Skip to main content

Advertisement

SpringerLink
Log in

Genetic studies of IgA nephropathy: past, present, and future

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and an important cause of kidney disease in young adults. Highly variable clinical presentation and outcome of IgAN suggest that this diagnosis may encompass multiple subsets of disease that are not distinguishable by currently available clinical tools. Marked differences in disease prevalence between individuals of European, Asian, and African ancestry suggest the existence of susceptibility genes that are present at variable frequencies in these populations. Familial forms of IgAN have also been reported throughout the world but are probably underrecognized because associated urinary abnormalities are often intermittent in affected family members. Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently demonstrated. Recent data indicates that these IgA1 glycosylation defects are inherited and constitute a heritable risk factor for IgAN. Because of the complex genetic architecture of IgAN, the efforts to map disease susceptibility genes have been difficult, and no causative mutations have yet been identified. Linkage-based approaches have been hindered by disease heterogeneity and lack of a reliable noninvasive diagnostic test for screening family members at risk of IgAN. Many candidate-gene association studies have been published, but most suffer from small sample size and methodological problems, and none of the results have been convincingly validated. New genomic approaches, including genome-wide association studies currently under way, offer promising tools for elucidating the genetic basis of IgAN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Beerman I, Novak J, Wyatt RJ, Julian BA, Gharavi AG (2007) The genetics of IgA nephropathy. Nat Clin Pract Nephrol 3:325–338

    Article  CAS  PubMed  Google Scholar 

  2. D’Amico G (1987) The commonest glomerulonephritis in the world; IgA nephropathy. Q J Med 64:709–727

    Google Scholar 

  3. Donadio JV, Grande JP (2002) IgA nephropathy. N Engl J Med 347:738–748

    Article  CAS  PubMed  Google Scholar 

  4. Barratt J, Feehally J (2005) IgA nephropathy. J Am Soc Nephrol 16:2088–2097

    Article  CAS  PubMed  Google Scholar 

  5. D’Amico G, Imbasciati E, Barbiano Di Belgioioso G, Bertoli S, Fogazzi G, Ferrario F, Fellin G, Ragni A, Colasanti G, Minetti L, Ponticelli C (1985) Idiopathic IgA mesangial nephropathy. Clinical and histological study of 374 patients. Medicine 64:49–60

    PubMed  Google Scholar 

  6. Hall YN, Fuentes EF, Chertow GM, Olson JL (2004) Race/ethnicity and disease severity in IgA nephropathy. BMC Nephrol 5:10

    Article  PubMed  Google Scholar 

  7. Hoy WE, Hughson MD, Smith SM, Megill DM (1993) Mesangial proliferative glomerulonephritis in southwestern American Indians. Am J Kidney Dis 21:486–496

    CAS  PubMed  Google Scholar 

  8. Smith SM, Harford AM (1995) IgA nephropathy in renal allografts: increased frequency in Native American patients. Ren Fail 17:449–456

    Article  CAS  PubMed  Google Scholar 

  9. Hughson MD, Megill DM, Smith SM, Tung KS, Miller G, Hoy WE (1989) Mesangiopathic glomerulonephritis in Zuni (New Mexico) Indians. Arch Pathol Lab Med 113:148–157

    CAS  PubMed  Google Scholar 

  10. O’Connell PJ, Ibels LS, Thomas MA, Harris M, Eckstein RP (1987) Familial IgA nephropathy: a study of renal disease in an Australian aboriginal family. Aust NZ J Med 17:27–33

    Google Scholar 

  11. Casiro OG, Stanwick RS, Walker RD (1988) The prevalence of IgA nephropathy in Manitoba Native Indian children. Can J Public Health 79:308–310

    CAS  PubMed  Google Scholar 

  12. Julian BA, Quiggins PA, Thompson JS, Woodford SY, Gleason K, Wyatt RJ (1985) Familial IgA nephropathy. Evidence of an inherited mechanism of disease. N Engl J Med 312:202–208

    Article  CAS  PubMed  Google Scholar 

  13. Levy M (1989) Familial cases of Berger’s disease and anaphylactoid purpura more frequent than previously thought. Am J Med 87:246–248

    Article  CAS  PubMed  Google Scholar 

  14. Paterson AD, Liu XQ, Wang K, Magistroni R, Song X, Kappel J, Klassen J, Cattran D, St George-Hyslop P, Pei Y (2007) Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36. J Am Soc Nephrol 18:2408–2415

    Article  CAS  PubMed  Google Scholar 

  15. Scolari F, Amoroso A, Savoldi S, Mazzola G, Prati E, Valzorio B, Viola BF, Nicola B, Movilli E, Sandrini M, Campanini M, Maiorca R (1999) Familial clustering of IgA nephropathy: further evidence in an Italian population. Am J Kidney Dis 33:857–865

    Article  CAS  PubMed  Google Scholar 

  16. Karnib HH, Sanna-Cherchi S, Zalloua PA, Medawar W, D’Agati VD, Lifton RP, Badr K, Gharavi AG (2007) Characterization of a large Lebanese family segregating IgA nephropathy. Nephrol Dial Transplant 22:772–777

    Article  CAS  PubMed  Google Scholar 

  17. Johnston PA, Brown JS, Braumholtz DA, Davison AM (1992) Clinico-pathological correlations and long-term follow-up of 253 United Kingdom patients with IgA nephropathy. A report from the MRC Glomerulonephritis Registry. Q J Med 84:619–627

    CAS  PubMed  Google Scholar 

  18. Rambausek M, Hartz G, Waldherr R, Andrassy K, Ritz E (1987) Familial glomerulonephritis. Pediatr Nephrol 1:416–418

    Article  CAS  PubMed  Google Scholar 

  19. Schena FP, Scivittaro V, Ranieri E, Sinico R, Benuzzi S, Di Cillo M, Aventaggiato L (1993) Abnormalities of the IgA immune system in members of unrelated pedigrees from patients with IgA nephropathy. Clin Exp Immunol 92:139–144

    Article  CAS  PubMed  Google Scholar 

  20. Schena FP, Scivittaro V, Ranieri E (1993) IgA nephropathy: pros and cons for a familial disease. Contrib Nephrol 104:36–45

    CAS  PubMed  Google Scholar 

  21. Frasca GM, Soverini L, Gharavi AG, Lifton RP, Canova C, Preda P, Vangelista A, Stefoni S (2004) Thin basement membrane disease in patients with familial IgA nephropathy. J Nephrol 17:778–785

    PubMed  Google Scholar 

  22. Durner M, Greenberg DA, Hodge SE (1992) (1992) Inter- and intrafamilial heterogeneity: effective sampling strategies and comparison of analysis methods. Am J Hum Genet 51:859–870

    CAS  PubMed  Google Scholar 

  23. Durner M, Greenberg DA (1992) Effect of heterogeneity and assumed mode of inheritance on lod scores. Am J Med Genet 42:271–275

    Article  CAS  PubMed  Google Scholar 

  24. Cavalli-Sforza LL, King MC (1986) Detecting linkage for genetically heterogeneous diseases and detecting heterogeneity with linkage data. Am J Hum Genet 38:599–616

    CAS  PubMed  Google Scholar 

  25. Ott J (1986) The number of families required to detect or exclude linkage heterogeneity. Am J Hum Genet 39:159–165

    CAS  PubMed  Google Scholar 

  26. Gharavi AG, Yan Y, Scolari F, Schena FP, Frasca GM, Ghiggeri GM, Cooper K, Amoroso A, Viola BF, Battini G, Caridi G, Canova C, Farhi A, Subramanian V, Nelson-Williams C, Woodford S, Julian BA, Wyatt RJ, Lifton RP (2000) IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet 26:354–357

    Article  CAS  PubMed  Google Scholar 

  27. Bisceglia L, Cerullo G, Forabosco P, Torres DD, Scolari F, Di Perna M, Foramitti M, Amoroso A, Bertok S, Floege J, Mertens PR, Zerres K, Alexopoulos E, Kirmizis D, Ermelinda M, Zelante L, Schena FP, European IgAN Consortium (2006) Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci. Am J Hum Genet 79:1130–1134

    Article  CAS  PubMed  Google Scholar 

  28. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309

    Article  CAS  PubMed  Google Scholar 

  29. Obara W, Iida A, Suzuki Y, Tanaka T, Akiyama F, Maeda S, Ohnishi Y, Yamada R, Tsunoda T, Takei T, Ito K, Honda K, Uchida K, Tsuchiya K, Yumura W, Ujiie T, Nagane Y, Nitta K, Miyano S, Narita I, Gejyo F, Nihei H, Fujioka T, Nakamura Y (2003) Association of single-nucleotide polymorphisms in the polymeric immunoglobulin receptor gene with immunoglobulin A nephropathy (IgAN) in Japanese patients. J Hum Genet 48:293–299

    CAS  PubMed  Google Scholar 

  30. Ohtsubo S, Iida A, Nitta K, Tanaka T, Yamada R, Ohnishi Y, Maeda S, Tsunoda T, Takei T, Obara W, Akiyama F, Ito K, Honda K, Uchida K, Tsuchiya K, Yumura W, Ujiie T, Nagane Y, Miyano S, Suzuki Y, Narita I, Gejyo F, Fujioka T, Nihei H, Nakamura Y (2005) Association of a single-nucleotide polymorphism in the immunoglobulin mu-binding protein 2 gene with immunoglobulin A nephropathy. J Hum Genet 50:30–35

    Article  CAS  PubMed  Google Scholar 

  31. (1999) Freely associating. Nat Genet 22:1–2

  32. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP (2007) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 370:1453–1457

    Article  Google Scholar 

  33. Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart A, Birkett N (2009) STrengthening the REporting of Genetic Association Studies (STREGA)-an extension of the STROBE statement. Genet Epidemiol 33:581–598

    Article  PubMed  Google Scholar 

  34. Hiki Y, Odani H, Takahashi M, Yasuda Y, Nishimoto A, Iwase H, Shinzato T, Kobayashi Y, Maeda K (2001) Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int 59:1077–1085

    Article  CAS  PubMed  Google Scholar 

  35. Tomana M, Matousovic K, Julian BA, Radl J, Konecny K, Mestecky J (1997) Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int 52:509–516

    Article  CAS  PubMed  Google Scholar 

  36. Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J (1999) Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest 104:73–81

    Article  CAS  PubMed  Google Scholar 

  37. Raska M, Moldoveanu Z, Suzuki H, Brown R, Kulhavy R, Hall S, Vu HL, Carlsson F, Lindahl G, Tomana M, Julian BA, Wyatt RJ, Mestecky J, Novak J (2007) Identification and characterization of CMP-NeuAc:GalNAc-IgA1 α2, 6-sialyltransferase in IgA1-producing cells. J Mol Biol 369:69–78

    Article  CAS  PubMed  Google Scholar 

  38. Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, Julian BA, Tomana M, Wyatt RJ, Edberg JE, Alarcón GS, Kimberly RP, Tomino Y, Mestecky J, Novak J (2008) IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest 118:629–639

    CAS  PubMed  Google Scholar 

  39. Li GS, Zhang H, Lv JC, Shen Y, Wang HY (2007) Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy. Kidney Int 71:448–453

    Article  CAS  PubMed  Google Scholar 

  40. Zhu L, Tang W, Li G, Lv J, Ding J, Yu L, Zhao M, Li Y, Zhang X, Shen Y, Zhang H, Wang H (2009) Interaction between variants of two glycosyltransferase genes in IgA nephropathy. Kidney Int 76:190–198

    Article  CAS  PubMed  Google Scholar 

  41. Pirulli D, Crovella S, Ulivi S, Zadro C, Bertok S, Rendine S, Scolari F, Foramitti M, Ravani P, Roccatello D, Savoldi S, Cerullo G, Lanzilotta SG, Bisceglia L, Zelante L, Floege J, Alexopoulos E, Kirmizis D, Ghiggeri GM, Frasca G, Schena FP, Amoroso A (2009) Genetic variant of C1GalT1 contributes to the susceptibility to IgA nephropathy. J Nephrol 22:152–159

    CAS  PubMed  Google Scholar 

  42. Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, Julian BA, Tomana M, Wyatt RJ, Edberg JC, Alarcon GS, Kimberly RP, Tomino Y, Mestecky J, Novak J (2008) IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest 118:629–639

    CAS  PubMed  Google Scholar 

  43. Buck KS, Smith AC, Molyneux K, El-Barbary H, Feehally J, Barratt J (2008) B-cell O-galactosyltransferase activity, and expression of O-glycosylation genes in bone marrow in IgA nephropathy. Kidney Int 73:1128–1136

    Article  CAS  PubMed  Google Scholar 

  44. Smith AC, de Wolff JF, Molyneux K, Feehally J, Barratt J (2006) O-glycosylation of serum IgD in IgA nephropathy. J Am Soc Nephrol 17:1192–1199

    Article  CAS  PubMed  Google Scholar 

  45. Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, Huang WQ, Anreddy SR, Hall S, Hastings MC, Lau KK, Cook WJ, Novak J (2007) Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int 71:1148–1154

    Article  CAS  PubMed  Google Scholar 

  46. Lau KK, Wyatt RJ, Moldoveanu Z, Tomana M, Julian BA, Hogg RJ, Lee JY, Huang WQ, Mestecky J, Novak J (2007) Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schonlein purpura. Pediatr Nephrol 22:2067–2072

    Article  PubMed  Google Scholar 

  47. Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, Mestecky J, Novak J, Julian BA (2008) Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol 19:1008–1014

    Article  PubMed  Google Scholar 

  48. Lin X, Ding J, Zhu L, Shi S, Jiang L, Zhao M, Zhang H (2009) Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant 24:3372–3375

    Article  CAS  PubMed  Google Scholar 

  49. Tam KY, Leung JC, Chan LY, Lam MF, Tang SC, Lai KN (2009) Macromolecular IgA1 taken from patients with familial IgA nephropathy or their asymptomatic relatives have higher reactivity to mesangial cells in vitro. Kidney Int 75:1330–1339

    Article  CAS  PubMed  Google Scholar 

  50. Kiryluk K, Moldoveanu Z, Sanders JT, Suzuki H, Julian BA, Mesteky J, Novak J, Gharavi AG, Wyatt RJ (2009) Aberrant glycosylation of IgA1 is inherited in pediatric Henoch-Schönlein nephritis. J Am Soc Nephrol 20:435A (abstract PO1408)

    Google Scholar 

  51. Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, Chatham WW, Suzuki Y, Wyatt RJ, Moldoveanu Z, Lee JY, Robinson J, Tomana M, Tomino Y, Mestecky J, Novak J (2009) Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest 119:1668–1677

    CAS  PubMed  Google Scholar 

  52. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Kramer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T (2008) Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet 4:e1000166

    Article  PubMed  Google Scholar 

  53. Denham S, Koppelman GH, Blakey J, Wjst M, Ferreira MA, Hall IP, Sayers I (2008) Meta-analysis of genome-wide linkage studies of asthma and related traits. Respir Res 9:38

    Article  PubMed  Google Scholar 

  54. Hardy J, Singleton A (2009) Genomewide association studies and human disease. N Engl J Med 360:1759–1768

    Article  CAS  PubMed  Google Scholar 

  55. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909

    Article  CAS  PubMed  Google Scholar 

  56. Dudbridge F, Gusnanto A (2008) Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 32:227–234

    Article  PubMed  Google Scholar 

  57. Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108

    Article  CAS  PubMed  Google Scholar 

  58. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  CAS  PubMed  Google Scholar 

  59. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389

    Article  CAS  PubMed  Google Scholar 

  60. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 447:661–678

    Article  Google Scholar 

  61. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–1463

    Article  CAS  PubMed  Google Scholar 

  62. van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MC, Bethel G, Holmes GK, Feighery C, Jewell D, Kelleher D, Kumar P, Travis S, Walters JR, Sanders DS, Howdle P, Swift J, Playford RJ, McLaren WM, Mearin ML, Mulder CJ, McManus R, McGinnis R, Cardon LR, Deloukas P, Wijmenga C (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39:827–829

    Article  PubMed  Google Scholar 

  63. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira RC, Pant PV, Ballinger DG, Kosoy R, Demirci FY, Kamboh MI, Kao AH, Tian C, Gunnarsson I, Bengtsson AA, Rantapää-Dahlqvist S, Petri M, Manzi S, Seldin MF, Rönnblom L, Syvänen AC, Criswell LA, Gregersen PK, Behrens TW (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358:900–909

    Article  CAS  PubMed  Google Scholar 

  64. International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40:204–210

    Article  Google Scholar 

  65. McCarroll SA, Altshuler DM (2007) Copy-number variation and association studies of human disease. Nat Genet 39:S37–S42

    Article  CAS  PubMed  Google Scholar 

  66. Carter NP (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nat Genet 39:S16–S21

    Article  CAS  PubMed  Google Scholar 

  67. Schaschl H, Aitman TJ, Vyse TJ (2009) Copy number variation in the human genome and its implication in autoimmunity. Clin Exp Immunol 156:12–16

    Article  CAS  PubMed  Google Scholar 

  68. Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L, Heward JM, Gough SC, de Smith A, Blakemore AI, Froguel P, Owen CJ, Pearce SH, Teixeira L, Guillevin L, Graham DS, Pusey CD, Cook HT, Vyse TJ, Aitman TJ (2007) FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 39:721–723

    Article  CAS  PubMed  Google Scholar 

  69. de Cid R, Riveira-Munoz E, Zeeuwen PL, Robarge J, Liao W, Dannhauser EN, Giardina E, Stuart PE, Nair R, Helms C, Escaramis G, Ballana E, Martin-Ezquerra G, den Heijer M, Kamsteeg M, Joosten I, Eichler EE, Lazaro C, Pujol RM, Armengol L, Abecasis G, Elder JT, Novelli G, Armour JA, Kwok PY, Bowcock A, Schalkwijk J, Estivill X (2009) Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet 41:211–215

    Article  PubMed  Google Scholar 

  70. Cheung VG, Spielman RS (2002) The genetics of variation in gene expression. Nat Genet 32(Suppl):522–525

    Article  CAS  PubMed  Google Scholar 

  71. Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, Guhathakurta D, Sieberts SK, Monks S, Reitman M, Zhang C, Lum PY, Leonardson A, Thieringer R, Metzger JM, Yang L, Castle J, Zhu H, Kash SF, Drake TA, Sachs A, Lusis AJ (2005) An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 37:710–717

    Article  CAS  PubMed  Google Scholar 

  72. Schadt EE (2009) Molecular networks as sensors and drivers of common human diseases. Nature 461:218–223

    Article  CAS  PubMed  Google Scholar 

  73. Li B, Leal SM (2009) Discovery of rare variants via sequencing: implications for the design of complex trait association studies. PLoS Genet 5:e1000481

    Article  PubMed  Google Scholar 

  74. Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305:869–872

    Article  CAS  PubMed  Google Scholar 

  75. Romeo S, Pennacchio LA, Fu Y, Boerwinkle E, Tybjaerg-Hansen A, Hobbs HH, Cohen JC (2007) Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 39:513–516

    Article  CAS  PubMed  Google Scholar 

  76. Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP (2008) Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40:592–599

    Article  CAS  PubMed  Google Scholar 

  77. Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA 106:19096–19101

    Article  CAS  PubMed  Google Scholar 

  78. Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42:30–35

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Krzysztof Kiryluk is supported by the Daland Fellowship from the American Philosophical Society and Grant Number KL2 RR024157 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Bruce A. Julian, Robert J. Wyatt, Francesco Scolari, Jan Novak, and Ali G. Gharavi are supported by Grant Number DK082753 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The authors also acknowledge other grants from NIDDK supporting their research of IgAN: DK078244, DK080301, DK075868, DK071802, and DK077279. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NCRR, NIDDK, or NIH.

Conflicts of Interest

None

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, Russ Berrie Pavilion #413, New York, NY, 10032, USA

    Krzysztof Kiryluk & Ali G. Gharavi

  2. Departments of Microbiology and Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Bruce A. Julian & Jan Novak

  3. Division of Pediatric Nephrology, Department of Pediatrics, Children’s Foundation Research Center at the Le Bonheur Children’s Medical Center, University of Tennessee Health Sciences Center, Memphis, TN, USA

    Robert J. Wyatt

  4. Division of Nephrology, Università e Spedali Civili, Brescia, Italy

    Francesco Scolari

  5. Renal Division of First Hospital, Institute of Nephrology, Peking University, Beijing, China

    Hong Zhang

Authors
  1. Krzysztof Kiryluk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruce A. Julian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert J. Wyatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesco Scolari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Novak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ali G. Gharavi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali G. Gharavi.

Additional information

Answers:

1. d

2. e

3. b

4. d

5. e

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table 1S

Index of published genetic association studies in IgA nephropathy sorted by publication year (data from 1994 to 09/01/2009) (DOC 3642 kb)

Questions

Questions

(Answers appear following the reference list)

  1. 1.

    Which is true about familial forms of IgAN?

    1. a.

      Familial forms of IgAN have only been observed in genetically isolated populations

    2. b.

      Patients with familial IgAN should never be transplanted because of high risk of recurrence

    3. c.

      Patients with familial IgAN can be identified based on their characteristic presenting symptoms

    4. d.

      Most familial IgAN displays autosomal dominant inheritance

    5. e.

      b and d

  2. 2.

    Which is true about glycosylation defects of IgA1 in IgAN?

    1. a.

      It is associated with a generalized defect in glycosylation of most circulating immunoglobulins

    2. b.

      The abnormally glycosylated IgA1 has a higher propensity for immune complex formation and deposition in mesangium

    3. c.

      Elevated levels of galactose-deficient IgA1 correlate with symptoms and prognosis in IgAN

    4. d.

      Elevated levels of galactose-deficient IgA1 are observed in large proportion of family members of IgAN patients

    5. e.

      b and d

  3. 3.

    Which is true about genetic studies of IgAN?

    1. a.

      Consistent association of IgAN with cytokine haplotypes have been identified

    2. b.

      Multiple different genes can cause familial IgAN because different families demonstrate linkage to different segments of the genome

    3. c.

      Glycosylation defects in IgAN are caused by mutations in the C1GALT1 (beta-1,3 galatosylatransferase gene)

    4. d.

      Genome-wide association studies will be able to detect rare genes with small effect that contribute to IgAN

    5. e.

      b and d

  4. 4.

    Which is true about serum levels of galactose-deficient IgA1:

    1. a.

      Elevated serum level of galactose-deficient IgA1 is sufficient to make the diagnosis of IgAN

    2. b.

      Normal serum level of galactose-deficient IgA1 is sufficient to exclude the diagnosis of IgAN

    3. c.

      Elevated serum level of galactose-deficient IgA1 is required for the development and progression of IgAN

    4. d.

      In the populations studied to date, inherited factors are estimated to account for approximately 50% of the total variation in galactose-deficient IgA1 levels

    5. e.

      None of the above

  5. 5.

    Which is NOT true about genetic studies of IgAN:

    1. a.

      Genetic heterogeneity decreases power of linkage studies of familial IgAN

    2. b.

      The results of genetic association studies may be biased if cases and controls are derived from heterogenous populations

    3. c.

      Most candidate gene associations in sporadic IgAN have not been replicated

    4. d.

      Galactose-deficient IgA1 level represents a promising endophenotype for genetic linkage and association studies

    5. e.

      Several common copy-number polymorphisms have been consistently associated with IgAN

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiryluk, K., Julian, B.A., Wyatt, R.J. et al. Genetic studies of IgA nephropathy: past, present, and future. Pediatr Nephrol 25, 2257–2268 (2010). https://doi.org/10.1007/s00467-010-1500-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-010-1500-7

Keywords

Search

Navigation