P= 5.2 × 10–^6 ,ttest] and higher AST [beta =
0.234 (1.7 U/L),P= 1.2 × 10–^7 ,ttest], but no
association with HDL or ALT (P> 0.05,ttest)
(Fig. 2A).
We then tested this collection of rare delete-
riousvariantsforassociationwithCAD,show-
ing a consistent association with decreased
risk (odds ratio = 0.64,P= 0.006,Ztest) (Fig.
2B). The association was protective in both
the DiscoverEHR and UKBB data, although
the effect was much more significant in the
UKBB data (P= 0.6 versus 0.001, likelihood
ratio test). The rare nature of these variants
will require additional large sequence-based
cohorts to validate this association, but the
results are consistent with the pattern of as-
sociation for quantitative traits and suggestive
of alterations in B4GALT1 function providing
protection from CAD.
B4GALT1p.Asn352Ser is associated with
increased levels of incompletely synthesized
glycans on glycoproteins
The carbohydrate-deficient transferrin test
(CDT) ( 32 ), which assesses glycosylation lev-els of transferrin and apolipoprotein CIII
(ApoCIII), is used clinically to diagnose pa-
tients with congenital disorders of glycosyla-
tion. We performed the CDT in serum samples
from 28 participants from the three genotype1224 3 DECEMBER 2021•VOL 374 ISSUE 6572 science.orgSCIENCE
Fig. 4..B4GALT1p.Asn352Ser decreases galac-
tosyltransferase activity.(A) Percentage of^352 Asn
B4GALT1 galactosylation activity of^352 Asn B4GALT1
and^352 Ser B4GALT1 immunoprecipitated proteins
from transfected COS-7 cells (mean ± SEM,n= 4).
(B) Enzymatic activity of recombinant B4GALT1
(^352) Ser protein (open circles) and (^352) Asn protein
(solid circles). Decrease in substrate UDP-Gal was
measured as peak area by hydrophilic interaction
chromatographyÐmass spectroscopy over eight
different time points (mean ± SEM,n= 3).Pvalues
are based onttest.
Fig. 5.B4galt1p.Asn353Ser germline knock-in mice phenocopy the human phenotype.(AandB)
Heterozygous and homozygous knock-in mice fed a standard chow diet showed lower levels of plasma LDL-C
and higher levels of AST compared with wild-type mice. (CandD) Trends toward decreased fibrinogen
and increased IgG were detected inB4galt1knock-in mice.Pvalues are based onFtest. Data are represented
as mean ± SEM (n= 14/group, two biological replicates).
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