Clinical Nephrology Epidemiology Clinical Trials

Kidney International (2002) 62, 963970; doi:10.1046/j.1523-1755.2002.00507.x

Nephropath i! tpe 1 dia"ete#: $ %a!i&e#tatio! o& i!#'(i!
re#i#ta!)e a!d %'(tip(e *e!eti) #'#)epti"i(itie#+
,'rther e-ide!)e &ro% the .itt#"'r*h /pide%io(o* o& 0ia"ete#
1o%p(i)atio! 2t'd
3re-or 4 5r)hard, 6'e-,a!* 1ha!*, 7o"ert / ,erre((, Na!) .etro a!d 0e%etri'# / /((i#
0epart%e!t o& /pide%io(o*, 8rad'ate 2)hoo( o& .'"(i) 9ea(th, :!i-er#it o& .itt#"'r*h; 0epart%e!t o& Ne'ro#'r*er,
2)hoo( o& ;edi)i!e, :!i-er#it o& .itt#"'r*h; 0epart%e!t o& 9'%a! 8e!eti)#, 8rad'ate 2)hoo( o& .'"(i) 9ea(th,
:!i-er#it o& .itt#"'r*h; a!d 0epart%e!t o& .ediatri)#, Nephro(o*, 2)hoo( o& ;edi)i!e, :!i-er#it o& .itt#"'r*h,
.itt#"'r*h, .e!!#(-a!ia
1orre#po!de!)e: 3re-or 4. 5r)hard, ;.0., :!i-er#it o& .itt#"'r*h, 0<7 ='i(di!*, 3512 ,i&th $-e!'e, .itt#"'r*h, .$
15213 :2$. /-%ai(: tjo>pitt.ed'
7e)ei-ed 7 2epte%"er 2001; 7e-i#ed 25 ;ar)h 2002; $))epted 2? ;ar)h 2002.
ABSTRACT
Nephropathy in type 1 diabetes: A maniestation o ins!lin resistance and
m!ltiple genetic s!sceptibilities" #!rther e$idence rom the %ittsb!rgh
Epidemiology o &iabetes Complication St!dy'
Bac(gro!nd
The pathogenesis o diabetic nephropathy remains !nclear) altho!gh pre$io!s
reports implicate a *ide range o p!tati$e genetic and metabolic actors'
+ethods
,ncident and pre$alent cases o o$ert nephropathy -.N/) deined as an alb!min
e0cretion rate1222 g3min in at least t*o o the three timed !rines) rom the
%ittsb!rgh Epidemiology o &iabetes Complication St!dy -a prospecti$e
epidemiologic st!dy o an incident cohort o childhood onset type 1 diabetic
s!b4ects/ *ere st!died'
Res!lts
,ncidence analyses re$eal dierences in !ni$ariate baseline ris( actors that
predict .N *ithin 5 years o meas!rement 6lo*7density lipoprotein -8&8/
cholesterol) triglycerides) *hite blood cell co!nt) and hypertension9 and those
that predict in the long7term) that is) 6 to 12 years ater baseline) hemoglobin A1
-:b A1/' Estimated gl!cose disposal rate -calc!lated !sing a orm!la deri$ed
rom e!glycemic7hyperins!linemic clamp st!dies/) ho*e$er) strongly -P ;
2'221/ predicted .N thro!gho!t ollo*7!p' Comparing indi$id!als *ho *ere
most s!sceptible to .N -those *ith an onset beore 22 years d!ration o type 1
diabetes and beore the de$elopment o other ad$anced complications/ *ith the
least s!sceptible -late or no occ!rrence o .N despite the de$elopment o other
ad$anced complications/ re$ealed other*ise !ndetected genetic associations
6that is) apolipoprotein E -Apo E/) angtiotensin7con$erting en<yme
insertion3deletion -ACE ,3&/) and lipoprotein lipase -8%8/ Hind,,,
polymorphism/ *ith odds ratios ranging rom 2'= to >'1'
1
Concl!sions
,n type 1 diabetes ins!lin resistance is an !nderlying ris( state or .N) *hich
may be accelerated by other dist!rbances -or e0ample) hypertension and
dyslipidemia/' A no$el approach to classiying -that is) phenotyping/ s!b4ects)
*hich compares those at the e0tremes o s!sceptibility) re$eals strong genetic
associations and important interactions *ith other ris( actors not other*ise
apparent'
?ey*ords:
diabetic nephropathy) le$els) ApoE) ACE) predictors) lipids) blood press!re
5-ert dia"eti) !ephropath (5N) )arrie# a hi*h ri#@ o& %orta(it i! tpe 1 dia"ete# !ot
o!( i! it# oA! ri*ht
1
, "'t a(#o a# a ri#@ &a)tor &or )oro!ar arter di#ea#e (1$0)
2
. 3he
!at're o& thi# a##o)iatio! Aith 1$0 i# i!tri*'i!*, &or de#pite the #tro!* a##o)iatio! #ee! i!
the i!itia( report# &ro% the 2te!o 1(i!i)
2
, re)e!t o"#er-atio!# &ro% "oth the :!ited
2tate#
3,4
a!d /'rope
5,6
#'**e#t the a##o)iatio! i# (ar*e(, i& !ot tota((, exp(ai!ed "
di#t'r"ed )o!*e!ita( -a#)'(ar di#ea#e (1B0) ri#@ &a)tor#, !ota"( "(ood pre##'re,
(ipid#/(ipoprotei!#, i!&(a%%ator %ar@er#, a!d #%o@i!*. 5N a(#o appear# to "e a #tro!*er
ri#@ &a)tor &or 1$0 i! %e! tha! i! Ao%e! Aith tpe 1 dia"ete#
3,4
.
Chether the#e 1B0 ri#@ &a)tor %ediator# o& the 5N-1$0 (i!@ ari#e (ar*e( &ro% the Ae((-
@!oA! e&&e)t o& re!a( di#ea#e o! "(ood pre##'re a!d (ipid %eta"o(i#%, or Ahether the
re#'(t &ro% "oth 5N a!d 1$0 #hari!* the #a%e ri#@ &a)tor# a!d/or *e!eti) #'#)epti"i(it,
i# di&&i)'(t to deter%i!e. 3he de%o!#tratio! that "(ood (ipid# a!d "(ood pre##'re predi)t
the i!)ide!)e o& %i)roa("'%i!'ria (;$) %i*ht #'pport the (atter hpothe#i#, &or ;$ i# a!
ear(, #o%eti%e# re-er#i"(e, #ta*e o& 5N
7
. $# ;$ i# a(#o a##o)iated Aith i!#'(i! re#i#ta!)e
i! the !o!-tpe 1 dia"ete# pop'(atio!, the po##i"i(it ari#e# that i!#'(i! re#i#ta!)e, Ahi)h
i# Ae((-@!oA! to "e re(ated to "(ood pre##'re e(e-atio!, di#t'r"ed (ipid %eta"o(i#% a!d
1$0
?
%a '!der(ie "oth 5N a!d 1$0 a!d pro-ide the (i!@ "etAee! the% i! tpe 1
dia"ete#.
2e-era( #t'die# pro-ide #'pport &or #')h a! i!#'(i! re#i#ta!)e-re!a( (i!@ i! tpe 1
dia"ete#. 6ip et al ha-e reported that 14 tpe 1 dia"eti) #'"je)t# Aith ;$ had #i*!i&i)a!t(
(oAer *(')o#e di#po#a( d'ri!* e'*()e%i)-hperi!#'(i!e%i) )(a%p #t'die# tha! did
%at)hed )o!tro(#, e-e! a&ter a))o'!ti!* &or "(ood pre##'re a!d "od %a## i!dex
9
, Ahi(e
0e 1o#%o et al dreA atte!tio! to the hi*h pre-a(e!)e o& 1$0 ri#@ &a)tor# i! pare!t# o&
tpe 1 dia"ete# #'"je)t# Aith a("'%i!'ria
10
. 3he#e a'thor# a(#o re)e!t( #'**e#ted that
the rate o& pro*re##io! o& 5N %a "e predi)ted, i! tpe 1 dia"ete#, " a -aria!t o& a!
i!hi"itor o& i!#'(i! #i*!a(i!* .11 *()oprotei!
11
. $ &'rther #et o& data a(#o #'**e#t that the
a!*iote!#i!-)o!-erti!* e!D%e i!#ertio!/de(etio! ($1/ E/0) po(%orphi#% i# a##o)iated
Aith predi#po#itio! to "oth 5N i! tpe 1 dia"ete#
12
a!d to i!#'(i! re#i#ta!)e
13
. 9oAe-er, it
i# the 0 a((e(e that predi#po#e# to 5N
12
a!d the E a((e(e that i# (i!@ed to i!#'(i!
re#i#ta!)e
13
. 5ther #t'die# ha-e )a#t do'"t o! the $1/ E/0 re(atio!#hip to 5N i! tpe 1
dia"ete#
14
. <i@eAi#e, the e-ide!)e o& Ahether $1/ i!hi"itio! i%pro-e# i!#'(i! #e!#iti-it
a!d *(')o#e to(era!)e i# a(#o )o!tro-er#ia( Aith #o%e report# #hoAi!* !o e&&e)t
15
, Ahi(e
other# #'**e#t a! i%pro-e%e!t i! i!#'(i! #e!#iti-it a!d *(')o#e (e-e(# Aith '#e o& $1/
i!hi"itor#
16,17
.
$!other pote!tia( *e!eti) po(%orphi#% re(ated to "oth 1$0 a!d i!#'(i! re#i#ta!)e i# the
apo(ipoprotei! / ($po /), Aherei! $po /2 i# a##o)iated Aith i%paired -er-(oA-de!#it
(ipoprotei! (B<0<) re%!a!t )(eara!)e a!d tpe 3 d#(ipide%ia, a!d $po /4 i# (i!@ed to
hi*her )ho(e#tero( (e-e(# a!d 1$0
1?
. $! i!tera)tio! "etAee! $po /3/2 a!d i!#'(i! (e-e(#
Aa# a(#o #ee! i! the ;7,E3 !e#ted-)a#e )o!tro( a!a(#e# i! that i!#'(i! (e-e( Aa# o!(
predi)ti-e o& 1$0 i! the #'"*ro'p o& tria( parti)ipa!t# Aith $po /3/2 phe!otpe
19
.
E!tri*'i!*(, a #i%i(ar $po //i!#'(i! i!tera)tio! ha# "ee! reported i! $(Dhei%erF# di#ea#e,
Aherei! tho#e Aitho't $po /4 ha-e i!#'(i! re#i#ta!)e
20
. E! additio!, re)e!t #t'die# ha-e
2
a(#o #'**e#ted a##o)iatio!# "etAee! the $po / po(%orphi#% a!d 5N i!
dia"ete#
21,22,23,24,25,26
.
E! order to &'rther addre## the#e G'e#tio!#, Ae ha-e exa%i!ed the 10-ear &o((oA-'p
data o& the .itt#"'r*h /pide%io(o* o& 0ia"ete# 1o%p(i)atio!# 2t'd )ohort o& )hi(dhood-
o!#et tpe 1 dia"ete#. E! parti)'(ar, Ae addre## (1) the predi)ti-e poAer (a!d ti%e )o'r#e
o& predi)tio!) &or 5N o& 1B0 ri#@ &a)tor#, i!)('di!* i!#'(i! re#i#ta!)e, '#i!* a #'rro*ate
%ar@er He#ti%ated *(')o#e di#po#a( rate (e807)I, Ahi)h ha# "ee! pre-io'#( -a(idated "
e'*()e%ia-hperi!#'(e%i) )(a%p #t'die#
27
&or de-e(opi!* 5N; (2) Ahether #pe)i&i)
*e!eti) po(%orphi#%# H$1/ E/0, $po / a!d (ipoprotei! (ipa#e (<.<) HindEEEI, Ahi)h ha-e
"ee! pre-io'#( (i!@ed to i!#'(i! re#i#ta!)e, 5N, a!d/or (ipid %eta"o(i#%, di#ti!*'i#h
tho#e Aith hi*h a!d (oA #'#)epti"i(it &or 5N; a!d (3) Ahether the *e!eti) po(%orphi#%#
re(ate to 5N ri#@ -ia i!#'(i! re#i#ta!)e a!d/or other %ea#'red ri#@ &a)tor#.
+ET:.&S
3he .itt#"'r*h /pide%io(o* o& 0ia"ete# 1o%p(i)atio!# (/01) 2t'd i# a 10-ear
pro#pe)ti-e #t'd "a#ed o! a Ae((-de&i!ed )ohort o& ad'(t# Aith )hi(dhood-o!#et (J17
ear# o(d) tpe 1 dia"ete# %e((it'#. 3here Aere 65? e(i*i"(e #'"je)t# (325 Ao%e! a!d 333
%e!) dia*!o#ed "etAee! 4a!'ar 1, 1950, a!d ;a 30, 19?0, Aho Aere &ir#t #ee! at
"a#e(i!e (19?6 to 19??). 3Ao #'"pop'(atio!# are #t'died i! thi# report, the &ir#t o& Ahi)h
)o%pare# i!)ide!)e data deri-ed &ro% the 4?5 #'"je)t# Aitho't 5N at "a#e(i!e Aho ha-e
"ee! &o((oAed 'p "ie!!ia(( therea&ter. ,or the#e a!a(#e#, a pro#pe)ti-e de#i*! Aa# '#ed
i! Ahi)h "a#e(i!e ri#@ &a)tor# Aere )o%pared to )o%p(i)atio! i!)ide!)e o-er the e!#'i!*
10 ear#. 3he #e)o!d #'"pop'(atio! )o%pare# tho#e de#i*!ated hi*h( K#'#)epti"(eK to
tho#e de#i*!ated hi*h( Kre#i#ta!tK i! ter%# o& 5N (-ide i!&ra). $(( )a#e#, "oth i!)ide!t
a!d pre-a(e!t, at "a#e(i!e Aere a-ai(a"(e &or thi# *e!eti) a!a(#i#. 2'#)epti"i(it to 5N
Aa# de&i!ed a# de-e(opi!* 5N Aithi! 20 ear# o& tpe 1 dia"ete# o!#et a!d at (ea#t 4
ear# "e&ore de-e(opi!* either o& the other tAo ad-a!)ed %i)ro-a#)'(ar )o%p(i)atio!#
(pro(i&erati-e reti!opath or di#ta( #%%etri)a( po(!e'ropath). 3ho#e re#i#ta!t to 5N
Aere de&i!ed a# tho#e Aith at (ea#t 20 ear# o& tpe 1 dia"ete# d'ratio! Aho either did
!ot de-e(op 5N, or i& the did, did !ot de-e(op 5N &or at (ea#t 4 ear# a&ter de-e(opi!*
"oth o& the other tAo )o%p(i)atio!#. E! thi# Aa, Ae #t'died tAo *ro'p# o& #'"je)t# Aho,
a(tho'*h #'#)epti"(e to %i)ro-a#)'(ar )o%p(i)atio!# i! *e!era(, Aere either #pe)i&i)a((
#'#)epti"(e or re#i#ta!t to 5N.
=e&ore atte!di!* ea)h ))(e o& exa%i!atio!#, i!&or%atio! Aa# )o((e)ted " G'e#tio!!aire
)o!)er!i!* de%o*raphi) )hara)teri#ti)#, %edi)a( hi#tor, a!d hea(th )are "eha-ior# a#
pre-io'#( de#)ri"ed.
2?,29
$t ea)h ))(e, "oth a #ta!dardiDed %edi)a( hi#tor a!d )(i!i)a(
exa%i!atio! Aere per&or%ed " a trai!ed i!ter!i#t to do)'%e!t )o%p(i)atio!# o& dia"ete#.
=(ood pre##'re Aa# %ea#'red " a ra!do%-Dero #ph*%o%a!o%eter a))ordi!* to a
#ta!dardiDed proto)o( H9perte!#io! 0ete)tio! a!d ,o((oA-:p (90,.)I
30
a&ter a 5-%i!'te
re#t period. =(ood pre##'re (e-e(# Aere a!a(Ded, '#i!* the %ea! o& the #e)o!d a!d third
readi!*#. 3ho#e o! "(ood pre##'re %edi)atio!# or Aith a "(ood pre##'reL140/90 %% 9*
Aere )(a##i&ied a# hperte!#i-e.
,a#ti!* "(ood #a%p(e# Aere a##aed &or (ipid#, (ipoprotei!#, a!d he%o*(o"i! (9" $1).
9i*h-de!#it (ipoprotei! (90<) )ho(e#tero( Aa# deter%i!ed " a hepari! a!d %a!*a!e#e
pro)ed're, a %odi&i)atio!
31
o& the <ipid 7e#ear)h 1(i!i)# %ethod
32
. 1ho(e#tero( Aa#
%ea#'red e!D%ati)a((
33
, a# Aere tri*()eride#
34
. <oA-de!#it (ipoprotei! (<0<)
)ho(e#tero( (e-e(# Aere )a()'(ated &ro% %ea#'re%e!t# o& the (e-e(# o& tota( )ho(e#tero(,
tri*()eride#, a!d 90< )ho(e#tero(
35
.
2ta"(e *()o#(ated 9" $1 Aa# ori*i!a(( %ea#'red i! #a(i!e-i!)'"ated #a%p(e# "
%i)ro)o('%! )atio! ex)ha!*e )hro%ato*raph (E#o(a", $@ro!, 5hio, :2$). 5! 5)to"er
26, 19?7, the %ethod Aa# )ha!*ed to hi*h-per&or%a!)e (iG'id )hro%ato*raph (9.<1)
(0ia%at, =io-7ad <a"oratorie#, 9er)'(e#, 1$, :2$). 3he tAo %ethod# Aere hi*h(
3
)orre(ated (r M 0.95; 0ia%at 9" $1 M 0.1? N 1.00 E#o(a" 9" $1). 3he di&&ere!)e "etAee!
the %ea!# o& the tAo %ethod# Aa# 0.15?O (!or%a( ra!*e, 4.9O to 7.3O 9" $1).
Nephropath #tat'# Aa# deter%i!ed "a#ed o! )o!#i#te!t re#'(t# &ro% at (ea#t tAo o& three
ti%ed 'ri!e )o((e)tio!# (24-ho'r, o-er!i*ht, ra!do% ti%ed po#t-)(i!i)) a!d 'ri!e a("'%i!
ex)retio! rate# ($/7). :ri!ar a("'%i! Aa# deter%i!ed i%%'!o!ephe(o%etri)a((
36
. 5N
Aa# de&i!ed a# a! $/7L200 */%i! or e!d-#ta*e re!a( di#ea#e (/270; re!a( dia(#i# or
tra!#p(a!t). e807 Aa# )a()'(ated '#i!* the eG'atio!: e807 M 24.31-12.22 (Aai#t hip
ratio) 3.29 Hhperte!#io! #tat'# (140/90 %% 9* or o! %edi)atio!#)I 0.57 (9" $1).
3hi# eG'atio! Aa# deri-ed &ro% a #'"#t'd o& 24 /01 parti)ipa!t# (12 %e! a!d 12
Ao%e! draA! &ro% (oA, %idd(e a!d hi*h a*e-#pe)i&i) terti(e# o& i!#'(i! re#i#ta!)e ri#@
&a)tor# i! order to repre#e!t the #pe)tr'% o& i!#'(i! re#i#ta!)e) Aho '!derAe!t
e'*()e%i)-hperi!#'(i!e%i) )(a%p #t'die#
27
. 3hi# #'"*ro'p Aa# )o%para"(e to tho#e
#t'died i! thi# report ex)ept &or a (oAer 90< )ho(e#tero( (P M 0.02). .ro(i&erati-e
reti!opath (.7) Aa# deter%i!ed " #tereo#)opi) &'!d'# photo*raph a!d *rade# 60N o!
the %odi&ied $ir(ie 9o'#e 2#te% or (a#er therap &or .7. 02. Aa# "a#ed o! a )(i!i)a(
!e'ro(o*i)a( e-a('atio!, per&or%ed " a trai!ed i!ter!i#t, )o!#i#te!t Aith that '#ed &or the
0113
37
.
.eriphera( (%pho)te 0N$ Aa# i#o(ated " the #a(ti!*-o't pro)ed're o& ;i((er, 0@e# a!d
.o(e#@
3?
a!d $po /, $1/ E/0, a!d <.< HindEEE *e!otpe# Aere deter%i!ed " the
%ethod# o& 9ix#o! a!d Ber!ier
39
, 3iret et al
40
, a!d $h! et al
41
, re#pe)ti-e(. 8e!otpe#
Aere a##i*!ed " dire)t )o%pari#o! to )o!tro(# o& @!oA! *e!otpe.
Statistical analyses
1o!ti!'o'# -aria"(e# Aere )o%pared a)ro## *ro'p# " 2t'de!t t te#t Aith tri*()eride#
"ei!* (o* tra!#&or%ed prior to te#ti!*. 1ate*ori)a( -aria"(e# Aere )o%pared a)ro## *ro'p#
" )hi-#G'are te#t#. 3he#e a!a(#e# Aere "a#ed o! ri#@ &a)tor# (predi)tor#) a##e##ed at
"a#e(i!e 3a"(e 1.
Table 1' Baseline characteristics o type 1 diabetes s!b4ects by incidence o$ert
nephropathy -.N/ stat!s: %ittsb!rgh Epidemiology o &iabetes
Complications St!dy 127year ollo*7!p) mean S& or @ -N/
Next ta"(e P ,i*'re a!d ta"(e# i!dex

No .N -N
A B2=/
.N 1 to 5 years
ater baseline
-N A 2>/
.N 6 to 12
years ater
baseline -N A
2=/
P $al!e No
$s' .N 2 to
5 years
P $al!e No
$s' .N 6 to
12 years
$*e years 25.99 7.?6 30.72 7.91 24.94 6.74 0.003 0.4?2
0'ratio! years 1?.01 7.29 21.00 7.53 15.17 7.00 0.040 0.042
e807
mg/Kg/min
?.37 1.4? 7.07 1.67 7.35 1.77 0.000 0.001
Cai#t hip ratio 0.?1 0.07 0.?5 0.07 0.?2 0.0? 0.004 0.715
9" $1 % 10.22 1.72 10.?3 2.31 11.79 2.21 0.0?3 0.000
90< )ho(e#tero(
mg/dL
54.?2 11.?
3
51.50 13.46 55.04 11.01 0.161 0.924
<0< )ho(e#tero(
mg/dL
107.31 2?.
01
126.59 32.?1 116.15 35.31 0.001 0.133
3ri*()eride#
mg/dL
93.22 74.6
0
12?.23 76.46 105.36 55.73 0.001 0.134
N-90<
)ho(e#tero(
mg/dL
125.34 33.
54
150.24 37.64 135.21 40.?5 0.000 0.13?
4

No .N -N
A B2=/
.N 1 to 5 years
ater baseline
-N A 2>/
.N 6 to 12
years ater
baseline -N A
2=/
P $al!e No
$s' .N 2 to
5 years
P $al!e No
$s' .N 6 to
12 years
Chite "(ood )e((
)o'!t 10
3
/mm
3
6.23 1.71 7.79 2.14 6.22 1.60 0.000 0.99?
2#to(i) "(ood
pre##'re mm
Hg
109.11 10.
99
114.11 12.6? 109.10 16.00 0.024 0.997
0ia#to(i) "(ood
pre##'re mm
Hg
70.03 ?.?4 72.4? 10.?0 70.76 9.63 0.169 0.670
2ex % female
49 (N M
210)
56 (N M 15) 45 (N M 13) 0.506 0.667
9perte!#io! % 5 (N M 21) 19 (N M 5) 7 (N M 2) 0.012 0.642
/-er #%o@ed %
32 (N M
130)
4? (N M 13) 39 (N M 11) 0.094 0.45
$""re-iatio!# are: e807, e#ti%ated *(')o#e di#po#a( rate; 9" $1, he%o*(o"i! $; 90<,
hi*h-de!#it (ipoprotei!; <09, (oA-de!#it (ipoprotei!
Next ta"(e P ,i*'re a!d ta"(e# i!dex
E! additio!, a *e!eti) a!a(#i# Aa# per&or%ed o! a hi*h( #e(e)t #'"*ro'p o& #'"je)t#
)ho#e! to %axi%iDe the extre%e# o& #'#)epti"i(it to !ephropath a# de#)ri"ed ear(ier
3a"(e# 2 a!d 3. $(( #'"je)t# (i!)('di!* tho#e Aith 5N at "a#e(i!e) Aere )o!#idered &or
i!)('#io! i! thi# a!a(#i#. 3he a##o)iatio! o& three *e!eti) po(%orphi#%# Aith
#'#)epti"i(it #tat'# Aa# exa%i!ed '#i!* )hi-#G'are te#ti!* a!d )a()'(atio! o& odd ratio#
a!d )o!&ide!)e i!ter-a(#. $ &i!a( %'(ti-ariate 1ox proportio!a( haDard# re*re##io! a!a(#i#
Aa# )o!d')ted addi!* the *e!eti) %ar@er# ide!ti&ied i! the *e!eti) #'"*ro'p to the
ori*i!a( "a#e(i!e predi)tor# o& 10-ear i!)ide!)e 3a"(e 4.
Table 2' Characteristics o E&C st!dy s!bpop!lation designated nephropathy
s!sceptible or resistant)
a
mean S& or @ -N/
Next ta"(e P .re-io'# ta"(e P ,i*'re a!d ta"(e# i!dex
S!sceptible Resistant P $al!e
N'%"er 23 61 Q
$*e years 23.4 4.4 32.5 6.06 0.000
0'ratio! years 13.5 3.2 24.5 6.09 0.000
9" $ % 11.1 1.90 10.6 1.?3 0.374
/807 mg/kg/min 7.9 1.65 7.5 1.?3 0.32?
Cai#t hip ratio 0.?1 0.0? 0.?4 0.07 0.164
90< )ho(e#tero( mg/dL 59.9 15.7 52.? 10.9 0.025
<0< )ho(e#tero( mg/dL 121.9 50.7 115.7 30.2 0.525
<o* tri*()eride# mg/dL 4.54 0.49 4.41 0.52 0.311
No!-90< )ho(e#tero( mg/dL 142.7 50.? 134.7 36.3 0.439
Chite "(ood )e(( 10
3
/mm
3
6.6? 1.49 6.52 1.95 0.741
2#to(i) "(ood pre##'re mm Hg 114.9 9.93 112.0 15.1 0.412
5
S!sceptible Resistant P $al!e
0ia#to(i) "(ood pre##'re mm
Hg
74.5 10.5 72.? 10.? 0.540
8e!der % male 33.3 (7) 42.5 (2?) 0.343
9perte!#io! % 4.? (1) 16.1 (10) 0.275
/-er #%o@ed % 15.0 (3) 52.5 (32) 0.003
$""re-iatio!# are: 9" $, he%o*(o"i! $; e807, e#ti%ated *(')o#e di#po#a( rate; 90<,
hi*h-de!#it (ipoprotei!; <0<, (oA-de!#it (ipoprotei!.
a
2ee text &or de&i!itio!
Table C' .dds ratio or o$ert nephropathy -.N/ in association *ith s!sceptible
and resistant s!bgro!ps
a
: %ittsb!rgh Epidemiology o &iabetes
Complications St!dy cohort stat!s as o 127year ollo*7!p data
Next ta"(e P .re-io'# ta"(e P ,i*'re a!d ta"(e# i!dex
.dds ratio =5@ Conidence inter$al
$1/ 0/0 -#. E/E or E/0 2.94 1.09?.33
$po / 2/2 or 2/3 -#. re#t 5.09 1.3219.60
$po / 4/3 or 4/4 -#. re#t 3.31 1.119.??
$po / !o! 3/3 -#. 3/3 7.12 2.5420.36
<.< HindEEE N/-, -/- -#. N/
N
3.56 1.250.12
$""re-iatio!# are: $1/ 0/0, a!*iote!#i!-)o!-erti!* e!D%e de(etio!/de(etio!; $1/ E/E,
a!*iote!#i!-)o!-erti!* e!D%e i!#ertio!/i!#ertio!; $1/ E/0, a!*iote!#i!-)o!-erti!*
e!D%e i!#ertio!/de(etio!; $po /, apo(ipoprotei! /; <.<, (ipoprotei!.
a
2ee text &or de&i!itio!
Next ta"(e P .re-io'# ta"(e P ,i*'re a!d ta"(e# i!dex
Table B' +!lti$ariate predictors -incl!de genetic polymorphisms/ o the 127year
incidence o o$ert nephropathy -.N/ in the %ittsb!rgh Epidemiology o
&iabetes Complications St!dy
.re-io'# ta"(e P ,i*'re a!d ta"(e# i!dex
+odel 1 +odel 2 +odel C +odel B
.R P $al!e .R P $al!e .R P $al!e .R P $al!e
,'(( 10-ear i!)ide!)e
$po / (!ot 3/3) 0.57 0.0? 0.50 0.03 0.55 0.07
$1/ 0/0 0.?3 0.56 1.06 0.?6 1.26 0.52
<.< HindEEE (!ot N/
N)
0.97 0.93 0.90 0.76 0.?6 0.64 N/$
e807 0.62 J0.001 0.63 J0.001
Chite "(ood )e((# 1.21 0.02
0 to 4.99 ear i!)ide!)e
$po / (!ot 3/3) 0.69 0.3? 0.74 0.4? 0.63 0.29 0.66 0.35
6
+odel 1 +odel 2 +odel C +odel B
.R P $al!e .R P $al!e .R P $al!e .R P $al!e
$1/ 0/0 0.56 0.1? 0.67 0.36 0.?6 0.74 0.73 0.50
<.< HindEEE (!ot N/
N)
1.56 0.30 1.59 0.2? 1.45 0.39 1.53 0.33
Chite "(ood )e((# 1.49 J0.001 1.42 J0.001 1.39 0.002
e807 0.6? 0.001 0.69 0.002
0'ratio! 1.06 0.04
5 to 10 ear po#t "a#e(i!e i!)ide!)e
$po / (!ot 3/3) 0.44 0.0? 0.31 0.02 0.30 0.01
$1/ 0/0 1.23 0.63 1.5? 0.42 1.79 0.31
<.< HindEEE (!ot N/
N)
0.56 0.24 0.36 0.06 0.39 0.0? N/$
89" 1.91 J0.001 1.5? 0.003
e807 0.70 0.04
=a#e(i!e predi)tor# a-ai(a"(e &or %ode(i!*: $po(ipoprotei! / ($po /; !ot 3/3: 6e#/No),
a!*iote!#i!-)o!-erti!* e!D%e i!#ertio!/de(etio! ($1/ E/0), (oA-de!#it (ipoprotei! (<0<)
HindEEE, d'ratio! o& tpe 1 dia"ete#, e#ti%ated *(')o#e di#po#a( rate (e807), Aai#t hip
ratio, "od %a## i!dex (=;E), 89", 90< )ho(e#tero(, <0< )ho(e#tero(, tri*()eride#, !o!-
90< )ho(e#tero(, ##to(i) "(ood pre##'re, a!d dia#to(i) "(ood pre##'re.
.re-io'# ta"(e P ,i*'re a!d ta"(e# i!dex
RESD8TS
3a"(e 1 )o!tra#t# the "a#e(i!e (19?6 to 19??) )hara)teri#ti)# o& the 56 #'"je)t# Aho Ae!t
o! to de-e(op 5N d'ri!* either the &ir#t 5 ear#, or 6 to 10 ear# a&ter "a#e(i!e ri#@ &a)tor
%ea#'re%e!t, Aith the 429 Aho did !ot. 3ho#e de-e(opi!* 5N Aithi! 5 ear# o& "a#e(i!e
Aere o(der a!d had a (o!*er d'ratio! o& tpe 1 dia"ete# tha! tho#e Aho re%ai!ed 5N
&ree, Ahi(e tho#e de-e(opi!* 5N (ater (6 to 10 ear# pa#t "a#e(i!e) Aere #i%i(ar( a*ed
"'t had a #horter d'ratio! tha! the 5N-&ree *ro'p. E! the ear(-o!#et *ro'p, #tro!*
re(atio!#hip# (P J 0.001) Aere #ee! "etAee! the i!)ide!)e o& 5N a!d e807, Aai#t hip
ratio, Ahite "(ood )e((#, tota( a!d <0< )ho(e#tero(, a!d tri*()eride# (or !o!-90<
)ho(e#tero(). 9oAe-er, o!( e807 a(o!* Aith 9" $1 (P J 0.001) #tro!*( predi)ted 5N i!
the K(aterK 5N i!)ide!t *ro'p. 9" $1 Aa# Aea@( re(ated to Kear(K 5N (P M 0.0?). <i@e the
(ipid &a)tor#, "(ood pre##'re (either ##to(i) or hperte!#io!) Aa# o!( re(ated to 5N ear(
i! the o!#et *ro'p. ,'rther%ore, "(ood pre##'re appeared to "e a Aea@er predi)tor tha!
the (ipid %ea#'re#.
E! a 1ox re*re##io! %ode( to Ahi)h a(( '!i-ariate predi)tor# (P J 0.05) i! 3a"(e 1 Aere
a-ai(a"(e, o!( e807 (P J 0.0001) a!d Ahite "(ood )e(( )o'!t (P M 0.01) 2 (o* (i@e(ihood
M 4?1.9 Aere #hoA! to "e i!depe!de!t predi)tor# o& 5N ("oth ear( a!d (ate )o%"i!ed).
$# e807 i# a &'!)tio! o& Aai#t hip ratio, 9" $1 a!d hperte!#io!, the %ode( Aa# repeated
Aitho't e807 "ei!* a-ai(a"(e. $# a!ti)ipated, 9" $1 (P J 0.000), Ahite "(ood )e(( )o'!t (P
J 0.001), a!d ##to(i) "(ood pre##'re (P M 0.002) Aere i!depe!de!t predi)tor# Aith 2
(o* (i@e(ihood a# 4?6.1. 3he#e tAo %ode(# had #i%i(ar 2 (o* (i@e(ihood a!d &it eG'a(( Ae((
Ahe! the de-ia!)e re#id'a(# Aere exa%i!ed. 1o%pari#o! o& the#e tAo %ode(# Aere the!
%ade o! the "a#i# o& $@ai@eF# E!&or%atio! 1riterio! ($E1 M -2 (o* (i@e(ihood N 2 !'%"er
o& para%eter# i! the %ode() "a#ed o! Ahi)h the e807 %ode( i# pre&era"(e to the %ode(
Aith 9" $1 a!d ##to(i) "(ood pre##'re. $(tho'*h the !'%"er o& i!)ide!t )a#e# i# #%a((
Ahe! #trati&ied " o!#et (Aithi! 5 ear# or &ro% 6 to 10 ear#), 1ox %ode(# per&or%ed
Aith a!d Aitho't e807 "ei!* a-ai(a"(e #'**e#t that e807 (P M 0.001) a!d Ahite "(ood
7
)e(( )o'!t (P J 0.001) are ear( predi)tor# a!d 9" $1) (P J 0.001) i# the %ai! (o!*-ter%
predi)tor.
E! order to deter%i!e i& the three )a!didate *e!e# exa%i!ed, $1/ E/0 po(%orphi#%, $po
/ po(%orphi#% (/2, /3, a!d /4) a!d <.< HindEEE (N/-), re(ated to 5N #'#)epti"i(it,
the#e po(%orphi#%# Aere exa%i!ed i! the tAo #'"*ro'p# de&i!ed ear(ier, 5N #'#)epti"(e
(N M 23) a!d 5N re#i#ta!t (N M 61). 3a"(e 2 #hoA# the "a#e(i!e ri#@ &a)tor# &or the#e tAo
#'"*ro'p# Ahi(e 3a"(e 3 #hoA# odd# ratio# a!d 95O )o!&ide!)e i!ter-a(#.
$# #hoA! i! 3a"(e 3, ho%oD*o#it &or the $1/ 0 a((e(e i# a##o)iated Aith #'#)epti"i(it to
5N, Ahi(e the pre#e!)e o& either a! $po /2 or a! $po /4 a((e(e Aa# re(ated to
#'#)epti"i(it #tat'#. E! )o!tra#t, the a"#e!)e o& a <.< HindEEE (N) a((e(e Aa# a##o)iated
Aith #'#)epti"i(it.
E! order to deter%i!e i& the#e *e!eti) po(%orphi#%# Aere re(ated to !ephropath
i!depe!de!t o& the #pe)i&i) ri#@ &a)tor# ide!ti&ied ear(ier, three %'(tip(e (o*i#ti) re*re##io!
a!a(#e# Aere r'! Aherei! ea)h *e!eti) %ar@er Aa# e!tered &o((oAed " the other ri#@
&a)tor# #e(e)ted " &orAard #tepAi#e re*re##io!. =e)a'#e o& the #%a(( !'%"er#, $po /
Aa# e!tered a# !o!-3/3 -er#'# the re#t, $1/ a# 0/0 -er#'# the re#t a!d <.< HindEEE a#
N/N -er#'# the re#t.
E! the $po / %ode(, a*e (P M 0.002), e807 (P M 0.003), a!d ##to(i) "(ood pre##'re (P M
0.015) Aere a(( #i*!i&i)a!t predi)tor# o& 5N. 9oAe-er, the 57 &or !o!-$po / 3/3 do'"(ed
to 14.92 ()o%pared to 3a"(e 2), a(tho'*h it# #i*!i&i)a!)e de)(i!ed (P M 0.015). E! the $1/
%ode(, a*e, e807, a!d ##to(i) "(ood pre##'re pro*re##i-e( red')ed "oth the odd# ratio
a!d P -a('e &or 0/0 to 1.71 (P M 0.564). ,or the <.< HindEEE %ode(, a*e, e807, a!d
##to(i) "(ood pre##'re e!tered the %ode( Ahi(e the odd# ratio &or !o! N/N i!)rea#ed to
?.77 (a(tho'*h a*ai! the P -a('e Aea@e!ed &ro% 0.02 to 0.06). ;ode(i!* a&ter e(i%i!ati!*
either e807 or ##to(i) "(ood pre###'re (a# the are re(ated) did !ot a(ter the <.< &i!di!*#
(!o!#i*!i&i)a!t a# a"o-e), a(tho'*h the odd# ratio &or de-e(opi!* 5N Aa# hi*her Ahe!
e807 Aa# a-ai(a"(e.
,i!a((, ha-i!* ide!ti&ied the#e *e!eti) a##o)iatio!# Aith 5N '#i!* the #e(e)t #'#)epti"i(it
#'"*ro'p#, Ae repeated the ori*i!a( i!)ide!)e a!a(#e# a&ter &ir#t e!teri!* the three
*e!eti) %ar@er# i!to the 1ox proportio!a( haDard %ode( 3a"(e 4. No!e o& the three
po(%orphi#%# ($1/ E/0, <.< HindEEE, or $po /) Aere #i*!i&i)a!t i! the &i!a( %ode( Aith a((
56 5N i!)ide!t )a#e# a# the o't)o%e -aria"(e. 2i%i(ar(, the#e po(%orphi#%# did !ot
)o!tri"'te to the %ode( &or ear( o!#et 5N (0 to 5 ear# po#t "a#e(i!e). 9oAe-er, &or the
(ater o!#et *ro'p (6 to 10 ear# po#t "a#e(i!e), $po / (P M 0.01) #i*!i&i)a!t( )o!tri"'ted
a(o!* Aith e807 a!d 89", a!d the <.< HindEEE #hoAed a "order(i!e re(atio!#hip (P M
0.0?) i! the oppo#ite dire)tio! (!o! N/N Aa# prote)ti-e). Et i# a(#o #ee! that the #tre!*th
o& the $po / (!ot 3/3) a!d <.< HindEEE a##o)iatio!# i!)rea#e# Aith the additio! o& 89"
a!d e807 to the %ode(.
&,SCDSS,.N
3he#e re#'(t# pro-ide a '!iG'e opport'!it to a##e## "oth the *e!eti) a!d i!#'(i!
re#i#ta!)e )o!tri"'tio!# to 5N i! a Ae((-)hara)teriDed )hi(dhood-)ohort tpe 1 dia"ete#
repre#e!tati-e epide%io(o*i)a(( o& a pop'(atio!-"a#ed re*i#tr
42
. 3he %ajor &i!di!*# are
the )(ear de%o!#tratio! that e807 (i!#'(i! #e!#iti-it) i# the predo%i!a!t predi)tor o& 5N
a(o!* Aith Ahite "(ood )e(( )o'!t a!d that "(ood pre##'re ("eo!d a! a##o)iatio! Aith
e807) a!d (ipid# appear to o!( predi)t i! the #hort ter%. 3hi# #'**e#t# that the (atter
%ai!( a)t a# (ate-#ta*e a))e(erator# or pre)ipitator# rather tha! '!der(i!* etio(o*i)
&a)tor#. E! additio!, thi# #t'd a(#o pre#e!t# a !o-e( Aa to exp(ore *e!eti) #'#)epti"i(it
a!d re-ea(#, i! a #pe)i&i) #'"*ro'p, e!ha!)ed ri#@ a##o)iated Aith $po /, $1/ E/0, a!d
<.< HindEEE po(%orphi#%# a!d i%porta!t i!tera)tio!# a!d i!terdepe!de!)ie# Aith other
ri#@ &a)tor#, a# #hoA! i! 3a"(e 4.
8
3he )o!)ept that i!#'(i! re#i#ta!)e i# a##o)iated Aith 5N ha# "ee! propo#ed "e&ore. 6ip
et al
13
exp(ored i!#'(i! re#i#ta!)e a# a! '!der(i!* &a)tor i! tpe 1 dia"ete# a!d &o'!d a
red')ed *(')o#e di#po#a( i! a #%a(( *ro'p Aith ;$, Ahi(e 0e 1o#%o ha# pote!tia(( (i!@ed
#')h a #'#)epti"i(it to a .11 i!#'(i! #i*!a(i!* *()oprotei!
11
. 9oAe-er, o'r# i# the &ir#t
#t'd to '#e e807 (a! eG'atio! deri-ed &ro% e'*()e%i)-hperi!#'(i!e%i) )(a%p #t'die#)
i! a (ar*e )ohort o& tpe 1 dia"ete#. No!ethe(e##, it )a! "e ar*'ed that, a# thi# eG'atio!
to e#ti%ate 807 i# "a#ed o! three ri#@ &a)tor# (Aai#t hip ratio, 9" $1, a!d hperte!#io!),
a(( Ae are doi!* i# K#tati#ti)a( %a!ip'(atio!.K Chi(e e807 i# '!do'"ted( a #tati#ti)a(
)a()'(atio!, thi# )o%p'tatio! i# #tro!*( re(ated to %ea#'red 807 (r M 0.76)
27
a!d tho#e
#)ori!* hi*h o! e807 )(ear( ha-e "etter i!#'(i! #e!#iti-it a!d red')ed 5N ri#@.
,'rther%ore, the ph#io(o*i)a( "a#i# o& i!#'(i! #e!#iti-it "ei!* re(ated to Aai#t hip ratio,
hperte!#io!, a!d *(')o#e i!to(era!)e i# Ae(( &o'!ded a!d de#)ri"ed " %a!
a'thoritie#
43,44,45
. 5! "a(a!)e, a!d i! the )o!text o& prior tpe 1 dia"ete# #t'die#, it #ee%#
rea#o!a"(e to )o!)('de that the #tro!* predi)ti-e poAer o& e807 tr'( re&(e)t# i!#'(i!
re#i#ta!)e a# a pathoph#io(o*i)a( ri#@ &a)tor a!d !ot j'#t a #tati#ti)a( a!o%a(. $# e807
i# a predi#po#i!* &a)tor &or tAo Ae((-e#ta"(i#hed 5N predi)tor#, !a%e( hperte!#io! a!d
*()e%ia
46,47
, a# Ae(( a# "ei!* a #tro!* )orre(ate o& ex)e## )e!tra( adipo#it (repre#e!ted
i! o'r a!a(#e# " Aai#t hip ratio), it )o'(d "e a -er p(a'#i"(e '!der(i!* aetio(o*i)
&a)tor
4?
.
3he ro(e o& *()e%ia, per #e, i# parti)'(ar( i!tri*'i!*. Et i# Ae(( e#ta"(i#hed a# a %ajor
predi)tor &or ;$
47,49
, Ahi)h i# a! o"(i*ator pre)'r#or o& 5N a(tho'*h 5N i# &ar &ro% a!
i!e-ita"(e )o!#eG'e!)e o& ;$ a# re)e!t( re-ieAed " 1ara%ori, ,ioretto, a!d ;a'er
50
.
3he 0113 )(ear( #hoAed the "e!e&it o& red')i!* *()e%ia i! de(ai!* (or pre-e!ti!*) thi#
ear( #ta*e
47
. 9oAe-er, *()e%ia appear# to "e a Aea@er predi)tor o& the &'rther
pro*re##io! o& ;$ to 5N e-e! i! the 0113
51
. Carra% et al ha-e re)e!t( pro-ided &'rther
i!#i*ht o! thi# pro*re##io! Aith 4-ear &o((oA-'p data &ro% the 4o#(i! 1(i!i) that #hoAed
that pro*re##io! o& ;$ to &ra!@ a("'%i!'ria ro#e #teep( "etAee! a! 9" $1 o& 7.5 to ?.0O
a!d the! &(atte!ed o't
52
. E! a! ear(ier 1996 report, Ae pre#e!ted data )o!)er!i!* the
#tepAi#e pro*re##io! o& !or%a( a("'%i!'ria to ;$ a!d the! o!to 5N
53
. 9" $1 Aa# a
predi)tor o& ;$ *oi!* o! to 5N i! %e! (10.?O -er#'# 10.1O, P J 0.02) "'t !ot Ao%e!
(10.7O -er#'# 10.?O, P J N2). $(tho'*h the#e data Aere !ot i!)('ded i! a re)e!t
re-ieA, 1ara%ori, ,ioretto, a!d ;a'er
50
a(#o exa%i!ed the pro*re##io! o& ;$ to 5N a!d
)o!)('ded that rate# Aere *e!era(( (oAer tha! ori*i!a(( proje)ted a!d that there Aa# a
!eed &or !eA %ar@er# to ide!ti& tho#e at tr'e ri#@. 3he )'rre!t a!a(#i# th'# atte%pt# to
pro-ide &'rther i!#i*ht i!to the#e i##'e# " exp(ori!* the te%pora( re(atio!#hip "etAee!
*()e%ia, "(ood pre##'re, a!d d#(ipide%ia a!d #'"#eG'e!t 5N. 3he )'rre!t data are
)o!#i#te!t Aith *()e%ia "ei!* a! '!der(i!* )o!#i#te!t ri#@ &a)tor (eadi!* to "oth ;$ i!
the #hort ter%
49
a!d to 5N o-er the (o!*-ter% 3a"(e 1 Aith d#(ipide%ia ("oth i!)rea#ed
<0< )ho(e#tero( a!d tri*()eride#) "ei!* a #hort-ter% predi)tor or pro%oter (o!( "e)o%e#
re(e-a!t (ater i! the pro)e## a!d a)t# %ai!( to a))e(erate the pro)e##). =(ood pre##'re,
per #e, Ao'(d #ee% 3a"(e 1 to &o((oA a #i%i(ar patter! a(tho'*h it appear# to "e a Aea@er
predi)tor/pro%oter. 5! thi# "a#i#, the *e!era( '!der(i!* patho(o* i# re(ated to
hper*()e%ia a!d it# ti##'e )o!#eG'e!)e# a!d thi# e&&e)t Ai(( "e #ee! o-er a pro(o!*ed
&o((oA-'p period. Et th'# &o((oA#, a# Ae ha-e pre-io'#( ar*'ed, that %o#t tpe 1 dia"eti)
#'"je)t# Ai(( de-e(op %o#t %i)ro-a#)'(ar )o%p(i)atio!# *i-e! #'&&i)ie!t *()e%i)
expo#'re
49,54
. E& that i# the )a#e, the! i! the %ajorit o& )a#e#, *e!eti) #'#)epti"i(it Ao'(d
ha-e o!( a %i!or ro(e to p(a *i-e! a! o-erridi!* i!&('e!)e o& *()e%ia a!d d'ratio!.
Cith that i! %i!d, Ae de)ided to exp(ore o'r data"a#e &or the ex)eptio!a( )a#e# that
Ao'(d %o#t (i@e( repre#e!t the *e!eti) #'#)epti"i(itie#, Ahi)h are !ot )o!tri"'ti!* to the
%ajorit o& *()e%i) re(ated )a#e#. 3hi# K)o%p(i)atio!K pro&i(i!* Aa# de#i*!ed to ide!ti&
#'"je)t# Aith #pe)i&i) #'#)epti"i(it (or re#i#ta!)e) to o!e parti)'(ar )o%p(i)atio! o't o&
the triopath o& .7, di#ta( #%%etri) po(!e'ropath (02.), a!d 5N. E! thi# #t'd, Ae
)o!tra#ted the 5N-#'#)epti"i(e a!d 5N-re#i#ta!t #'"je)t# Aith the #'#)epti"(e )o%pri#i!*
tho#e Aho de-e(op 5N ear( ("e&ore 20 ear# o& d'ratio!) a!d at (ea#t 4 ear# "e&ore .7
or 02., a!d the re#i#ta!t a# tho#e Aho ha-e *o!e 20N ear# o& tpe 1 dia"ete# Aitho't
5N de#pite ha-i!* .7 a!d 02.. 3he *e!e# Ae )ho#e to exa%i!e Aere tho#e pre-io'#(
re(ated to 5N ($1/ E/0 a!d $po /) or it# ri#@ &a)tor# (pro%oter#), "(ood pre##'re ($1/
E/0), (ipoprotei! %eta"o(i#% ($po/ a!d <.< HindEEE), a!d i!#'(i! re#i#ta!)e ($1/ E/0 a!d
9
$po/). Ce a!ti)ipated that the po(%orphi#%# a##o)iated Aith the p'tati-e ri#@ &a)tor
Ao'(d exa)er"ate the predi)ti-e poAer o& that &a)tor. 8e!era((, hoAe-er, the re-er#e i#
tr'e, #'**e#ti!* that the#e *e!eti) &a)tor# are Khidde!K d'e to the o-erridi!* i!&('e!)e o&
*()e%ia a!d other phe!otpi) ri#@ &a)tor#, (ipoprotei! (e-e(# a!d "(ood pre##'re, to Ahi)h
the#e *e!e# )o!tri"'te i! a %'(ti&a)toria( Aa.
E! the )a#e o& $1/ E/0, Ahi(e the 0/0 #tate ha# "ee! i!)o!#i#te!t( re(ated to 5N ri#@
14,55
,
it i# the E a((e(e that i# re(ated to i!#'(i! re#i#ta!)e
13
. 5'r de%o!#tratio! that 0/0 i# o!(
predi)ti-e i! the #'#)epti"(e/re#i#ta!t #'"*ro'p (57 M 2.9, P M 0.04) "'t (o#e# #tre!*th
a!d #i*!i&i)a!)e (57 M 1.71, P M 0.564) i! the &'(( 1ox %ode( Ahe! a*e, e807 a!d
##to(i) "(ood pre##'re are pre#e!t, i# )o!#i#te!t Aith it ha-i!* a #%a(( ro(e, (ar*e(
a))o'!ted &or " "(ood pre##'re a!d i!depe!de!t o& the a##o)iatio! "etAee! the E a((e(e
a!d i!#'(i! re#i#ta!)e. E!tere#ti!*(, at the #tep that e807 e!tered the 1ox %ode(, the
odd# ratio &or 0/0 i!)rea#ed #(i*ht(, perhap# #'**e#ti!* that it# i!&('e!)e i# )o'!tera)ted
(%a#@ed) " the $1/ i!hi"itor#/i!#'(i! re#i#ta!)e a##o)iatio!. 3he#e re#'(t#, there&ore,
#hed (i*ht o! po##i"(e exp(a!atio!# &or the i!)o!#i#te!) i! the (iterat're )o!)er!i!* $1/
0/0 a!d the de-e(op%e!t o& 5N.
3he a##o)iatio! "etAee! either $po /2 or $po /4 a!d i!)rea#ed 5N ri#@ (57 M 7.2, P J
0.001) i# parti)'(ar( i!tri*'i!*. E! o'r a!a(#i# o& the #'#)epti"(e/re#i#ta!t #'"*ro'p, thi#
ri#@ i# i!depe!de!t o& (a!d po##i"( e!ha!)ed ") )o!tro((i!* &or a*e, e807 a!d ##to(i)
"(ood pre##'re (57 M 14.9, P J 0.01). 3he#e re#'(t# #'**e#t, there&ore, that either the
di#t'r"ed (ipoprotei! patter!# a##o)iated Aith $po / (i!)rea#ed <0< )ho(e#tero( Aith $po
/4 a!d tri*()eride#/!o!-90< )ho(e#tero( Aith $po /2), or other !o!-%ea#'red &a)tor#
a##o)iated Aith the#e po(%orphi#%#/(ipoprotei!#, i!)rea#e# ri#@ o& 5N. 2o%e #'pport &or
thi# )o!)('#io! i# draA! &ro% 3a"(e 1, Ahi)h #hoA# <0< )ho(e#tero( a!d tri*()eride# (or
"oth a# !o!-90< )ho(e#tero() a# "ei!* predi)ti-e#. 1(ear(, hoAe-er, i! o'r
#'#)epti"(e/re#i#ta!t #'"*ro'p, !o!-$po / 3/3 appeared to pro-ide "etter predi)tio! o&
5N ri#@ tha! the (ipoprotei!#, Ahi)h %a, there&ore, o!( partia(( repre#e!t the %eta"o(i)
di#t'r"a!)e (a!d 5N ri#@) a##o)iated Aith !o!-$po / 3/3 *e!otpe#. 3he (iterat're o! $po
/ a!d 5N ri#@ i# )o!tro-er#ia(, Aith #o%e #t'die# reporti!* a##o)iatio! "etAee! the /2
a((e(e a!d #'#)epti"i(it i! tpe 1
21,22,56
a!d tpe 2
23
dia"ete# Ahi(e other# #hoA !o $po /2
a##o)iatio! i! tpe 1 dia"ete#
24,57
or e-e! prote)tio! i! tpe 2 dia"ete#
11
. $ re)e!t detai(ed
&a%i( #t'd &ro% the 4o#(i! *ro'p pro-ide# parti)'(ar #'pport &or the $po /2 a((e(e,
Aherei! tpe 1 dia"ete# )a#e# Aith dia"eti) !ephropath Aere 3.1 ti%e# %ore (i@e( to "e
a )arrier o& /2 a((e(e tha! a )o!tro( *ro'p )hara)teriDed " a"#e!)e o& 5N a&ter 15N ear#
o& tpe 1 dia"ete#
21
. E! a re(ated &a%i(-"a#ed #t'd, pare!t# heteroD*o'# &or $po /2
a((e(e pre&ere!tia(( tra!#%itted the /2 a((e(e to o&&#pri!* Aith 5N. 5ther po(%orphi#%#
&(a!@i!* the $po / re*io! Aere !ot a##o)iated Aith !ephropath, #'**e#ti!* that $po /
it#e(& i# the )riti)a( *e!e. <i@e i! o'r a!a(#e# i! that #t'd, a *reater e&&e)t (odd# ratio)
Aa# #ee! Aith a (o!*er d'ratio!, a(tho'*h their data #'**e#t !o a##o)iatio! Aith $po /4.
E!tere#ti!*(, "oth tri*()eride# a!d )ho(e#tero( Aere hi*her i! their )a#e#, )o!#i#te!t Aith
"oth a! $po /2 (tri*()eride) a!d $po /4 ()ho(e#tero() e&&e)t. 3he )'rre!t a!a(#e#,
there&ore, " '#i!* a *reater de*ree o& #e(e)tio! (i!)('#io! o& the pre#e!)e o& .7 a!d
02.) ha# per%itted the ide!ti&i)atio! o& the $po /4 #'#)epti"i(it, a!d re-ea( the )o%p(ex
i!terre(atio!#hip# "etAee! *e!eti) predi#po#itio! a!d other ri#@ &a)tor#.
2i%i(ar ar*'%e!t# %a app( to o'r <.< HindEEE &i!di!*#, that it i# it# !o!-(ipid e&&e)t#
that pro%ote re!a( di#ea#e &or it i# the (N) a((e(e that i# !or%a(( a##o)iated Aith
i!)rea#ed tri*()eride# a!d de)rea#ed 90< )ho(e#tero(. Che! a*e, e807, a!d ##to(i)
"(ood pre##'re e!tered the <.< %ode(, the odd# ratio &or a"#e!)e o& the <.< HindEEE (N/N)
*e!otpe ro#e &ro% 3.6 to ?.?, a(tho'*h the P -a('e &e(( &ro% 0.02 to 0.06. $*ai!, the
(ipoprotei! )o!)e!tratio!# do !ot appear to exp(ai! the a##o)iatio!. E!tri*'i!*(, i! the
%'(ti-ariate i!)ide!)e a!a(#i# o& )a#e# Aith o!#et 6 to 10 ear# a&ter ri#@ &a)tor
%ea#'re%e!t, <.< !o! N/N #'"je)t# appeared prote)ted Ahe! $po /, 89", a!d e807
Aere )o!tro((ed, &'rther '!der#)ori!* the )o%p(exitie# o& *e!eti) #'#)epti"i(itie#
C.NC8DS,.N
10
This study confirms the importance of non-glycemic factors including lipids and !lood pressure in the
pathogenesis of "# in type 1 dia!etes and pro$ides further support that insulin resistance has a central
role to play% &t also raises the possi!ility that the 'hite !lood cell count is an important ris( factor
along 'ith t'o lipid-related genetic factors )po* and +,+ Hind&&&% -urthermore the predicti$e $alue
of these genetic mar(ers is parado.ically strengthened after ad/ustment for insulin resistance and !lood
pressure 'hile a 'ea(er )0* 121 association 'ith "# suscepti!ility is lost after a similar ad/ustment%
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14