1: 11–22.
Fagarasan S, Kawamoto S, Kanagawa O, Suzuki K . Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol 2010; 28: 243–273.
Strugnell RA, Wijburg OLC . The role of secretory antibodies in infection immunity. Nat Rev Microbiol 2010; 8: 656–667.
Hammarström L, Smith C . Genetic Approach to Common Variable Immunodeficiency and IgA Deficiency, 2nd edn. Oxford University Press: New York, NY, USA, 2007, pp 313–325.
Al-Herz W, Bousfiha A, Casanova J-L, Chapel H, Conley ME, Cunningham-Rundles C et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 2011; 2: 54–80.
Al-Attas RA, Rahi AH . Primary antibody deficiency in Arabs: first report from eastern Saudi Arabia. J Clin Immunol 1998; 18: 368–371.
Kanoh T, Mizumoto T, Yasuda N, Koya M, Ohno Y, Uchino H et al. Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis. Vox Sang 1986; 50: 81–86.
Jörgensen GH, Gardulf A, Sigurdsson MI, Arnlaugsson S, Hammarström L, Ludviksson BR . Health-related quality of life (HRQL) in immunodeficient adults with selective IgA deficiency compared with age- and gender-matched controls and identification of risk factors for poor HRQL. Qual Life Res 2014; 23: 645–658.
Ludvigsson JF, Neovius M, Hammarström L . IgA deficiency & mortality: a population-based cohort study. J Clin Immunol 2013; 33: 1317–1324.
Boomsma D, Busjahn A, Peltonen L . Classical twin studies and beyond. Nat Rev Genet 2002; 3: 872–882.
Kouvalainen K, Moilanen I . Intrapair similarity of immunoglobulin levels in twins. Acta Genet Med Gemellol (Roma) 1987; 36: 509–515.
Di Franco P, Brai M, Misiano G, Piazza AM, Giorgi G, Cossarizza A et al. Genetic and environmental influences on serum levels of immunoglobulins and complement components in monozygotic and dizygotic twins. J Clin Lab Immunol 1988; 27: 5–10.
Huntley CC, Stephenson RL . IgA deficiency: family studies. N C Med J 1968; 29: 325–331.
Lewkonia RM, Gairdner D, Doe WF . IgA deficiency in one of identical twins. Br Med J 1976; 1: 311–313.
Ulfarsson J, Gudmundsson S, Birgisdóttir B, Kjeld JM, Jensson O . Selective serum IgA deficiency in Icelanders. Frequency, family studies and Ig levels. Acta Med Scand 1982; 211: 481–487.
Alper CA, Husain Z, Larsen CE, Dubey DP, Stein R, Day C et al. Incomplete penetrance of susceptibility genes for MHC-determined immunoglobulin deficiencies in monozygotic twins discordant for type 1 diabetes. J Autoimmun 2006; 27: 89–95.
McGue M, Gerrard JW, Lebowitz MD, Rao DC . Commingling in the distributions of immunoglobulin levels. Hum Hered 1989; 39: 196–201.
Borecki IB, McGue M, Gerrard JW, Lebowitz MD, Rao DC . Familial resemblance for immunoglobulin levels. Hum Genet 1994; 94: 179–185.
Yang C, Jie W, Yanlong Y, Xuefeng G, Aihua T, Yong G et al. Genome-wide association study identifies TNFSF13 as a susceptibility gene for IgA in a South Chinese population in smokers. Immunogenetics 2012; 64: 747–753.
Viktorin A, Frankowiack M, Padyukov L, Chang Z, Melén E, Sääf A et al. IgA measurements in over 12 000 Swedish twins reveal sex differential heritability and regulatory locus near CD30L. Hum Mol Genet 2014; 23: 4177–4184.
Janzi M, Odling J, Pan-Hammarström Q, Sundberg M, Lundeberg J, Uhlén M et al. Serum microarrays for large scale screening of protein levels. Mol Cell Proteomics 2005; 4: 1942–1947.
Ferreira RC, Pan-Hammarström Q, Graham RR, Fontán G, Lee AT, Ortmann W et al. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. PLoS Genet 2012; 8: e1002476.
Ferreira RC, Pan-Hammarström Q, Graham RR, Gateva V, Fontán G, Lee AT et al. Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nat Genet 2010; 42: 777–780.
Olerup O, Smith CI, Hammarström L . Different amino acids at position 57 of the HLA-DQ beta chain associated with susceptibility and resistance to IgA deficiency. Nature 1990; 347: 289–290.
Cunningham-Rundles C, Fotino M, Rosina O, Peter JB . Selective IgA deficiency, IgG subclass deficiency, and the major histocompatibility complex. Clin Immunol Immunopathol 1991; 61: S61–S69.
MacHulla HK, Schönermarck U, Schaaf A, Müller LP, Kloss C, Krüger J et al. HLA-A, B, Cw and DRB1, DRB3/4/5, DQB1, DPB1 frequencies in German immunoglobulin A-deficient individuals. Scand J Immunol 2000; 52: 207–211.
Rioux JD, Goyette P, Vyse TJ, Hammarström L, Fernando MMA et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci USA 2009; 106: 18680–18685.
Mohammadi J, Ramanujam R, Jarefors S, Rezaei N, Aghamohammadi A, Gregersen PK et al. IgA deficiency and the MHC: assessment of relative risk and microheterogeneity within the HLA A1 B8, DR3 (8.1) haplotype. J Clin Immunol 2010; 30: 138–143.
Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995; 57: 289–300.
Neale M, Boker S, Xie G, Maes H . Mx: Statistical Modeling. Department of Psychiatry: Richmond, VA, USA, 2006.
Pai MK, Davison M, Bedritis I, Zipursky A . Selective IgA deficiency in Rh-negative women. Vox Sang 1974; 27: 87–91.
Oen K, Petty RE, Schroeder ML . Immunoglobulin A deficiency: genetic studies. Tissue Antigens 1982; 19: 174–182.
Petty RE, Sherry DD, Johannson J . Anti-IgA antibodies in pregnancy. N Engl J Med 1985; 313: 1620–1625.
Thibault L, Beauséjour A, de Grandmont MJ, Long A, Goldman M, Chevrier M-C . Establishment of an immunoglobulin A-deficient blood donor registry with a simple in-house screening enzyme-linked immunosorbent assay. Transfusion 2006; 46: 2115–2121.
Palmer DS, O’Toole J, Montreuil T, Scalia V, Yi Q-L, Goldman M et al. Screening of Canadian Blood Services donors for severe immunoglobulin A deficiency. Transfusion 2010; 50: 1524–1531.
Clark JA, Callicoat PA, Brenner NA, Bradley CA, Smith DM Jr . Selective IgA deficiency in blood donors. Am J Clin Pathol 1983; 80: 210–213.
Cassidy JT, Burt A, Petty R, Sullivan D . Selective IgA deficiency in connective tissue diseases. N Engl J Med 1969; 280: 275.
Bachmann R . Studies on the serum gamma-A-globulin level. 3. The frequency of A-gamma-A-globulinemia. Scand J Clin Lab Invest 1965; 17: 316–320.
Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G et al. Selective IgA deficiency in autoimmune diseases. Mol Med 2011; 17: 1383–1396.
Sayarifard F, Aghamohammadi A, Haghi-Ashtiani MT, Rajab A, Irani H, Ahmadian JH et al. Evaluation of serum IgA levels in Iranian patients with type 1 diabetes mellitus. Acta Diabetol 2012; 49: 131–135.
Poulsen P, Grunnet LG, Pilgaard K, Storgaard H, Alibegovic A, Sonne MP et al. Increased risk of type 2 diabetes in elderly twins. Diabetes 2009; 58: 1350–1355.
Petersen I, Nielsen MMF, Beck-Nielsen H, Christensen K . No evidence of a higher 10 year period prevalence of diabetes among 77,885 twins compared with 215,264 singletons from the Danish birth cohorts 1910-1989. Diabetologia 2011; 54: 2016–2024.
Cardwell CR, Stene LC, Joner G, Cinek O, Svensson J, Goldacre MJ et al. Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 2008; 51: 726–735.
Phillips J, Gill N, Sikdar K, Penney S, Newhook LA . History of cesarean section associated with childhood onset of T1DM in Newfoundland and Labrador, Canada. J Environ Public Health 2012; 2012: 635097.
Lee HC, Gould JB, Boscardin WJ, El-Sayed YY, Blumenfeld YJ . Trends in cesarean delivery for twin births in the United States: 1995–2008. Obstet Gynecol 2011; 118: 1095–1101.
Hamilton BE, Martin JA, Ventura SJ . Births: preliminary data for 2012. Natl Vital Stat Rep 2013; 62 (3): 1–20.
Khashan AS, Kenny LC, Lundholm C, Kearney PM, Gong T, Almqvist C . Mode of obstetrical delivery and type 1 diabetes: a sibling design study. Pediatrics 2014; 134: e806–e813.
Bønnelykke B . Maternal age and parity as predictors of human twinning. Acta Genet Med Gemellol (Roma) 1990; 39: 329–334.
Cardwell CR, Carson DJ, Patterson CC . Parental age at delivery, birth order, birth weight and gestational age are associated with the risk of childhood type 1 diabetes: a UK regional retrospective cohort study. Diabet Med 2005; 22: 200–206.
Rami B, Schneider U, Imhof A, Waldhör T, Schober E . Risk factors for type I diabetes mellitus in children in Austria. Eur J Pediatr 1999; 158: 362–366.
Quintero-Ronderos P, Montoya-Ortiz G . Epigenetics and autoimmune diseases. Autoimmune Dis 2012; 2012: 593720.
Greer JM, McCombe PA . The role of epigenetic mechanisms and processes in autoimmune disorders. Biologics 2012; 6: 307–327.
Magnusson PKE, Almqvist C, Rahman I, Ganna A, Viktorin A, Walum H et al. The Swedish Twin Registry: establishment of a biobank and other recent developments. Twin Res Hum Genet 2013; 16: 317–329.
Lichtenstein P, De Faire U, Floderus B, Svartengren M, Svedberg P, Pedersen NL . The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies. J Intern Med 2002; 252: 184–205.
Leslie S, Donnelly P, McVean G . A statistical method for predicting classical HLA alleles from SNP data. Am J Hum Genet 2008; 82: 48–56.
Dilthey AT, Moutsianas L, Leslie S, McVean G . HLA*IMP—an integrated framework for imputing classical HLA alleles from SNP genotypes. Bioinformatics 2011; 27: 968–972.
Dilthey A, Leslie S, Moutsianas L, Shen J, Cox C, Nelson MR et al. Multi-population classical HLA type imputation. PLoS Comput Biol 2013; 9: e1002877.
Olerup O, Aldener A, Fogdell A . HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Tissue Antigens 1993; 41: 119–134.
Abolhassani H, Wang N, Frankowiack M, Krogh-Andersen K, Feng M, Rezaei N et al. A Novel ZBTB24 Mutation p.C383S in a Patient Presenting as Common Variable Immunodeficiency. Am J Clin Exp Immunol (submitted).
Johansson SG, Högman CF, Killander J . Quantitative immunoglobulin determination. Comparison of two methods. Estimation of normal levels and levels in persons lacking IgA and IgD. Acta Pathol Microbiol Scand 1968; 74: 519–530.
Natvig JB, Harboe M, Fausa O, Tveit A . Family studies in individuals with selective absence of gamma-A-globulin. Clin Exp Immunol 1971; 8: 229–236.
Frommel D, Moullec J, Lambin P, Fine JM . Selective serum IgA deficiency. Frequency among 15,200 French blood donors. Vox Sang 1973; 25: 513–518.
Kornstad L, Nordhagen R . Immunodeficiency and autoimmunity. I. Selective IgA deficiency in thyroid autoimmunity. Int Arch Allergy Appl Immunol 1974; 47: 942–945.
Cassidy JT, Nordby GL . Human serum immunoglobulin concentrations: prevalence of immunoglobulin deficiencies. J Allergy Clin Immunol 1975; 55: 35–48.
Vyas GN, Perkins HA, Yang YM, Basantani GK . Healthy blood donors with selective absence of immunoglobulin A: prevention of anaphylactic transfusion reactions caused by antibodies to IgA. J Lab Clin Med 1975; 85: 838–842.
Koistinen J . Selective IgA deficiency in blood donors. Vox Sang 1975; 29: 192–202.
Holt PD, Tandy NP, Anstee DJ . Screening of blood donors for IgA deficiency: a study of the donor population of south-west England. J Clin Pathol 1977; 30: 1007–1010.
Gudmundsson S, Jensson O . Frequency of IgA deficiency in blood donors and Rh negative women in Iceland. Acta Pathol Microbiol Scand C 1977; 85: 87–89.
Yadav M, Iyngkaran N . Low incidence of selective IgA deficiency in normal Malaysians. Med J Malaysia 1979; 34: 145–148.
Wells JV, McNally MP, King MA . Selective IgA deficiency in Australian blood donors. Aust N Z J Med 1980; 10: 410–413.
Ropars C, Muller A, Paint N, Beige D, Avenard G . Large scale detection of IgA deficient blood donors. J Immunol Methods 1982; 54: 183–189.
Sharon R, Amar A . IgA deficiency in Israeli blood donors. J Clin Pathol 1982; 35: 582–583.
Hunt AF, Allen DL, Aries DL, Strange JJ . A protocol for sensitive large-scale screening of blood donors for IgA deficiency. Vox Sang 1985; 48: 84–88.
Strothman R, White MB, Testin J, Chen SN, Ball MJ . HLA and IgA deficiency in blood donors. Hum Immunol 1986; 16: 289–294.
Ozawa N, Shimizu M, Imai M, Miyakawa Y, Mayumi M . Selective absence of immunoglobulin A1 or A2 among blood donors and hospital patients. Transfusion 1986; 26: 73–76.
Courault K . Detection of IgA defects in blood donors using an enzyme immunoassay. Folia Haematol Int Mag Klin Morphol Blutforsch 1987; 114: 257–263.
Winter PM, Manndorff P . The frequency of IgA-deficiency in the Austrian population. A protocol for large-scale screening by ELISA and a study on 3056 blood donors. Infusionstherapie (Basel, Switzerland) 1988; 15: 221–224.
Kramer J, Kassai T, Medgyesi GA, Tauszik T, Füst G . Screening of IgA deficiency by ELISA: population frequency in Hungary. Haematologia (Budap) 1988; 21: 233–238.
Ezeoke AC . Selective IgA deficiency (SIgAD) in Eastern Nigeria. Afr J Med Med Sci 1988; 17: 17–21.
Munks R . Rapid large scale screening of blood donor plasma for IgA deficiency, confirmation and quantitation. Transfus Sci 1989; 10: 155–159.
Carneiro-Sampaio MM, Carbonare SB, Rozentraub RB, de Araújo MN, Riberiro MA, Porto MH . Frequency of selective IgA deficiency among Brazilian blood donors and healthy pregnant women. Allergol Immunopathol (Madr) 1989; 17: 213–216.
Schulenburg BJ, Plapp FV, Rachel JM . A rapid screening test for detection of IgA deficiency. Transfusion 1991; 31: 633–635.
Feng L . Epidemiological study of selective IgA deficiency among 6 nationalities in China. Zhonghua Yi Xue Za Zhi 1992; 72: 88–90 128.
Mohabir LA, Rees TJ . Screening for IgA deficiency on the Olympus PK7100 by haemagglutination inhibition. Transfus Med 1995; 5: 275–279.
Pereira L, Sapiña A, Arroy J, Viñuelas J, Bardají R, Prieto L . Prevalence of selective IgA deficiency in Spain: more than we thought. Blood 1997; 90: 893.
Munks R, Booth JR, Sokol RJ . A comprehensive IgA service provided by a blood transfusion center. Immunohematology 1998; 14: 155–160.
Sanz C, Freire C, Ordinas A, Pereira A . An enzyme-linked immunosorbent assay applicable to screen blood donors for IgA deficiency. Haematologica 1999; 84: 887–890.
Pérez Vaquero MA, Vesga Carasa MA, López Urrutia A . Frequency of selective IgA deficiency in Basque Country. Med Clin (Barc) 2000; 115: 339–440.
Litzman J, Sevcíková I, Stikarovská D, Pikulová Z, Pazdírková A, Lokaj J . IgA deficiency in Czech healthy individuals and selected patient groups. Int Arch Allergy Immunol 2000; 123: 177–180.
Weber-Mzell D, Kotanko P, Hauer AC, Goriup U, Haas J, Lanner N et al. Gender, age and seasonal effects on IgA deficiency: a study of 7293 Caucasians. Eur J Clin Invest 2004; 34: 224–228.
Chandran S, Khetan D, Chaudhary R, Misra R, Aggarwal A . Low prevalence of IgA deficiency in north Indian population. Indian J Med Res 2006; 123: 653–656.
Duran J, Lopes C, Rangel G, Ruivo I . IgA deficiency in a Portuguese donor population. Vox Sang 2008; 95: 177–177.
Nosratabadi R, Moghadam ES, Arababadi MK, Khosravi S, Hassanshahi G . IgA deficiency frequency in Zahedan blood transfusion services donors. J Med Sci 2008; 8: 519–522.
Rezvan H, Ahmadi D, Esmailzadeh S, Dayhimi I . Selective deficiency of immunoglobulin A among healthy voluntary blood donors in Iran. Blood Transfus 2009; 7: 152–154.
Janzi M, Kull I, Sjöberg R, Wan J, Melén E, Bayat N et al. Selective IgA deficiency in early life: association to infections and allergic diseases during childhood. Clin Immunol 2009; 133: 78–85.
Feng ML, Zhao YL, Shen T, Huang H, Yin B, Liu RZ et al. Prevalence of immunoglobulin A deficiency in Chinese blood donors and evaluation of anaphylactic transfusion reaction risk. Transfus Med 2011; 21: 338–343.
Baştürk B, Sari S, Aral A, Dalgiç B . Prevalence of selective immunoglobulin A deficiency in healthy Turkish school children. Turk J Pediatr 2011; 53: 364–368.
We are grateful to the study participants for contributing to our research. We thank the FIMM High Throughput Biomedicine Unit for technical assistance. The work was sponsored by the Theme center for inflammatory diseases, Karolinska Institutet, Stockholm County Council and the Swedish Research Council. TwinGene is supported by the Swedish Research Council (M-2005 1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation (no. 20070481).
The authors declare no conflict of interest.
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