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Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans.

ABSTRACT: Chromosome 20q12-q13.1 has been linked to type 2 diabetes (T2D) in multiple populations. We examined the influence of genes in this region on T2D and BMI in two European American case-control populations. SNPs were genotyped in 300 diabetic patients and 310 controls. A subset of 72 SNPs were further genotyped in 470 cases and 442 controls. All genes examined showed evidence of association with T2D in the initial sample (additive P-value [P(a)]=0.00090-0.045). SNPs near PREX1 were also associated in the second case-control population (P(a)=0.017-0.042). The combined analysis resulted in the same SNPs, among others, associated with T2D (P(a)=0.0013-0.041). Stratification analysis by T2D status showed that association with BMI was observed solely in cases (P(a)=0.0018-0.041). Mediation testing revealed that 30-40% of the effects of these SNPs on T2D were significantly mediated by BMI. SNPs near PREX1 may contribute to T2D susceptibility mediated through effects of adiposity in European Americans.

SUBMITTER: Lewis JP

PROVIDER: S-EPMC2977534 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans.

Lewis Joshua P JP Palmer Nicholette D ND Ellington Jennifer B JB Divers Jasmin J Ng Maggie C Y MC Lu Lingyi L Langefeld Carl D CD Freedman Barry I BI Bowden Donald W DW

Genomics 20100730 4

Chromosome 20q12-q13.1 has been linked to type 2 diabetes (T2D) in multiple populations. We examined the influence of genes in this region on T2D and BMI in two European American case-control populations. SNPs were genotyped in 300 diabetic patients and 310 controls. A subset of 72 SNPs were further genotyped in 470 cases and 442 controls. All genes examined showed evidence of association with T2D in the initial sample (additive P-value [P(a)]=0.00090-0.045). SNPs near PREX1 were also associated ...[more]

PMID: 20650312

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Project description:The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility.

Dataset Information

Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans.

Publications

Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans.

Similar Datasets

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