Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients

Sandra L. Dabora, Penelope Roberts, Andres Nieto, Ron Perez, Sergiusz Jozwiak, David Franz, John Bissler, Elizabeth A. Thiele, Katherine Sims, David J. Kwiatkowski

Research output: Contribution to journalArticle

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Abstract

Tuberous sclerosis complex (TSC) is a familial hamartoma syndrome in which renal involvement is common and, at times, life threatening. We have investigated the potential effect of a non-TSC gene on renal disease in a cohort of 172 TSC patients with TSC2 mutations. Patients were genotyped for an interferon-γ (IFN-γ) microsatellite polymorphism, within intron 1, for which one common allele (allele 2, with 12 CA repeats) has been shown to have a higher expression of IFN-γ. A χ2 analysis was used to examine the association between IFN-γ allele 2 and the development of kidney angiomyolipomas (KAMLs) in this TSC2 cohort. Because of the age-dependent development of KAMLs in TSC, we initially focused on the 127 patients who were >5 years old. Additional subgroup analyses were done to investigate the influence of age and gender. The transmission/disequilibrium test (TDT) was also performed in a subset of this cohort (46 probands) for whom parent and/or sibling samples were available for analysis. Both χ2 analysis and TDT suggested an association between IFN-γ allele 2 and the absence of KAMLs in patients who have known TSC2 mutations. Among the 127 patients who were >5 years old, KAMLs were present in 95 (75%) and were absent in 32 (25%). In the group with KAML present, the frequency of IFN-γ allele 2 was 56%; in the group with KAML absent, the frequency of IFN-γ allele 2 was significantly higher, at 78% (P = .02, by χ2 analysis). The family-based TDT analysis gave similar results, with a TDT statistic (TDT χ2 = 5.45) corresponding to a P value of .02. Subgroup analyses show that both age and gender may influence the impact of this association. Although these results should be replicated in other populations with TSC, the present study suggests that modifier genes play a role in the variable expression of TSC and also suggests a potential therapy for KAMLs in patients with TSC.

Original languageEnglish (US)
Pages (from-to)750-758
Number of pages9
JournalAmerican Journal of Human Genetics
Volume71
Issue number4
DOIs
StatePublished - Jan 1 2002

Fingerprint

Angiomyolipoma
Interferons
Tuberous Sclerosis
Alleles
Kidney
Gene Frequency
Modifier Genes
Mutation
Hamartoma
Sclerosis
Microsatellite Repeats
Introns
Siblings

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Dabora, S. L., Roberts, P., Nieto, A., Perez, R., Jozwiak, S., Franz, D., ... Kwiatkowski, D. J. (2002). Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. American Journal of Human Genetics, 71(4), 750-758. https://doi.org/10.1086/342718

Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. / Dabora, Sandra L.; Roberts, Penelope; Nieto, Andres; Perez, Ron; Jozwiak, Sergiusz; Franz, David; Bissler, John; Thiele, Elizabeth A.; Sims, Katherine; Kwiatkowski, David J.

In: American Journal of Human Genetics, Vol. 71, No. 4, 01.01.2002, p. 750-758.

Research output: Contribution to journalArticle

Dabora, SL, Roberts, P, Nieto, A, Perez, R, Jozwiak, S, Franz, D, Bissler, J, Thiele, EA, Sims, K & Kwiatkowski, DJ 2002, 'Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients', American Journal of Human Genetics, vol. 71, no. 4, pp. 750-758. https://doi.org/10.1086/342718
Dabora, Sandra L. ; Roberts, Penelope ; Nieto, Andres ; Perez, Ron ; Jozwiak, Sergiusz ; Franz, David ; Bissler, John ; Thiele, Elizabeth A. ; Sims, Katherine ; Kwiatkowski, David J. / Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. In: American Journal of Human Genetics. 2002 ; Vol. 71, No. 4. pp. 750-758.
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abstract = "Tuberous sclerosis complex (TSC) is a familial hamartoma syndrome in which renal involvement is common and, at times, life threatening. We have investigated the potential effect of a non-TSC gene on renal disease in a cohort of 172 TSC patients with TSC2 mutations. Patients were genotyped for an interferon-γ (IFN-γ) microsatellite polymorphism, within intron 1, for which one common allele (allele 2, with 12 CA repeats) has been shown to have a higher expression of IFN-γ. A χ2 analysis was used to examine the association between IFN-γ allele 2 and the development of kidney angiomyolipomas (KAMLs) in this TSC2 cohort. Because of the age-dependent development of KAMLs in TSC, we initially focused on the 127 patients who were >5 years old. Additional subgroup analyses were done to investigate the influence of age and gender. The transmission/disequilibrium test (TDT) was also performed in a subset of this cohort (46 probands) for whom parent and/or sibling samples were available for analysis. Both χ2 analysis and TDT suggested an association between IFN-γ allele 2 and the absence of KAMLs in patients who have known TSC2 mutations. Among the 127 patients who were >5 years old, KAMLs were present in 95 (75{\%}) and were absent in 32 (25{\%}). In the group with KAML present, the frequency of IFN-γ allele 2 was 56{\%}; in the group with KAML absent, the frequency of IFN-γ allele 2 was significantly higher, at 78{\%} (P = .02, by χ2 analysis). The family-based TDT analysis gave similar results, with a TDT statistic (TDT χ2 = 5.45) corresponding to a P value of .02. Subgroup analyses show that both age and gender may influence the impact of this association. Although these results should be replicated in other populations with TSC, the present study suggests that modifier genes play a role in the variable expression of TSC and also suggests a potential therapy for KAMLs in patients with TSC.",
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