PPARG and ADIPOQ gene polymorphisms increase type 2 diabetes mellitus risk in Asian Indian Sikhs: Pro12Ala still remains as the strongest predictor

Sanghera, Dharambir Kaur; Demirci, Fatma Yesim; Been, Latonya; Ortega, Lyda; Ralhan, Sarju; Wander, Gurpreet Singh; Mehra, Narinder Kumar; Singh, Jairup; Aston, Christopher Eric; Mulvihill, John Joseph; Kamboh, Ilyas Mohammad

doi:10.1016/j.metabol.2009.07.043

« Previous Next »Metabolism - Clinical and Experimental
Volume 59, Issue 4 , Pages 492-501, April 2010

PPARG and ADIPOQ gene polymorphisms increase type 2 diabetes mellitus risk in Asian Indian Sikhs: Pro12Ala still remains as the strongest predictor

Dharambir Kaur Sanghera
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Corresponding author. Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Tel.: +1 405 271 8001x43064; fax: +1 405 271 6027.
Fatma Yesim Demirci
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA
Latonya Been
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Lyda Ortega
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Sarju Ralhan
- Hero DMC Heart Institute, Ludhiana, 141001 Punjab, India
Gurpreet Singh Wander
- Hero DMC Heart Institute, Ludhiana, 141001 Punjab, India
Narinder Kumar Mehra
- All India Institute of Medical Sciences and Research, 110608 New Delhi, India
Jairup Singh
- Central University of Punjab, 151001 Bathinda, India
Christopher Eric Aston
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
John Joseph Mulvihill
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Ilyas Mohammad Kamboh
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA

Received 26 December 2008; accepted 29 July 2009. published online 21 October 2009.

Abstract

We have examined the association of 14 tagging single nucleotide polymorphisms (tagSNPs) in peroxisome proliferator activated receptor–γ transcripts 1 and 2 (PPARG1 and 2) and 5 tagSNPs in adiponectin (ADIPOQ) genes for their effect on type 2 diabetes mellitus (T2D) risk in Asian Indian Sikhs. A total of 554 T2D cases and 527 normoglycemic controls were examined for association with T2D and other subphenotypes of T2D. With the exception of a strong association of PPARG2/Pro12Ala with T2D (odds ratio, 0.13; 95% confidence interval, 0.03-0.56; P = .0007), no other tagSNP in the PPARG locus revealed any significant association with T2D in this population. Similarly, none of the tagSNPs in the ADIPOQ gene was associated with T2D susceptibility in single-site analysis. However, haplotype analysis provided strong evidence of association of these loci with T2D. Three-site haplotype analysis in the PPARG locus using the 2 marginally associated SNPs (P/rs11715073 and P/rs3892175) in combination with Pro12 Ala (P/rs1801282) revealed a strong association of 1 “risk” (CGC) (P = .003, permutation P = .015) and 1 “protective” (CAC) (P = .001, permutation P = .005) haplotype associated with T2D. However, the major effect still appears to be driven by Pro12Ala, as the association of these haplotypes did not remain significant when analyzed conditional upon Pro12Ala (P = .262). In addition, 2-site haplotype analysis in the ADIPOQ locus using only 2 marginally associated SNPs (AD/rs182052 and AD/rs7649121) revealed a significant protective association of the GA haplotype with T2D (P = .009, permutation P = .026). Multiple linear regression analysis also revealed significant association of an ADIPOQ variant (AD/rs12495941) with total body weight (P = .010), waist (P = .024), and hip (P = .021), although these associations were not significant after adjusting for multiple testing. Our new findings strongly suggest that the genetic variation in PPARG and ADIPOQ loci could contribute to the risk for the development of T2D in Indian Sikhs. Identification of causal SNPs in these important biological and positional candidate genes would help determine the true physiologic significance of these loci in T2D and obesity.