GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence

Karen M. Eny, Helen L. Lutgers, John Maynard, Barbara E K Klein, Kristine E. Lee, Gil Atzmon, Vincent M. Monnier, Jana V. Van Vliet-Ostaptchouk, Reindert Graaff, Pim Van Der Harst, Harold Snieder, Melanie M. Van Der Klauw, David R. Sell, S. Mohsen Hosseini, Patricia A. Cleary, Barbara H. Braffett, Trevor J. Orchard, Timothy J. Lyons, Kerri Howard, Ronald Klein & 6 others Jill P. Crandall, Nir Barzilai, Sofiya Milman, Danny Ben-Avraham, Bruce H R Wolffenbuttel, Andrew D. Paterson

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Aims/hypothesis: Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. Methods: Cohort 1 included 1,082 participants, 35-67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18-90 years. Results: rs1495741 was significantly associated with SF in Cohort 1 (p<6×10 -10), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p=8.3×10 -42) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r2=1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2-SF signal, we examined 11 compounds assayed from skin biopsies (n=198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p=0.017). Conclusions/interpretation: We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.

Original languageEnglish (US)
Pages (from-to)1623-1634
Number of pages12
JournalDiabetologia
Volume57
Issue number8
DOIs
StatePublished - 2014

Fingerprint

Genome-Wide Association Study
Single Nucleotide Polymorphism
Fluorescence
Skin
Type 1 Diabetes Mellitus
Genotype
Glyoxal
Linkage Disequilibrium
Diabetes Complications
Acetylation
Phenotype
Biopsy

Keywords

  • Acetylation
  • Genome-wide association study
  • NAT2
  • Skin autofluorescence
  • Skin fluorescence
  • Skin intrinsic fluorescence

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Eny, K. M., Lutgers, H. L., Maynard, J., Klein, B. E. K., Lee, K. E., Atzmon, G., ... Paterson, A. D. (2014). GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. Diabetologia, 57(8), 1623-1634. https://doi.org/10.1007/s00125-014-3286-9

GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. / Eny, Karen M.; Lutgers, Helen L.; Maynard, John; Klein, Barbara E K; Lee, Kristine E.; Atzmon, Gil; Monnier, Vincent M.; Van Vliet-Ostaptchouk, Jana V.; Graaff, Reindert; Van Der Harst, Pim; Snieder, Harold; Van Der Klauw, Melanie M.; Sell, David R.; Hosseini, S. Mohsen; Cleary, Patricia A.; Braffett, Barbara H.; Orchard, Trevor J.; Lyons, Timothy J.; Howard, Kerri; Klein, Ronald; Crandall, Jill P.; Barzilai, Nir; Milman, Sofiya; Ben-Avraham, Danny; Wolffenbuttel, Bruce H R; Paterson, Andrew D.

In: Diabetologia, Vol. 57, No. 8, 2014, p. 1623-1634.

Research output: Contribution to journalArticle

Eny, KM, Lutgers, HL, Maynard, J, Klein, BEK, Lee, KE, Atzmon, G, Monnier, VM, Van Vliet-Ostaptchouk, JV, Graaff, R, Van Der Harst, P, Snieder, H, Van Der Klauw, MM, Sell, DR, Hosseini, SM, Cleary, PA, Braffett, BH, Orchard, TJ, Lyons, TJ, Howard, K, Klein, R, Crandall, JP, Barzilai, N, Milman, S, Ben-Avraham, D, Wolffenbuttel, BHR & Paterson, AD 2014, 'GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence', Diabetologia, vol. 57, no. 8, pp. 1623-1634. https://doi.org/10.1007/s00125-014-3286-9
Eny, Karen M. ; Lutgers, Helen L. ; Maynard, John ; Klein, Barbara E K ; Lee, Kristine E. ; Atzmon, Gil ; Monnier, Vincent M. ; Van Vliet-Ostaptchouk, Jana V. ; Graaff, Reindert ; Van Der Harst, Pim ; Snieder, Harold ; Van Der Klauw, Melanie M. ; Sell, David R. ; Hosseini, S. Mohsen ; Cleary, Patricia A. ; Braffett, Barbara H. ; Orchard, Trevor J. ; Lyons, Timothy J. ; Howard, Kerri ; Klein, Ronald ; Crandall, Jill P. ; Barzilai, Nir ; Milman, Sofiya ; Ben-Avraham, Danny ; Wolffenbuttel, Bruce H R ; Paterson, Andrew D. / GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. In: Diabetologia. 2014 ; Vol. 57, No. 8. pp. 1623-1634.
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T1 - GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence

AU - Eny, Karen M.

AU - Lutgers, Helen L.

AU - Maynard, John

AU - Klein, Barbara E K

AU - Lee, Kristine E.

AU - Atzmon, Gil

AU - Monnier, Vincent M.

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Graaff, Reindert

AU - Van Der Harst, Pim

AU - Snieder, Harold

AU - Van Der Klauw, Melanie M.

AU - Sell, David R.

AU - Hosseini, S. Mohsen

AU - Cleary, Patricia A.

AU - Braffett, Barbara H.

AU - Orchard, Trevor J.

AU - Lyons, Timothy J.

AU - Howard, Kerri

AU - Klein, Ronald

AU - Crandall, Jill P.

AU - Barzilai, Nir

AU - Milman, Sofiya

AU - Ben-Avraham, Danny

AU - Wolffenbuttel, Bruce H R

AU - Paterson, Andrew D.

PY - 2014

Y1 - 2014

N2 - Aims/hypothesis: Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. Methods: Cohort 1 included 1,082 participants, 35-67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18-90 years. Results: rs1495741 was significantly associated with SF in Cohort 1 (p<6×10 -10), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p=8.3×10 -42) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r2=1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2-SF signal, we examined 11 compounds assayed from skin biopsies (n=198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p=0.017). Conclusions/interpretation: We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.

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KW - Acetylation

KW - Genome-wide association study

KW - NAT2

KW - Skin autofluorescence

KW - Skin fluorescence

KW - Skin intrinsic fluorescence

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