The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925G>A

The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat

“…In contrast to the regression models including 4925G>A, inclusion of rs41272110 into the regression models did not abolish the association of PNR10 and PNR11 alleles with low Lp(a) (isoform-adjusted model: PNR10: β = −8.74, P = 3.89e-16; PNR11: β = −11.52, P = 5.71e-13; supplemental Table S2 ). Conversely, adding subsequently also KIV-2 4925G>A to the regression model with rs41272110 showed a significant Lp(a)-decreasing effect of 4925G>A (β = −25.42, P = 3.05E-40), a significant Lp(a) increase in carriers of rs41272110 (β = +4.49, P = 0.0018), which is in line with what we have shown previously ( 35 ), and confirm no effect of the PNR alleles PNR10 or PNR11 (PNR10: β = +0.24, P = 0.82; PNR11: β = −1.84, P = 0.25; Table 4 ). This further supports that the effect of the PNR alleles PNR10 and PNR11 allele on Lp(a) is, indeed, caused by KIV-2 4925G>A and not by rs41272110.…”

“…Previous studies suggested an LD between alleles PNR10 and PNR11 and rs41272110 ( 24 , 26 ). We have shown recently that the individual effect of rs41272110 on Lp(a) depends on the KIV-2 4925G>A carrier status and that the Lp(a) decrease previously attributed to rs41272110 is produced by a partial LD with 4925G>A ( 35 ). Given the occurrence of the alleles PNR10 and PNR11 in the same isoform range as 4925G>A and rs41272110, we hypothesized that a similar mechanism might also cause the association of PNR10 and PNR11 with low Lp(a) plasma concentrations ( Fig.…”

“…We recently reported also a strong LD between 4925G>A and the well-known missense LPA variant Thr3888Pro (p.Thr1399Pro, rs41272110) ( 35 ). As others had suggested that the effect of the PNR on Lp(a) might derive from rs412722110 ( 24 , 26 ), we investigated whether the effect of PNR10 and PNR11 allele could indeed be caused by an LD with rs41272110 instead of an LD with 4925G>A.…”

“…Therefore, PCR assays do not differentiate whether a signal showing multiple 4925G>A occurrences stems from multiple mutated KIV-2 repeats on the same chromosome or on different chromosomes. Thus, the variant is reported as positive or negative carrier status ( 12 , 17 , 35 ). LD between the KIV-2 4925G>A and the alleles PNR10 and PNR11 was calculated using the R package genetics ( https://CRAN.R-project.org/package=genetics ).…”

“…Recently we have identified a strong LD between rs41272110 and the frequent, strongly Lp(a) and coronary artery disease (CAD) risk–lowering splice variant 4925G>A in the KIV-2 region ( 35 ). We showed that the effect of rs41272110 on Lp(a) and on CAD risk depends on the KIV-2 4925G>A and that the Lp(a)-lowering effect previously attributed to rs41272110 is indeed caused by this splice variant ( 35 ). The reported LD between rs41272110 and PNR10 ( 24 ) led us to the hypothesis that the association of long PNR alleles with low Lp(a) concentrations also could be mediated by KIV-2 4925G>A.…”