Association of the Distal Region of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Gene With Type 2 Diabetes in an African-American Population Enriched for Nephropathy
ABSTRACT Variants in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene have shown positive associations with diabetes and related phenotypes, including insulin resistance, metabolic syndrome, and type 1 diabetic nephropathy. Additionally, evidence for linkage for type 2 diabetes in African Americans was observed at 6q24-27, with the proximal edge of the peak encompassing the ENPP1 gene. Our objective was to comprehensively evaluate variants in ENPP1 for association with type 2 diabetic end-stage renal disease (ESRD).
Forty-nine single nucleotide polymorphisms (SNPs) located in the coding and flanking regions of ENPP1 were genotyped in 577 African-American individuals with type 2 diabetic ESRD and 596 African-American control subjects. Haplotypic association and genotypic association for the dominant, additive, and recessive models were tested by calculating a chi(2) statistic and corresponding P value.
Nine SNPs showed nominal evidence for association (P < 0.05) with type 2 diabetic ESRD in one or more genotypic model. The most significant associations were observed with rs7754586 (P = 0.003 dominant model, P = 0.0005 additive, and P = 0.007 recessive), located in the 3' untranslated region, and an intron 24 SNP (rs1974201: P = 0.004 dominant, P = 0.0005 additive, and P = 0.005 recessive). However, the extensively studied K121Q variant (rs1044498) did not reveal evidence for association with type 2 diabetic ESRD in this African-American population.
This study was the first to comprehensively evaluate variants of the ENPP1 gene for association in an African-American population with type 2 diabetes and ESRD and suggests that variants in the distal region of the ENPP1 gene may contribute to diabetes or diabetic nephropathy susceptibility in African Americans.
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- "African American association with T2DM-ESRD Genotypic association results for 208 SNPs from eight T2DM candidate genes: two Calpain 10 (CAPN10) SNPs, one Peroxisome proliferator–activated receptor γ (PPARG) SNP, five Transcription factor 7-like 2 (TCF7L2) SNPs, one ATP-sensitive inwardly rectifying potassium channel subunit Kir6.2 (KCNJ11) SNP, one Hepatic transcription factor 1 (TCF1) SNP, three Hepatocyte nuclear factor 4-α (HNF4A) SNPs (Sale et al. 2007), 146 Estrogen receptor α gene (ESR1) SNPs (Keene et al 2008b) and 49 Ectonucleotide Pyrophosphatase/ Phosphodiesterase 1 (ENPP1) SNPs, (Keene et al 2008a "
ABSTRACT: Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM-ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r2 = 0.101; P = 0.019) and in the combined set (r2 = 0.131; P = 3.57 x 10(-5)). The absolute difference between frequencies in parental populations, absolute delta, was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture.Human Genetics 09/2008; 124(2):147-54. DOI:10.1007/s00439-008-0532-6 · 4.52 Impact Factor
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ABSTRACT: Genome scans in African-Americans with end-stage renal disease (ESRD) identified linkage on chromosome 13q33 in the region containing the ephrin-B2 ligand (EFNB2) genes. Interactions between the ephrin-B2 receptor and ephrin-B2 ligand play essential roles in renal angiogenesis, blood vessel maturation, and kidney disease. The EFNB2 gene was evaluated as a positional candidate for non-diabetic and diabetic ESRD susceptibility in 1,071 unrelated African-American subjects; 316 with non-diabetic etiologies of ESRD, 394 with type 2 diabetes-associated ESRD and 361 healthy controls. Single nucleotide polymorphism (SNP) genotyping was performed on the Sequenom Mass Array System. Statistical analyses were computed using Dandelion version 1.26, Snpaddmix version 1.4 and Haploview version 3.32. Twenty-eight HapMap tag SNPs were genotyped spanning the 39 kilobases (kb) of the EFNB2 coding region, with average spacing of 1.43 kb. Analysis of 710 ESRD patient samples and 361 controls provided no evidence of single SNP associations in either diabetic or non-diabetic ESRD; although nominal evidence of association with all-cause ESRD was observed with a two SNP (p = 0.022) and three SNP (p = 0.023) haplotype, both containing SNPs rs7490924 and rs2391335 in intron 1. Although an attractive positional candidate gene, polymorphisms in the EFNB2 gene do not appear to contribute in a substantial way to non-diabetic, diabetic or all-cause ESRD susceptibility in African-Americans. Additional genes within the chromosome 13q33 linkage interval are likely contributors to African-American non-diabetic ESRD.American Journal of Nephrology 07/2008; 28(6):914-20. DOI:10.1159/000141934 · 2.65 Impact Factor
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ABSTRACT: Diabetes mellitus is the most common chronic metabolic disease. The raising diabetes epidemic is unfolding as an interaction between several environmental factors and a genetic predisposition. The aim of the current study was to evaluate the role of the PPARgamma-Pro12Ala and ENPP1-K121Q polymorphisms on type 2 diabetes (T2D) risk in a case-control study in the Tunisian population. To assess for any association of ENPP1-K121Q and PPARgamma-Pro12Ala polymorphisms with T2D risk, we analysed the genotypic and allelic distributions of each variant in the studied cohort. Our results support that the genetic variation at ENPP1-K121Q predisposes to T2D in the Tunisian population after adjustment on gender, age and BMI status (OR=1.55, 95%CI [1.11-2.16], p=0.007). Conversely, the PPARgamma-Pro12Ala variant seems not to have a significant effect on T2D risk in our Tunisian cohort. However, the minor A-allele would convey protection against overweight in the Tunisian population. In fact, the over weighted subjects showed a significantly lower frequency of A-allele than lean controls (OR=0.49, 95%CI [0.25-0.97], p=0.02). In conclusion, our findings support the hypothesis that ENPP1-121Q is involved in the genetic susceptibility of T2D in the Tunisian population, while the PPARgamma-12Ala allele may confer protection against overweight.Diabetes research and clinical practice 09/2008; 81(3):278-83. DOI:10.1016/j.diabres.2008.06.004 · 2.54 Impact Factor