Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study

Background: Low concentrations of lipoprotein(a) in plasma are associated with increased risk of type 2 diabetes, but whether this association is causal is unclear. Variations in the LPA gene affect lipoprotein(a) isoform size and concentrations in plasma. We therefore did a Mendelian randomisation study to investigate whether large isoform size, low concentrations in plasma, or both, are causally associated with type 2 diabetes.

Methods: We assessed data for adults from the Danish general population enrolled in the Copenhagen City Heart Study and the Copenhagen General Population Study, with and without type 2 diabetes. Eligible participants had data for lipoprotein(a) concentrations in plasma, LPA kringle IV type 2 (KIV-2) sums of repeats (affecting both isoform size and plasma concentrations), and carrier status for the LPA single-nucleotide polymorphism rs10455872 (mainly affecting concentrations in plasma).

Findings: 77,901 individuals had lipoprotein(a) data, of whom 28,567 (36·7%) had all three measurements. Low concentrations of lipoprotein(a) in plasma were associated with risk of type 2 diabetes, with adjusted odds ratios of 1·26 (1·09-1·45), 1·17 (1·01-1·36), 1·04 (0·90-1·21), and 1·05 (95% CI 0·90-1·22), respectively, for quintiles 1-4, compared with quintile 5 concentrations. High KIV-2 sums of repeats were associated with risk of type 2 diabetes (adjusted odds ratio 1·16, 95% CI 1·05-1·28) for KIV-2 quintile 5 versus quintiles 1-4 combined. Being a carrier of rs10455872 did not affect risk of type 2 diabetes. For a halving of lipoprotein(a) concentrations, the instrumental variable estimate of the causal odds ratio for type 2 diabetes was 1·15 (95% CI 1·05-1·27) for KIV-2 sum of repeats and 0·99 (0·95-1·03) for rs10455872 genotype.

Interpretation: Low lipoprotein(a) concentrations alone seem not to be causally associated with type 2 diabetes, but a causal association for large lipoprotein(a) isoform size cannot be excluded.

Funding: Danish Heart Foundation, Danish Council for Independent Research-Medical Sciences, IMK Almene Fund, and Johan and Lise Boserup's Fund.