Content area
Full Text
Hum Genet (2015) 134:111121 DOI 10.1007/s00439-014-1499-0
ORIGINAL INVESTIGATION
Genetic variation of the transthyretin gene in wildtype transthyretin amyloidosis (ATTRwt)
Jacquelyn L. Sikora Mark W. Logue Gloria G. Chan Brian H. Spencer Tatiana B. Prokaeva Clinton T. Baldwin David C. Seldin Lawreen H. Connors
Abstract Wild-type transthyretin amyloidosis (ATTRwt), typically diagnosed as congestive heart failure in elderly Caucasian men, features myocardial amyloid deposits of wild-type plasma protein transthyretin (TTR). ATTRwt is sporadic, its pathogenesis is poorly understood, and currently there are no biomarkers for diagnosis or prognosis. Genetic studies of variant-associated transthyretin amyloidosis have suggested that non-coding TTR gene variants modulate disease. We hypothesized that cis-acting regulatory elements in the TTR gene non-coding regions may modify expression, affecting ATTRwt onset and progression. We studied an ATTRwt cohort consisting of 108 Caucasian males ranging in age from 59 to 87 years with cardiomyopathy due to wild-type TTR deposition; results were compared to 118 anonymous controls matched by age, sex, and race. Four predicted non-coding regulatory regions and all exons in the TTR gene were sequenced using the
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s00439-014-1499-0
Web End =10.1007/s00439-014-1499-0 ) contains supplementary material, which is available to authorized users.
J. L. Sikora L. H. Connors (*)
Department of Pathology and Laboratory Medicine,
Boston University School of Medicine, 72 East Concord Street, K507, Boston, MA 02118, USAe-mail: [email protected]
J. L. Sikorae-mail: [email protected]
J. L. Sikora G. G. Chan B. H. Spencer T. B. Prokaeva D. C. Seldin L. H. Connors
Amyloidosis Center, Boston University School of Medicine, Boston, MA 02118, USA
M. W. Logue C. T. Baldwin D. C. Seldin
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Received: 7 August 2014 / Accepted: 10 October 2014 / Published online: 4 November 2014 Springer-Verlag Berlin Heidelberg 2014
Sanger method. Eleven common variants were identied; three variants were signicantly associated with ATTRwt (p < 0.05), though only one, rs72922940, remained near signicance (pcorrected = 0.083) after multiple testing cor
rection. Exon analyses demonstrated the occurrence of the p.G26S (G6S) polymorphism in 7 % of ATTRwt subjects and 12 % of controls; this variant was predicted to be a protective factor (p = 0.051). Four variants were sig
nicantly associated with age at onset and...