- Q. Liet al.,Science 325 , 855–859 (2009).
- K. Zhu, C. A. O’Keefe, V. N. Vukotic, R. W. Schurko, S. J. Loeb,
Nat. Chem. 7 , 514–519 (2015). - S. Krause, B. Feringa,Nat. Rev. Chem. 4 , 550– 562
(2020). - P. Martinez-Bulit, A. J. Stirk, S. J. Loeb,Trends Chem. 1 ,
588 – 600 (2019). - W. Danowskiet al.,Nat. Nanotechnol. 14 , 488– 494
(2019). - Mechanisorption is not to be confused with the macroscopic
concept of mechanosorption, which describes the usage of
mechanical forces to enhance physisorption in wood and
other materials. - R. D. Astumian, I. Derényi,Eur. Biophys. J. 27 , 474– 489
(1998). - Y. Wanget al.,Adv. Sci. 6 , 1802059 (2019).
- L. Caoet al.,Angew. Chem. Int. Ed. 55 , 4962– 4966
(2016). - Y. Jianget al.,Inorg. Chem. 57 , 15123–15132 (2018).
- L. Feng, G. S. Day, K.-Y. Wang, S. Yuan, H.-C. Zhou,Chem 6 ,
2902 – 2923 (2020). - P. Deriaet al.,J. Am. Chem. Soc. 135 , 16801– 16804
(2013). - Y. Wang, M. Frasconi, J. F. Stoddart,ACS Cent. Sci. 3 , 927– 935
(2017). - Coordinating oxidants such as nitrosonium hexafluorophosphate
(NOPF 6 ) were found to cleave coordination bonds between
Zr-BTB and MPCG13+, leading to failed mechanisorption. - Y. Penget al.,Nat. Commun. 9 , 187 (2018).
- W. Morris, W. E. Briley, E. Auyeung, M. D. Cabezas, C. A. Mirkin,
J. Am. Chem. Soc. 136 , 7261–7264 (2014). - H. C. Kolb, M. G. Finn, K. B. Sharpless,Angew. Chem. Int. Ed.
40 , 2004–2021 (2001). - J. C. Skou,Angew.Chem.Int.Ed. 37 , 2320– 2328
(1998). - P. Läuger,Angew. Chem. Int. Ed. 24 , 905–923 (1985).
ACKNOWLEDGMENTS
We acknowledge Foresight Institute and its 2021 Fellowship
Program for the support, and thank K.-Y. Wang, L. Zhang, H. Chen,
and Y. Jiao for experimental help and discussions.Funding:We
thank Northwestern University (NU) for its continued support
of this research. It made use of the Integrated Molecular Structure
Education and Research Center (IMSERC) NMR Facility and
X-Ray Facility at NU, which receives support from the Soft and
Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF
ECCS-2025633), NIH 1S10OD012016-01/1S10RR019071-01A1, the
International Institute for Nanotechnology (IIN), and NU. This
work also made use of the EPIC facility and the Keck-II facility of
Northwestern University’s Atomic and Nanoscale Characterization
Experimental Center (NUANCE), which receives support from the
SHyNE Resource (NSF ECCS-2025633), the IIN, and NU’s MRSEC
program (NSF DMR-1720139). O.K.F. acknowledges support from
Inorganometallic Catalyst Design Center, an Energy Frontier
Research Center funded by the U.S. Department of Energy (DOE),
Office of Science, Basic Energy Sciences (BES), under Award DE-
SC0012702.Author contributions:L.F., Y.Q., and J.F.S. conceived
of the study and designed experiments. L.F., Y.Q., Q.-H.G., J.S.W.S.,
H.W., and Y.F. conducted the synthesis. L.F. conducted NMR,
PXRD, and TGA analysis. Z.C., J.S.W.S., and O.K.F. conducted gas
sorption studies and IR measurements. K.H. contributed to the
TEM imaging studies in this work. L.F., Y.Q., Q.-H.G., J.S.W.S.,
R.D.A., and J.F.S. commented on the data and the presentation. All
authors contributed to data analysis. L.F., R.D.A., and J.F.S.
wrote the draft, with input from all authors.Competing interests:
L.F., Y.Q., and J.F.S. have a patent application lodged with
Northwestern University (INVO Reference No. NU 2021-183) based
on this work.Data and materials availability:All data are
available in the main text or the supplementary materials.
SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abk1391
Materials and Methods
Supplementary Text
Figs. S1 to S90
Tables S1 to S5
References ( 58 – 63 )
23 June 2021; accepted 1 October 2021
Published online 21 October 2021
10.1126/science.abk1391
HUMAN GENOMICSGenetic and functional evidence links a missense
variant inB4GALT1to lower LDL and fibrinogen
May E. Montasser^1 *†, Cristopher V. Van Hout2,3†, Lawrence Miloscio^2 †, Alicia D. Howard1,4,
Avraham Rosenberg^5 , Myrasol Callaway^5 , Biao Shen^5 , Ning Li^5 , Adam E. Locke^2 , Niek Verweij^2 ,
Tanima De^2 , Manuel A. Ferreira^2 , Luca A. Lotta^2 , Aris Baras^2 , Thomas J. Daly^5 , Suzanne A. Hartford^5 ,
Wei Lin^5 , Yuan Mao^5 , Bin Ye^2 , Derek White^5 , Guochun Gong^5 , James A. Perry^1 , Kathleen A. Ryan^1 ,
Qing Fang^5 , Gannie Tzoneva^2 , Evangelos Pefanis^5 , Charleen Hunt^5 , Yajun Tang^5 , Lynn Lee^5 ,
Regeneron Genetics Center Collaboration‡, Carole Sztalryd-Woodle1,6, Braxton D. Mitchell1,7,
Matthew Healy^8 , Elizabeth A. Streeten1,9, Simeon I. Taylor^1 , Jeffrey R. OÕConnell^1 ,
Aris N. Economides2,5, Giusy Della Gatta^2 §, Alan R. Shuldiner^2 §Increased blood levels of low-density lipoprotein cholesterol (LDL-C) and fibrinogen are independent
risk factors for cardiovascular disease. We identified associations between an Amish-enriched
missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1
(B4GALT1) and 13.9 milligrams per deciliter lower LDL-C (P= 4.1 × 10–^19 ) and 29 milligrams per
deciliter lower plasma fibrinogen (P= 1.3 × 10–^5 ).B4GALT1gene–based analysis in 544,955 subjects
showed an association with decreased coronary artery disease (odds ratio = 0.64,P= 0.006).
The mutant protein had 50% lower galactosyltransferase activity compared with the wild-type protein.
N-linked glycan profiling of human serum found serine 352 allele to be associated with decreased
galactosylation and sialylation of apolipoprotein B100, fibrinogen, immunoglobulin G, and transferrin.
B4galt1^353 Ser knock-in mice showed decreases in LDL-C and fibrinogen. Our findings suggest
that targeted modulation of protein galactosylation may represent a therapeutic approach to
decreasing cardiovascular disease.C
ardiovascular disease (CVD) is the lead-
ing cause of morbidity and mortality
worldwide ( 1 ). Elevated low-density lipo-
protein cholesterol (LDL-C) increases
arterial plaque formation and athero-
sclerosis, and fibrinogen increases the risk for
blood clotting and thrombosis. LDL-C is an
established risk factor for coronary artery
disease (CAD), and fibrinogen also plays a
potential role ( 2 – 4 ). Variations in LDL-C and
fibrinogen are governed by both genetic and
environmental factors, as well as by the inter-
play between them ( 5 , 6 ).
Rare and common genetic variants have
been identified for both LDL-C and fibrino-gen ( 7 – 9 ). However, few variants have been
found with pleiotropic effects on more than
one CAD risk factor. Similarly, therapeutic ap-
proaches to mitigating CAD risk have focused
on treating individual risk factors. Deeper
understanding of the genetic determinants of
LDL-C and fibrinogen may unveil new targets
fortherapythatmaybemoreefficaciousand
safer to treat or prevent CAD.
Founder populations can facilitate the iden-
tification of new disease associations with
DNA sequence variants that are enriched to
a higher frequency through genetic drift. In
homogeneous human populations in Iceland
( 10 ), Sardinia ( 11 ), Greenland ( 12 ), Samoa ( 13 ),
andtheOldOrderAmish(OOA)( 14 – 20 ),
enriched variants with large effect sizes asso-
ciated with complex diseases and traits have
been identified. Although such variants are
often rare or absent in the general popula-
tion, they can inform biological mechanisms
and provide therapeutic targets relevant to
all humans.Association analyses identifyB4GALT1
p.Asn352Ser as a new LDL-C variant
To identify genetic variants associated with
LDL-C, we performed whole-exome sequencing
(WES) and association analysis in 6890 OOA
subjects (table S1) ( 21 ). Linear mixed-model
association analysis identified previously ascer-
tained loci for LDL-C, as well as a previously
unidentified locus on the short arm of chromo-
some 9 (fig. S1 and table S2). A missense variant
(rs551564683, p.Asn352Ser) inB4GALT1(Fig. 1A)SCIENCEscience.org 3 DECEMBER 2021¥VOL 374 ISSUE 6572 1221
(^1) Division of Endocrinology, Diabetes and Nutrition and
Program for Personalized and Genomic Medicine,
Department of Medicine, University of Maryland School of
Medicine, Baltimore, MD 21201, USA.^2 Regeneron Genetics
Center, LLC, Tarrytown, NY 10591, USA.^3 Laboratorio
Internacional de Investigatión sobre el Genoma Humano,
Campus Juriquilla de la Universidad Nacional Autónoma de
México, Querétaro, Querétaro 76230, México.^4 Center for
Biologics Evaluation and Research, US Food and Drug
Administration, Silver Spring, MD 20993, USA.^5 Regeneron
Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.^6 US
Department of Veterans Affairs, Washington, DC 20420 USA.
(^7) Geriatrics Research and Education Clinical Center, VA
Medical Center, Baltimore, MD 21201, USA.^8 Enveda
Biosciences, Boulder, CO 80301, USA.^9 Division of Genetics,
Department of Pediatrics, University of Maryland School of
Medicine, Baltimore, MD 21201, USA.
*Corresponding author. Email: [email protected]
†These authors contributed equally to this work and are co-first
authors.‡A complete list of investigators contributing to the
Regeneron Genetics Center Collaboration is provided at the end of
this manuscript. §These authors contributed equally to this work
and are co-senior authors.
RESEARCH | RESEARCH ARTICLES