Previous epidemiological studies in Pima Indians have identified a protective role for higher HDL-C against the onset of T2D in women. In this study, we analyzed 35 SNPs from established HDL-C loci for association with HDL-C, T2D and related traits. Genotyping and analysis of these SNPs in 2,717 full-heritage Pima Indians informative for T2D status and lipid levels identified a significant association (P<0.05) for 14 SNPs with HDL-C. An un-weighted multialleleic genetic risk score analysis (GRS) including the 35 SNPs was significantly associated with HDL-C (P=3.6×10-6), however the 21 SNPs not associated with HDL-C did not had any effect on HDL-C levels even in combination (GRS [21 SNPs], P=0.08). Therefore, only 14 SNPs were further genotyped in 4,993 American Indian samples informative for T2D (2,777 informative for lipid levels) and analyzed for association with HDL-C, T2D and related traits in the combined sample. In this analysis, 6 of the 14 SNPs at the CETP, DOCK6, PPP1R3B, ABCA1 and APOA1-C3-A4-A5 loci reached genome wide significance (P<4.9×10-7)for HDL-C association. The GRS analysis including the 14 loci in the combined samples negatively correlated with HDL-C levels (ß= -0.92mg/dL, P=3.1x10-48) and had a strong positive correlation with insulin resistance as estimated by homeostasis assessment (HOMA-IR, P=8.6x10-5, ß (SD units) = 0.015). The GRS correlated positively with T2D (P=0.007, OR=1.03), but there was no interaction with gender (P=0.74). When analyzed individually, SNPs at the CETP, HNF4A and KLF14 loci significantly associated with type 2 diabetes only in female subjects (3.2×10-4 - 7.7×10-5), such that the HDL-C lowering allele increased the risk for T2D. The T2D risk alleles for the SNPs at the CETP and KLF14 loci were associated with increased insulin resistance in female subjects as estimated by HOMA-IR (P<0.05). In conclusion, our studies suggest a modest effect of the genetic predisposition for lower HDL-C on the risk for T2D in American Indians.

Variants Associated with HDL-C Levels: Assessment for Association with Type 2 Diabetes in American Indians

Piaggi P;
2015-01-01

Abstract

Previous epidemiological studies in Pima Indians have identified a protective role for higher HDL-C against the onset of T2D in women. In this study, we analyzed 35 SNPs from established HDL-C loci for association with HDL-C, T2D and related traits. Genotyping and analysis of these SNPs in 2,717 full-heritage Pima Indians informative for T2D status and lipid levels identified a significant association (P<0.05) for 14 SNPs with HDL-C. An un-weighted multialleleic genetic risk score analysis (GRS) including the 35 SNPs was significantly associated with HDL-C (P=3.6×10-6), however the 21 SNPs not associated with HDL-C did not had any effect on HDL-C levels even in combination (GRS [21 SNPs], P=0.08). Therefore, only 14 SNPs were further genotyped in 4,993 American Indian samples informative for T2D (2,777 informative for lipid levels) and analyzed for association with HDL-C, T2D and related traits in the combined sample. In this analysis, 6 of the 14 SNPs at the CETP, DOCK6, PPP1R3B, ABCA1 and APOA1-C3-A4-A5 loci reached genome wide significance (P<4.9×10-7)for HDL-C association. The GRS analysis including the 14 loci in the combined samples negatively correlated with HDL-C levels (ß= -0.92mg/dL, P=3.1x10-48) and had a strong positive correlation with insulin resistance as estimated by homeostasis assessment (HOMA-IR, P=8.6x10-5, ß (SD units) = 0.015). The GRS correlated positively with T2D (P=0.007, OR=1.03), but there was no interaction with gender (P=0.74). When analyzed individually, SNPs at the CETP, HNF4A and KLF14 loci significantly associated with type 2 diabetes only in female subjects (3.2×10-4 - 7.7×10-5), such that the HDL-C lowering allele increased the risk for T2D. The T2D risk alleles for the SNPs at the CETP and KLF14 loci were associated with increased insulin resistance in female subjects as estimated by HOMA-IR (P<0.05). In conclusion, our studies suggest a modest effect of the genetic predisposition for lower HDL-C on the risk for T2D in American Indians.
2015
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/925454
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact