Læknaneminn - 01.04.2016, Blaðsíða 144

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Landspítala og Læknasetursins. Notast var við
Kaplan­Meier aðferð með log­rank­prófi til að bera
saman hópa og Cox­aðhvarfsgreining til að meta lifun
græðlinga og sjúklinga, og línulega aðhvarfsgreiningu
til að meta tengsl gaukulsíunarhraða (rGSH) hjá
þegum 6­12 mánuðum eftir ígræðslu við aðra þætti .
Niðurstöður: Alls voru 149 nýru grædd í 146
sjúklinga á rannsóknartímabilinu (miðgildi aldurs 44
ár (3­76), 58,3% karlar). Endurígræðslur voru 21
talsins. Á Landspítala voru gerðar 79 ígræðslur en 70
aðgerðir fóru fram erlendis, þar af 18 nýru úr lifandi
gjöfum. Því fékk 65% sjúklinga nýra frá lifandi gjafa.
Miðgildi (spönn) aldurs við ígræðslu var 45 (3­76) ár
hjá þegum nýrna úr lifandi gjöfum en 50 (9­69) ár
þegar um látna gjafa var að ræða. Af sjúklingum sem
fengu nýra frá látnum gjafa höfðu 96% gengist undir
skilunarmeðferð fyrir ígræðslu á móti 69% þega nýrna
úr lifandi gjöfum. Kaldur blóðþurrðartími nýrna frá
látnum gjöfum var 20,5 (5­34) klst.. HLA­samræmi
var marktækt betra þegar um lifandi gjafa var að ræða
en 69% voru með ≥3 HLA­sameindir sameiginlegar á
móti 36,5% í tilviki látinna gjafa. Af lifandi gjöfunum
voru 79,4% líffræðilega skyldir þeganum. Alls létust
11 (7,4%) sjúklingar á tímabilinu, þar af 10 með
starfandi græðling. Ef afklippt (e. censored) er við
dauða með starfandi græðling töpuðust 11 græðlingar
á tímabilinu, þar af 6 (54,5%) vegna langvinnrar
græðlingsbilunar. Eins árs lifun græðlinga, reyndist
vera 98% (95% öryggismörk (95%ÖM) 95,7­
100), fimm ára lifun 95,5% (95%ÖM 92­99,1)
og tíu ára lifun 88,1% (95%ÖM 80,4­96,5). Ekki
fannst marktækur munur á lifun nýraþega né lifun
græðlinga með hliðsjón af tegund gjafa né þegar
ígræðslur á Landspítala voru bornar saman við aðrar
stofnanir. Þegar stakir þættir voru skoðaðir í Cox­
aðhvarfsgreiningu jók hækkandi aldur gjafa hættu á
græðlingstapi (Hættuhlutfall (HH) 1,076 (95%ÖM
1,014­1,143)) og hærri r­GSH 6­12 mánuðum eftir
ígræðslu virtist minnka hættuna á græðlingstapi (HH
0,949 (95%ÖM 0,910­0,992)). Fjölþáttagreining
sýndi að engir aðrir þættir en þessir tengdust
græðlings lifun. Fjölþátta línuleg aðhvarfsgreining
sýndi m.a. að sjálfstæð tengsl voru milli rGSH hjá
þegum 6­12 mánuðum eftir ígræðslu og aldurs gjafa
(β=­0,56, p=0.002), aldurs þega (β=­0,31, p=0,01)
og rGSH gjafa eftir aðgerð (β=0,44, p=0,0065).
Ályktun: Hlutfall nýrna frá lifandi gjöfum meðal
íslenskra nýraþega er hátt samanborið við aðrar þjóðir.
Lifun græðlinga og nýraþega virðist ekki síðri en gerist
á sjúkrahúsum þar sem aðgerðir eru tíðari. Þó smæð
þýðisins og góð lifun takmarki greiningu áhættuþátta
benda niðurstöður til þess að m.a. aldur gjafa og GSH
þega á fyrsta árinu eftir ígræðsluaðgerðina gætu haft
áhrif lifun græðlinga.
Genetics of coarctation of the
aorta in Iceland
Þorsteinn Björnsson1, Hilma Hólm2,3,
Tómas Guðbjartsson1,3, Hróðmar
Helgason3, Daníel F. Guðbjartsson2,4,
Unnur Þorsteinsdottir1,2, Kári Stefansson1,2
1Faculty of Medicine, University of
Iceland, 2deCODE genetics, 3Landspitali
University Hospital, 4School of
Engineering and Natural Sciences,
University of Iceland
Introduction: Coarctation of the aorta (CoA)
accounts for 3.8% of all congenital heart disease in
Iceland. Despite excellent surgical outcomes, CoA
can be a life­long disease with high rates of long­
term cardiovascular complications. The underlying
genetic basis and pathogenesis of CoA remains largely
unknown. The objective of this study was to search
for sequence variants that affect the risk of developing
CoA in Iceland.
Methods: The CoA cases were Icelanders (N=132)
who received the discharge diagnosis of CoA at
Landspitali University Hospital (LUH) in Reykjavik
between 1984 and 2015. Detailed phenotypic
information on CoA cases was gathered through a
centralized electronic database on patient’s records
(Saga system) as well as paper records at LUH. To
identify sequence variants that associate with CoA
risk, genome­wide association analysis (GWAS)
was performed using 31.6 million sequence variants
identified through whole­genome sequencing of
8,453 Icelanders that were subsequently imputed
into 390,000 Icelanders. The GWAS was performed
with the 132 CoA cases and as controls 240,000
Icelanders without CoA using logistic regression,
adjusting for gender, age and county.
Results: Through the CoA GWAS analysis we
identified a rare (0.35%) missense variant c.2161C>T
in exon 18 of the MYH6 gene that associates with
increased risk of CoA. MYH6 is a large gene that
encodes the alpha myosin heavy chain (αMHC),
a major component of the sarcomere of cardiac
muscle. The c.2161C>T mutation associates with
CoA with large effect, an OR of 31.4 (SD; 14.08,
69.83) and with high significance, P of 3.3 x 10­17.
The c.2161C>T results in the change of arginine to
tryptophan at amino acid 721 (p.Arg721Trp) in the
converter domain of the αMHC protein. This same
mutation has previously been reported to associate
with sick sinus syndrome. Of the 132 CoA cases, 24
were carriers of c.2161C>T; no significant phenotypic
difference was found between CoA carriers and non­
carriers of c.2161C>T. This may in part be explained
by the small size of the study. The MYH6 c.2161C>T
was not found outside of Iceland.
Discussion: The MYH6 gene has not previously
been reported to associate with CoA although other
very rare mutations in MYH6 have been linked to
both familial hypertrophic cardiomyopathy and
familial atrial septal defect. The c.2161C>T mutation
explains a large fraction or 19% of CoA cases in
Iceland, a figure rarely reported in genetic studies of
congenital heart disease. Expression of MYH6 has not
been detected in the aorta but it is highly expressed
throughout life in the atrium and in the ventricle
during embryonic cardiogenesis. The p.Arg721Trp
mutation in the converter domain of αMHC is
predicted to be damaging and might thus affect the
contractile function of αMHC in the heart. It is
conceivable that p.Arg721Trp predisposes to CoA by
reducing the contraction of the developing heart thus
reducing blood flow through the aorta which is in
line with the hemodynamic theory, a leading model
of CoA pathogenesis. This hypothesis is compatible
with the fact that MYH6 is not expressed in the aorta.