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Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: a study of 3,310 subjects from India and the US.

Been LF, Ralhan S, Wander GS, Mehra NK, Singh J, Mulvihill JJ, Aston CE, Sanghera DK - BMC Med. Genet. (2011)

Bottom Line: The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians.Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma, USA.

ABSTRACT

Background: Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.

Methods: We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.

Results: Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).

Conclusions: Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.

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Figure 1 describes structure of human KCNQ1 gene on chromosome 11. Top portion of the Figure 1 shows the position of four investigated SNPs from intron 11 and 15. Figure 1(A) shows pair-wise linkage disequilibrium (LD) (D') and Figure 1(B) shows pair-wise correlation (r2) between SNPs.
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Figure 1: Figure 1 describes structure of human KCNQ1 gene on chromosome 11. Top portion of the Figure 1 shows the position of four investigated SNPs from intron 11 and 15. Figure 1(A) shows pair-wise linkage disequilibrium (LD) (D') and Figure 1(B) shows pair-wise correlation (r2) between SNPs.

Mentions: Table 1 summarizes and compares the general characteristics of the two study cohorts used in this investigation. Among these subjects, the US cohort was younger and had earlier onset of T2D (42 years) compared to the Punjabi cohort (48 years). Diabetics in the Punjabi cohort had poor glycemic control showing significantly higher FBG levels (by 17 mg/dL) (p = 0.002) compared to the US cohort. HOMA-B (used as a surrogate marker for beta [β] cell function) were also significantly lower (by 33 units) (p = 4.64 × 10-8) and WHR significantly higher (by 5 units) (p <0.001) in the Punjabi cohort. The physical location and inter-marker distance of all investigated SNPs is shown in Figure 1. Linkage disequilibrium (LD) analysis revealed that all investigated SNPs were in very modest LD (D' ranging from 0.06-0.65) and showed poor correlation (r2 = 0.00-0.41) with each other. We did not continue genotyping rs2237897 after initial screening of 1,507 samples (815 T2D/692 controls) as this SNP was least frequent in our population; MAF in controls was 1% (additional file 1 Table S1). Compared to all other SNPs, this least frequent SNP was relatively in stronger LD with rs2237892 (D' = 0.65, r2 = 0.41). However, none of the three Japanese GWAS SNPs (rs2237892, rs2237895 and rs2237897) was correlated with rs231362 (r2<0.005) (Figure 1).


Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: a study of 3,310 subjects from India and the US.

Been LF, Ralhan S, Wander GS, Mehra NK, Singh J, Mulvihill JJ, Aston CE, Sanghera DK - BMC Med. Genet. (2011)

Figure 1 describes structure of human KCNQ1 gene on chromosome 11. Top portion of the Figure 1 shows the position of four investigated SNPs from intron 11 and 15. Figure 1(A) shows pair-wise linkage disequilibrium (LD) (D') and Figure 1(B) shows pair-wise correlation (r2) between SNPs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037841&req=5

Figure 1: Figure 1 describes structure of human KCNQ1 gene on chromosome 11. Top portion of the Figure 1 shows the position of four investigated SNPs from intron 11 and 15. Figure 1(A) shows pair-wise linkage disequilibrium (LD) (D') and Figure 1(B) shows pair-wise correlation (r2) between SNPs.
Mentions: Table 1 summarizes and compares the general characteristics of the two study cohorts used in this investigation. Among these subjects, the US cohort was younger and had earlier onset of T2D (42 years) compared to the Punjabi cohort (48 years). Diabetics in the Punjabi cohort had poor glycemic control showing significantly higher FBG levels (by 17 mg/dL) (p = 0.002) compared to the US cohort. HOMA-B (used as a surrogate marker for beta [β] cell function) were also significantly lower (by 33 units) (p = 4.64 × 10-8) and WHR significantly higher (by 5 units) (p <0.001) in the Punjabi cohort. The physical location and inter-marker distance of all investigated SNPs is shown in Figure 1. Linkage disequilibrium (LD) analysis revealed that all investigated SNPs were in very modest LD (D' ranging from 0.06-0.65) and showed poor correlation (r2 = 0.00-0.41) with each other. We did not continue genotyping rs2237897 after initial screening of 1,507 samples (815 T2D/692 controls) as this SNP was least frequent in our population; MAF in controls was 1% (additional file 1 Table S1). Compared to all other SNPs, this least frequent SNP was relatively in stronger LD with rs2237892 (D' = 0.65, r2 = 0.41). However, none of the three Japanese GWAS SNPs (rs2237892, rs2237895 and rs2237897) was correlated with rs231362 (r2<0.005) (Figure 1).

Bottom Line: The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians.Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma, USA.

ABSTRACT

Background: Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.

Methods: We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.

Results: Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).

Conclusions: Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.

Show MeSH
Related in: MedlinePlus