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Studies of association of AGPAT6 variants with type 2 diabetes and related metabolic phenotypes in 12,068 Danes.

Snogdal LS, Grarup N, Banasik K, Wod M, Jørgensen T, Witte DR, Lauritzen T, Nielsen AA, Brandslund I, Christensen C, Pedersen O, Yderstræde K, Beck-Nielsen H, Henriksen JE, Hansen T, Højlund K - BMC Med. Genet. (2013)

Bottom Line: The case-control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study.Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity.Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Type 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population.

Methods: Eleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case-control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study.

Results: None of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case-control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity.

Conclusions: Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied.

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Related in: MedlinePlus

Linkage disequilibrium (LD) plot across AGPAT6. The box at the top shows the AGPAT6 gene with the location of the 28 SNPs included in this study. The 11 tag SNPs are indicated by circles around the rs number of the SNPs. The LD plot is based on the measure of D’. Each diamond indicates the pair wise magnitude of LD, with dark grey diamonds indicating strong LD (D’ > 0.8) and light grey: uninformative. LD: linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies.
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Figure 1: Linkage disequilibrium (LD) plot across AGPAT6. The box at the top shows the AGPAT6 gene with the location of the 28 SNPs included in this study. The 11 tag SNPs are indicated by circles around the rs number of the SNPs. The LD plot is based on the measure of D’. Each diamond indicates the pair wise magnitude of LD, with dark grey diamonds indicating strong LD (D’ > 0.8) and light grey: uninformative. LD: linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies.

Mentions: SNP selection We performed tagging of the genomic region including AGPAT6 (HapMap release 27, Phase II + III, Feb. 09, B36, CEU panel; Chr8:41,544 kb - 41,607 kb (AGPAT6 position ± 10 kb)) using Haploview 4.2 (http://www.broadinstitute.org/haploview). See LD plot of AGPAT6 in Figure 1. Eleven SNPs captured all common variation with minor allele frequency (MAF) above 5% (n = 10) and low-frequency variation with MAF below 5% but above 1% (n = 1) variation in AGPAT6 (r2 >0.8). The selected SNPs have the following rs numbers: rs13252523, rs7357415, rs2977860, rs11785763, rs999188, rs17600159, rs2977845, rs10504041, rs12677439, rs6988044 and rs890220.


Studies of association of AGPAT6 variants with type 2 diabetes and related metabolic phenotypes in 12,068 Danes.

Snogdal LS, Grarup N, Banasik K, Wod M, Jørgensen T, Witte DR, Lauritzen T, Nielsen AA, Brandslund I, Christensen C, Pedersen O, Yderstræde K, Beck-Nielsen H, Henriksen JE, Hansen T, Højlund K - BMC Med. Genet. (2013)

Linkage disequilibrium (LD) plot across AGPAT6. The box at the top shows the AGPAT6 gene with the location of the 28 SNPs included in this study. The 11 tag SNPs are indicated by circles around the rs number of the SNPs. The LD plot is based on the measure of D’. Each diamond indicates the pair wise magnitude of LD, with dark grey diamonds indicating strong LD (D’ > 0.8) and light grey: uninformative. LD: linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231429&req=5

Figure 1: Linkage disequilibrium (LD) plot across AGPAT6. The box at the top shows the AGPAT6 gene with the location of the 28 SNPs included in this study. The 11 tag SNPs are indicated by circles around the rs number of the SNPs. The LD plot is based on the measure of D’. Each diamond indicates the pair wise magnitude of LD, with dark grey diamonds indicating strong LD (D’ > 0.8) and light grey: uninformative. LD: linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies.
Mentions: SNP selection We performed tagging of the genomic region including AGPAT6 (HapMap release 27, Phase II + III, Feb. 09, B36, CEU panel; Chr8:41,544 kb - 41,607 kb (AGPAT6 position ± 10 kb)) using Haploview 4.2 (http://www.broadinstitute.org/haploview). See LD plot of AGPAT6 in Figure 1. Eleven SNPs captured all common variation with minor allele frequency (MAF) above 5% (n = 10) and low-frequency variation with MAF below 5% but above 1% (n = 1) variation in AGPAT6 (r2 >0.8). The selected SNPs have the following rs numbers: rs13252523, rs7357415, rs2977860, rs11785763, rs999188, rs17600159, rs2977845, rs10504041, rs12677439, rs6988044 and rs890220.

Bottom Line: The case-control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study.Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity.Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Type 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population.

Methods: Eleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case-control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study.

Results: None of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case-control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity.

Conclusions: Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied.

Show MeSH
Related in: MedlinePlus