Kringle IV Type 2, Not Low Lipoprotein(a), as a Cause of Diabetes: A Novel Genetic Approach Using SNPs Associated Selectively with Lipoprotein(a) Concentrations or with Kringle IV Type 2 Repeats
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Kringle IV Type 2, Not Low Lipoprotein(a), as a Cause of Diabetes : A Novel Genetic Approach Using SNPs Associated Selectively with Lipoprotein(a) Concentrations or with Kringle IV Type 2 Repeats. / Tolbus, Andra; Mortensen, Martin B; Nielsen, Sune F; Kamstrup, Pia R; Bojesen, Stig E; Nordestgaard, Børge G.
In: Clinical Chemistry, Vol. 63, No. 12, 12.2017, p. 1866-1876.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Kringle IV Type 2, Not Low Lipoprotein(a), as a Cause of Diabetes
T2 - A Novel Genetic Approach Using SNPs Associated Selectively with Lipoprotein(a) Concentrations or with Kringle IV Type 2 Repeats
AU - Tolbus, Andra
AU - Mortensen, Martin B
AU - Nielsen, Sune F
AU - Kamstrup, Pia R
AU - Bojesen, Stig E
AU - Nordestgaard, Børge G
N1 - © 2017 American Association for Clinical Chemistry.
PY - 2017/12
Y1 - 2017/12
N2 - BACKGROUND: Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes.METHODS: We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study.RESULTS: We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86-1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17-1.69).CONCLUSIONS: Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats.
AB - BACKGROUND: Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes.METHODS: We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study.RESULTS: We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86-1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17-1.69).CONCLUSIONS: Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats.
KW - Journal Article
U2 - 10.1373/clinchem.2017.277103
DO - 10.1373/clinchem.2017.277103
M3 - Journal article
C2 - 28971985
VL - 63
SP - 1866
EP - 1876
JO - Clinical Chemistry
JF - Clinical Chemistry
SN - 0009-9147
IS - 12
ER -
ID: 185988574