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Clin Chem. 2017 Dec;63(12):1866-1876. doi: 10.1373/clinchem.2017.277103. Epub 2017 Sep 25.

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.

Author information

1
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
2
Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
3
The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark.
4
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; boerge.nordestgaard@regionh.dk.

Abstract

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.

PMID:
28971985
DOI:
10.1373/clinchem.2017.277103
[Indexed for MEDLINE]
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