Evidence for a pleiotropic QTL on chromosome 5q13 influencing both time to asthma onset and asthma score in French EGEA families.
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Texte intégral
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(117) ´u1I {©v ufy©" ¨`It"¢
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(119) y. . . . . {gs"¶"{!´;{G¶}t;rvg . . . r1¶tvr ,.pir{,¢ Ry"r2us Ry¥r "pqr {G¢ ¢;{,vG¶ us. {s"| t-u1 {Gy}s)Î y y;v!¶. "y¯¶"u
(120) ´-u}v y"u¶Är `"pqr {!s"¥IypirI{,ys¯y}s¯r1 ¨Z_pirbr1|"u rys" u
(121) . . y"vg¶. . r e;yt"R¢{GvG¶ ;y. . u u. . . uIu y}t. . . . . r' . "yUrs; uIu1¶ yCG;u. -us ;yt?"r¶ ;y}t"i¥I{G cr `"pqr r
(122) ` r¢1
(123) ¿y. . . ;us¯;u IyR ¨-u i_r¶?;{G g;u1 d¥I{,I ¨xr1 ,"pirCrGr1¢1
(124) "¼«¡y. ¥IIu}uÊy"¥E¶;{! ur' ¨u. t""ys. u
(125) ;rpd{!s"rI{Gy}s;. . u. ¢1y}s8 {G¶u u¶. u
(126) ;rp {!s"rI{Gy}sµjG;u1 /u {Zs-¶"{Z´{g¶t_rvG dIu"Iu1 /usu¶C¢us- y u1¶ y}©; uд-r{,ys; 6r L`;u. . r|-u. r. u u I{Gv`v¤r. {G c¥y$¶"{` u1r u}¼. ½.
(127) mS H PQbBcS=@"A: HAL author manuscript. Ë(;u r' `"pir /¢1y2u1 u"2u us«G8u. . . . . u rs;r1v!z.u¶Ä"2u
(128) ´{gyt; v! w¾ytz'{g|.ys?urvмjÁ"Å"Å.½ . r1 b©t;{GvZ`y. "y"vGuR ;u¢
(129) ItpÊy"¥ ¶"{, /u1r uiu;Iu / {Gy}s8(us;¢yp_r {Zs"|b©"yG s-ys;Ðr ¨G"pir{,¢ . rs;¶Cr1 `"pqr {G¢ ¼jË(;{G R ¢y u r1s"|.u1¶ ¥ 2yp. Å¿Ðy ³$Îr ¢1y2uby¥Õzu y. . r1 dr' ¨ {!|.s"u¶¿y s;y}s;. r1 ¨pir
(130) Ð{G¢1 crs;¶»`;uR ¢yIu1 y¥xÍ `ye³ u" u us" u¶»´"r {Gy"t" c¶.u1|2uu1 y"¥Ér ¨`_pir ¨u´8u {`_¼¬Ëy. inserm-00139064, version 1. ©" {`u¥Ivn /t_pipir2{!z.u1¤`"u ¥yt" ¢1vGr1 /u} by¥cr ¨`_pirC /u
(131) ´u2{ `. . . u u ¶"u¥I{!su¶n{Zs¯ yn u" R©". ¢y"pc©;{!s;{!s"|?¢1v`{s;{G¢1r1vÕ{!`u1pd Rrs"¶?vGu
(132) ´8u1vly¥L Iu1r p usI¼6§Is Iu Í«,;u t_p ¢1v,{!s;{G¢rv«{ upi L2u|"r2¶"{s;|eG;uRv!r ÕÍÁ piys`- . Ð|.r¶"u¶a¥ Iy"p. . . . y¥L;u ¥Iy"v,v!y. {s;|. r1 ¢1ypc"tgu1¶Î¥2u t;u
(133) s;¢ y¥«r1 ¨`;pirdr,`r1¢; . ,s"y Å ,-u ¨Í ¼Ë;{G Õ ¨t.pÊy¥«¢vG{!s;{g¢rv{ u1pi . Åa`yn¹ /µÕ "piIypi ©-u u1u
(134) s r1 ¨Z"pqr rG r¢1" Ð|. r¶"u1¶?¥ Iy"p. "y" ;{Zr1v`{g rI{Gys ¥ y"«r ¨G_pir. . r Ì|. yt""u¶ {!s yR³. . ¢1vgr /u Î;Å"(Í_Áers-¶)¹_¼§Is udÁ;_G8{g «³8 ¢vZr «´;r2{!r1©;vGuL©t;{`v È{sb ¨`u Í. . Å?`yn¹ ¨µlrs8¶. . r1 ¢ypc©;{!s-u¶. . {Z`. "u G-"u y¥r1sI{G r1 ¨`;pqrI{ ¢ u1r p us}x{Zs?G;u "r1 ¨RÍ%Ánpiy}s`" br e u"y u¶?{!saZ;u o  oj. }t;u1 ¨`{Gys"s"r1{GIu Ðs-y Iu1r piusI( Iu1r p u
(135) s {,-y}t"¾{Zs."rv!u1¶ ¨u y"{ ¶" ( 2ur
(136) p u
(137) s" { `¯{!s"r'v!u1¶ Iu1y"{g¶" ¥Iy"vGv,y {!s"|e`-ud¢1ys"¢1u y¥¤¢1yp©;{Zs;{!s"|e`2ur,p usÈrs"¶ -pqypd r¢1¢y2¶"{!s"|eyeG;u Á"Å"Å}³  § U|"t;{G¶.u1v,{!s"u r {Gys"rv-Ìu1r }jts"|crs"¶Ìw¾vGyy"¶Õ§Is; ¨ {!`t u Á"Å.ÅÁ°rs"¶c2u /t;vZ{!s"|c{!sy rscr' `"pirf u
(138) ´8uI{!, ¢y u«,r"{!s"|Ì"u«´"rv!t;u ¾Í'1Á;¹y}³¼. kq:<$@HÐÓD7g<8\. r1 ;u¥yp u1¶ {!s o  oj ¥,r1p {Gv,{Gu {, r
(139) Évgur yi {!©; {ZGiÕc w¾y}t"z'{g|.y}s u$rvмÁ;Åų¨¼'Ë+;u ufpir-u2 u1IuÕ¶;{G ` {!©"tu¶qr$rs r´;ur|;u pqrI"u1Õ¶"us {, y_¥cÍÅ ¢usI{!piy" |rs; ¢
(140) f rs"¶ .r1¶ r1s r´;u1 r1|-ud"u`u1Iy}z1.|;y" {!, y¥l±_¸ ¼ [ ] Õ¥Ðu1dI{G|"y2y}t8 »|-u
(141) s;y}`-u }t;r1v`{,a¢ys`2y"v,É`"u ¥{gs"rvc /rpv!u¯{!s"¢vt;¶.u¶ Í.ÍÅ?¥ rp {,v`{Gu} ¸Å_À  u
(142) s;y}`;{!s"| y"¥l¹"²½ p {,¢Iy" /ru1v,vG{u1 . . ±.
(143) ¨t©º%u¢` . . . . . {!`Rr
(144) +v!u1r1 ¨$ yqr `"pqr {G¢ {!©; ;¢1y}pc"2{G {Gs"|qÁ$Í1Ài|-u
(145) s-y-G"-u¶d;r us I²² Ê y¥(r'vgv. "r1Ius rs;¶ÌÁ;À"ÀÕ|"us-y},.;u¶c {!©" ¼ HAL author manuscript. H BH27GS HI7,=BF-B<$BF!Ó8S/:1S Ë{gp u¤yLr `"pqrlys; /u. . r 6rs_rvZ.zu1¶Lt; {s"|i ¨t" ´;{!´"rv"rs_rvZ- {` 6piuG;y.¶ ¼ auÕ¢ys" {G¶.u'Iu¶. "uÕpir I{!s;|rvGuÌIu1 {G¶}t;r1v` ¤¥` yp à y}x_y};y {`y}s;r1v";rz1r1I¶" «p y¶uvG"r1 «¶"u¥I{Zs8u¶x©wfrIv,y. inserm-00139064, version 1. . ª$ us`{`¢u ,wfr2v,y. . . . . rs-¶xª$2us{G¢uqͲ"À"À It; {!s"|»Ë+lË( ±_¼Å_¼.Ë"uÕy}©8 /u ´;u1¶c {Gpiu . . . . rs;¶. uuL¥,r{GvGt" u. I{!p u1 ,r1|"u rl¶;{g ur uby}s; u {ZsCr `"pir{G¢1 qrs"¶ ¢us; /y"I{Zs"| Ð{p u1 ,r1|-uer
(146) ¾u"rp {!s"r{gys¯y ¶u1r
(147) `O¥ 2yp. . r^¢ypc;u
(148) Ð{s_|Y¢1rt; u ¿{!s s;y}s; r1 ¨Z_pir I{G¢1 ¼iË(;u pir1,Ð{Zs;|r'v!u Iu {G¶}t;r1vb ¥ y". {gs"¶"{!´;{G¶}t;rv"{,{, Î.
(149). . δ Λ∧
(150) (β ) "u1Iu. {, fr¢us; yI{!s"|b{!s"¶;{!¢1r
(151) y. δ. ¢us; y {s"|. Ð{!piu. ,r¥ ¥Iu1¢u1¶. . . { ¢R{` fu t"rv`yRys-ui{g¥(`;uc¥,r{Gvgt"2uL{gpiui{, lv!u / É,"rsRG;u. ,ts"r¥ ¥Iu1¢ u¶ . . y zu yNy-G;u {G u. {, `;u u1 Ð{!pqr`u1¶. Λ ∧. . . ¢
(152) t;pct;vgrI{´uf©"r uv`{Zs;u "rzr1I¶q¥ t"s-¢{Gy}sxu´-r1v!t"ru1¶cr)r|"uÕrr ¨`"pirÕ¶"{gr|s-y {G r|;uÕr8ys; u
(153) {!¥ {{, «r ¨,"pirI{!¢y(r)r|-uÌr)u"rpd{!s"r{Gy}s {g¥){{` ¤t.s_r¥I¥Iu1¢
(154) u¶""rs"¶ ¢y"u¥I¥I{,¢{,us;r /y"¢1{Gr
(155) Ðu¶. . β. {G 6,-uLu ¨{gpir u¶x2u|"Iu1 {!ys. {!Gi¢1y}´;r2{Zr u«z"¼Ë(;ufys"vZ¢y-´-r2{grIul{s¢v!t"¶"u1¶{sL`;uÉpiy"¶.u1v. . r1 j u
(156) $¼. u1 ¢2{!{Z´-u ¨`r{G ¨{g¢ Ry¥r1|"u r
(157) r "pir ys; ¨u«r1|"u r
(158) Ìu"r1pi{!s"r{Gy}s rs-¶Upir {gs"|"rv!u. . u1 {G¶}t;r1v` g ®. u1Iu ¢yptu¶ {Zs¯r ,"pir{G¢ »r1s-¶Äs-y}s8,r `"pirI{G¢1 Rrs;¶U©¯|"us;¶u/¼ÈË(;u. pdu¶;{Zrs; ?y¥ ®. r¢1Iy" ?r ¨G;pqr ¢yIu^¢1vGr ¨u . . . u1Iu ¢yp"r2u¶ t; {s;|^s"ys; "rIrp u` {`¢. £t; /"r1v` ?rvGv`{g 6®lrs"Ë6u 2¼Ë"uf2u1vgrI{!ys- {©;u
(159) uusc ® rs"¶cr1 ¨Z_pirÕ /¢1y2u ©i_-ur1 pir1sc rs"c¢y 2u1vGr
(160) Ð{,y}s¼ÕvGv;¢1ypc"t`rI{ ys" . . . r 6u I{!piru1¶. u ul¶ys-u¤t; {!s"|i"ËlË6¯±¼Å¼. À.
(161) È{Zs".r1|"ubr1s"r1v!- {! dy"¥f`;uepir1,I{!s"|r'vgub u1 {!¶t"rv, . . . r q;u¥yp u1¶ t; {Zs"| G;u» r{gpct"p. . È{g"uv!{!-y"y¶xw¾{!s"yp {Gr1vpiuG;y.¶ f©;u1v$rs"¶x t;v`vgu g 8 /ybͲ²À;µ"¾v,¢r{G rs-¶df©"uv+Í
(162) ²"²² 2r' HAL author manuscript. . . {gpi;vGupius`u¶e{sR )w¾  oÕoÕÕÌˬo® f©;uv°rs;¶q t8vgvGu2, -; y Ͳ²_À /¼;Õ Õy"-y u¶dIy. . . "uLr {Grs-¢1u à ypc-ys"us g à 6p uG;y.¶"8Z{G Ép uG;y.¶R¶y"u1 s"y}Iu }t;{g2uLG;ucr1 / /t"pc{Gy}sby¥. . . . s"y" pqr'vg{!GRy"¥°"u¶"{G 2{!©"t{gys y¥$ ;u }t;rsI{!`r{Z´-uÌ"-u
(163) s;y}`."u ÕvG¢1r1{` Érs;¶dl©"u1v6Ͳ.²"² rs-¶R{G . . "u u¥Iy2u. inserm-00139064, version 1. ¨;u. . . uv`vd ¨t;{!`u1¶ y G8u rs"r1v!- {, Cy"¥epir,I{Gs|r'vgu 2u1 {g¶t_rvG . s;u rs;¶. .t",Iy. {g ¼ Ë(-u. "2{!s;¢1{!;vGu. y¥ ;{` r1." yr¢. ;{G¢^t; t_rv,v ¶"{, ;v!r. {, y. {!s 2y¶t;¢u. rNvgrIus. Ðt"s-y©" /u1,´8u¶j©;{!s"r d´-r1I{gr©;v,u
(164) ŵ,Í ;{G¢
(165) b¢1r"Gt" u É`"ucv`{!s"r1|.ui{!s"¥IypirI{Gysi©u
(166) uus "uly}©8 /u',´u1¶ t_rsÐ{ `r{!´;uÉ"-u
(167) s;y}`."ufrs"¶L`"ufpirI"u ¼1¡)yur¢iy©; u ´;u¶L-us"y}`8{!¢É´;rv!t"u1 "uYvZr`us , t"s-y}©; u1,´u¶ ´-r1I{gr©vGu ¢'rs `r1.u Z;u ´-rvt;uEy"¥ Í , ©-u1{!s"| r¥¥u¢
(168) Iu¶ {Z` " y©_r©;{`vg{`cª 1r1s;¶c`"uf´"rv!t;uÕy¥)Å ©;u1{s;|its"r1¥ ¥Iu1¢`u¶ {!`d; y©"r©{!v`{ZG Í,ª ¼.Ë"u{G¶"ur{G 6,"r "uC"Iy}©"r©;{,vG{!,n¥Iyd;uUv!r`usq´-r1I{gr©;vGu gya©;uCu t"rvy ͯ{!s-¢'Iu1r u r ,-uCy}©; uдu1¶ . . . . . . ;us"yg-;{G¢Ì´"rv!t;u1 f{!s"¢ ur' ¨u¼È{!s"r1|.uc{` ¤G;usb{!s´;u1 {!|"rIu¶d¥IyrvGvy. {!©;vGuc /ug Éy"¥ n´rvgt;u . . . {Z`{s {©; ;{!; . . ;us"yg-"uErs"¶OvgrIusb´;r2{!r1©;vGu. . rs;r1v!- {Zs;|L ®¾. $.
(169). . (#. =. . . 1͵Áµ. )= [ ". !. {g É`-uc¶"u¢{,vGuc¢y2u1 ;y}s-¶_{s;|qyd`"uL´"rvt;ucy¥( -uL""us;y},."uz .
(170) . ¼. . !. r1 C©_r u¶ ys `-uEu'p8{Z2{G¢rv» Ir1{! ¶_{ ¨,2{g©.tI{Gy}s¼ ¯-us. uÕ¶"{!´;{G¶u¶`;uf Ir1{!´"r'vZt;u {gsyeÍÅi¢ys; u¢
(171) t"{Z´-uL /t©-¢}v!r u1 «r1¢¢1yI¶;{s_|c`y {ZÐ . ¶u1¢1{`v!uc¶;{G ` {G©tÐ{gys¼§2¥ . . u1{!|.Iu¶»©b -u}{!«;Iy©"r©8{gv`{ {`u ¼8Ë(-uRv,{!s"e¥`t_s-¢
(172) I{Gys ©"u u1us `"udy©; /uдu1¶. . ¼. ]− . ¼ . µÐÍÅ _rs;¶ $. (#. `;u =. . ¢yI u ¨-y}s;¶"{s;| !. Iy ¢1vGr1 / u1 Í'g³ "r¶es"u|"r
(173) Ð{ ´udpir {gs"|"rvgudIu {G¶}t"rvG . . )= . −. $. (#. =. !. _Iy©_r©;{`v,{{,u . ). . u2u. ¼{g©;v,{!s"|- É©;u1vGy}s"|;{s"|. {GvGuR /{!©; c{!s ¢1vgr /u c¸.¨ÍÅe"r¶e;y {ZÐ{ ´u. u1 {G¶}t;r1v`
(174) ¼  {!´-us rd /uÈy¥6´-rvgt-u1 Õy¥j,8udv!rgus6´-r1I{gr©;v!u% {Zsbr {!©; 8{8G;u ¶{` I{!©.t{Gy}s y¥ pqrI"u1r1v`v,u1v`u1 É¥ IypO;u
(175) u1 yz|;yt; É"r us" r1piys"|d {©vG{!s"|; f{! ¶"{g 2{!©"tI{!ys. . 8{!¢ ¶.u
(176) ;us;¶" y}s y}s;uq"rIrp u`u1I. α(. . {!GIusd©"it /ucy"¥(r©;{gs-yp {grv. "2y}©"r©;{,v!{!,b`_rÈ {©8 . {`
(177) 6Í &. Iu1¢u{ ´u ².
(178) . . y}s;uCy"¥q`u y pir-uRrvGv,uvgu . {!`E¶"{G ur u¯r1v`v!uv!uU¥IIyp. ;{G ,-u1d;u
(179) ÐuIy}z1.|"yt; "r us. {`
(180) )Ũ¼ Ëju1 ¾¥Iycv`{!s_.r|-u Gst8vGv ""y}`-u} /{` Õy¥6s8yev`{!s"r1|.u ż¸ `"uirvIu s"rI{´ux-"y}`"u {g Õy¥Èv,{Gs"r1|-u ż¸ {, α= α> ) "u1 ¥Iyp u1¶¯t; {s_|¯rCv`{!"u1v`{;yy.¶_,Ir
(181) Ð{,y ,(® cIu ¨¤)®
(182) Ás G )
(183) ż¸ {Z ¯(®Ê©;u{s;| α α Í. ©8u1{!s"| `-u ¢yI2u1 ¨-y}s;¶"{s;| "y©"r1©;{!v,{!GCr1p y}s"|¿ {!©; . HAL author manuscript. −α. . . r1 ¨.pigy}I{G¢rvGvZ ¶"{g I{G©tu1¶er rRpd{"Gt;Iudy¥¾Å_¼!¸. . χ. rs"¶ Å_¼!¸. . χ
(184) . ¼)Ë;{G c ¨ rI{ ¨ {G¢R¶.{Z´;{G¶"u1¶R©". Á;vZs$ÍÅc{G +r Én ¢y"Iu-¼. inserm-00139064, version 1. au?u
(185) us;¶u¶. `-uÄ )w. p u
(186) G;y¶ y ©;{Z´"r2{grIu v`{Zs.r1|-u?rs_rvZ- {` y¥d"uUpirÐ{gs"|"rvGu. u1 {G¶}t;r1v` ¤rs;¶ir1 `"pir ¢yIu¥Iy"vGv,y. . . r1v ¼Í²²À ¼-Ë("u1 uÌrt"G;y2 « ;y. . . . {!s"|irsdr""Iy"r¢i"Iy"y u¶c©"c r1s"|"{!s r1s"|-{!sdu. u¶x`"r`"uvG{!"uvG{;yy.¶_,Ir
(187) Ð{Gyxu1 8t; u¶xyLu1 )¥y$,;uf"2u ¨us"¢u. . y¥°rl;vGu1{Gy} Iy}8{!¢ fË°¿{scptvI{´;r {!ruÉ´;r {!r1s-¢1uf¢ypc;ys"usÐ g à (rs"rv; {, «{G 6r ¨.piy}I{G¢rv,v!. . u t;{!´"rvgus«y»`"uR ¨t"pNy¥lv,{!;u1vG{;y.y¶;,rI{Gy u1 ¨g cy¥ t.s;{Z´"rI{grIuq à rs"rv ¨u Lr.vG{Gu¶ yeG;u. . " {Gs"¢1{!"rv¢yp"y}s;us Ly¥j ;ux r{I ¼ § s rR¥I{! l Ðu
(188) ;(r ;I{Zs;¢{;rv¢1ypc"ys-u
(189) s"` ,ª à rs"rvZ- {` . . . . r1 ir1;v`{gu¶ y `"uR y ."us-y},.;u1 ( ®Ors-¶ r1 ¨Z_pcr ¢y"Iu} `yCy©,r'{Zs y ts"¢yIuv!ru1¶. " {Gs"¢1{!"rvc¢ypc;ys"usÐ ft; {!s"| -Ë+lË. ±_¼Å_¼ Ë(;u ¨u ¢1ypc-ys;u
(190) s . . u2u G8u
(191) s t"©º u¢
(192) u¶ y. {gs"¶.u"us;¶us t.s{´;r {!ru v,{!s".r1|.ufr1s"r1v!- u1 ©_r u¶cysx`-uÉ (w piu
(193) `-y"¶_¼1§ sx"uÉ w rs"rv; {` . . u t; u¶UG;u ¶.u1¢1{Gv,u ¶"{G I{!©.t{Gy}sn¥Iy ur¢?ª à Ér' e¶"u1 ¢2{©u¶?r©"y´-u-¼j§ snrC u1¢y}s;¶? ¨`u r ¢y"pc©;{!s"u¶e u ¨È r{G I{G¢1$Ëj. . . r1 ¢ys" ¨`t-¢
(194) u1¶d©" tpip {gs"|R`"uits8{ ´;r2{Zr uc wYv,{!.u}v`{"y"y.¶".
(195). . rI{Gy g6® eu rI{G Ð{!¢ Uy©}r1{!s;u1¶E¥Iy ur¢Oy¥e -u y ª à 1ÎcË. . =. . . . ;u2uaG8u. ¶"{g 2{!©"tI{!ys y¥¯u1r¢»)® } Iu ¨ts"¶"u+`;uLs.tvGv°.;y1 "u {G fy"¥s;yev`{s;r|"u1{` frcp {Z.,t"2ucy¥ χ . Ï . χ . . ¼d{gs;¢u ,-u y "2{!s;¢1{!"rvd¢1yp"ys"us ¯r1IuE{s;¶u"us;¶usx`;u r ¨.piy}I{G¢. ¶"{g 2{!©"tI{!ys¯y"¥Ì`8u ¢1ypc©;{!s-u1¶Äu1 ¨`r{G Ð{G¢ ËO{, dr p {Z. t"2u y¥"!. χ #. Ï$ . χ%. Ï$!. χ. ¼ . ÍÅ.
(196) HAL author manuscript.
(197)
(198) !"#%$'&(*)
(199) )
(200) ,+-$'/. 0
(201) 1 Õ c u1us {!s Ë6r©;vGu Í "uiÁÀÀb|.us"y}`.;u¶ {!©;v`{s_|. c{!s-¢1v!t"¶"u¶ À1Á. . y¥ r1 "pir{G¢1 ¼8Ë(;u. inserm-00139064, version 1. r1 ÕÍÁx-u1rI ¨ÍÅ;¨ÍÀÎ{Z r1 ÌÍÁ "u1r ¨Í'Å"¨ÍÀi {!sUr `pir{,¢ »rs"¶ ÍÁ¯"u1r À. Í1À{gs¯s"ys;,r ,"pir{G¢ ¼+§s?r "pir
(202) Ð{G¢ 6`;u pdu¶;{Zrs , Á_¸- ±_¸ t"r1,I{Gv`u1 y¥fr1|-uerfr' "pir y}s8 /u r1 i³ "u1r ÐÁ; ÀÕr1s;¶ G;ubpdu¶"{grs¿y¥ ¶}t; r{,y}s y¥j¶"{, ur1 uÌ©;u uusRr|.uLrys; /u
(203) ¬rs-¶dr1|"uÕrju
(204) -r1p {Zs;rI{!ys r fÀc"u1r {Z`RÁ_¸- ±_¸ } t;r {,v,u ©"u{s;| ¸2bÍÍ/ ¼ Ë("ui"Iy};y {`y}s y¥Èpqr'vgu ¶"{G¶es"y}ȶ;{!¥¥Iu ©;u u1us r `"pirI{G¢drs-¶es"ys; r ¨G"pir{g¢ {©8 ¸.²_¼¸ rs"¶ ¸'¹ 2u ¨;u¢{!´"uv;b
(205) Å_¼ ³"Å/ ¼dy u
(206) ´u2 ;{,vGu G;u piu¶"{grsNy¥Cr|-u r u
(207) ;rp {!s"rI{Gy}s {!sRs;y}s; r1 ¨`"pirI{G¢1 ¶{G¶es"y}¤¶{G¥ ¥Iu1É©-u uus pirv u} Õrs"¶e¥IupirvGu ¨ ͸"¼gÍcur1I y¥ r|;u 13 54 ÍÁ$¼ Ádur ly¥r1|"u_
(208) Å_¼ ¹²2 -uLp u¶"{!r1sby¥r1|-ucr
(209) )r ,"pirys" /uj{!sRr `"pir{g¢ r1 c8{Z|."u{!s ¥Iupir1v`u1 L,"rs {!s pqrv,u ½ -ur1I iy¥lr|-u 63 74 ³ ;ur iy¥lr1|"u1 n
(210) Å_¼Å°Í ¼ Ë("t" ; /u r {!s"¢1v!t"¶"u¶qr Ér¢y}´;r {!ru{Zsi`"u à y}i;Iy"y {Gy}s;r1v"_rzrI¶" «piy.¶"u1v_¥ Iy"p 8{G¢ pqr I{!s_|.r1v`uf u {G¶t_rv, u2ufy}©"`r{s;u¶_¼Ë(-uf¶;{g ¨`2{!©tI{ ysiy¥_ ;u ufpir1,I{s_|.r1vGuf2u1 {!¶t"rvg È ¨"y u1¶ rfp u¶;{!rsxu t"rv`ycż Á;¹"'`"u Á¸. ±_¸ } t"r1,Ð{,v!u ©"u{s;|, IÅ_¼³-±q$Å_¼ ½_¸ ¼.Ë(;{G +.;u
(211) s-y-G"-uf¶"{G ¨;vGr
(212) -u¶ {g|s8{!¥I{,¢rs8 .u s;u1 , 086ÍÅ'9;: $ rs8¶Lt"ÐÐy {, Ð $
(213) ż Å°Í ¨ ¼ pdu¶;{Zrs ,Á¸.±"¸ }t"r,I{,vGu )y"¥r|;ufr
(214) u"r1p {!s_rI{ ysiy¥$rv,v; {!©; . Ë+r©;vGuLÍ. . . . . . . ®¾u|"rI¶"{!s"| G;uRr `"pirR ¢y2u1ÉÍ1À Ͳ ¡¬{Z|.t_IuLÍ. . rR ¢y2uiy¥«Á«ÍÁ . . . y¥l {© Õ"r¶ r ¢y uRy¥ zuIy_)¹À. y¥¤ ¢y2ud¹ rs;¶ ÍÁ . . . r ¢1yIuRy¥cÍ . r ¢y"Iudy¥ ³ Ër©;v u Í ¼¡){!|t"2u Íx ¨"y. . fG;u. ¶"{g 2{!©"tI{!ys y"¥pqrÐ{gs"|"rv,uIu} {G¶}t;r1vG fr¢1¢1yI¶"{!s"|dyq`"uc¥I{Z´ui¢1vgr /u1 ly¥( ;ucr1 `"pqrx ¢y u}¼- u
(215) "-u1¢
(216) Iu¶"GuÕpiu¶"{grs y"¥° ®. . r1 ¨pir
(217) Ð{G¢1 ,pxu1¶"{grs . . . r «pit"¢ vGy. . . u¬{gsds-y}s8,r `"pirI{G¢1 Ðp u¶"{grs.
(218). . ͼ,ͽ °`;rsR{!s. Å_¼³"Å ¼"§Is r1 ¨`"pirI{G¢1 _`"uipiu1¶"{Grs; fy"¥+ ®E¶;{!¶Rs;y}¬¶"{g¥I¥ u1 rpdys;|RG;u. ¥Iyt" ¢vZr' u Õy"¥+`8uqr `"pird ¢y2u Gu ucpiu¶"{grs8 f©"u1{!s"|bż ³;ÅR¥Iy ¢yIu1 Õy¥ÕÍ°Ábr1s-¶»³ rs;¶. Í"Í.
(219)
(220) Å_¼½}³ ¼}y . t"r1,I{Gv`u1 f{s;¢ ur u¶qr "uÕr ¨`"pirÕ ¢yIuL{s;¢ ur u¶;},;{G « r1s"|.uÉ©8u1{!s"|IÅ_¼g͸.Å_¼ ±Å¥y)r ¢1y2uÕu}t;r1vy ;rs;¶ IÅ_¼ Á-½" Å_¼±³ ¥IyCr ¢1y uEu } t"rvdy ³¼i§ s" u1u} I{s;|.vZ-d "u^¶}t"IrI{!ys y"¥ ¶;{G ur u "r¶ r^ {gp {Gvgr ¶"{g 2{!©"tI{!ysir¢Iy" ¤G;u¥ y"t"r `"pir ¢1yIu¢1vGr1 u1 ,
(221) Å_¼À1ÁI { Rpiu¶"{grs8 y¥6Ài¥Iyj ¢yIu Å_¼¸'¹q¥Iyr ¢1y" uy¥)¹ ,. u´;u2} -uÌIrs.|;uÕy¥ ;uÕÁ¸.,±_¸. HAL author manuscript. y¥eÍ rs;¶C³?r1s-¶Up u¶.{grs; ey¥i±?¥yi ¢y"Iu} Ry¥Á rs"¶ ¹_¼«Ë"uU."u1rpirsn r1s"?¢yI u1vGr
(222) Ð{!ys. inserm-00139064, version 1. . ©"u uu
(223) s,-uÉpir1,Ð{Zs;|r'v!u +Iu {G¶t"rvG +rs"¶Ì`-uÉr ,"pirl ¢y"Iu. . . r jÅ_¼ ³$Í . ≤. . Í
(224) Å 9;: /¼.
(225) 6+($
(226) 0
(227) +
(228) ( '
(229) 56
(230) ,
(231) ,+. . Ë(;uÌ|-u
(232) s;ypiu {G¶"uv,{s;r|"uLIu t"v!I ¥ y"(Guft.s;{Z´-r1I{grIuLrs;rvZ- {G Éy"¥(pirÐ{Gs"|"r1v`uLIu1 {G¶t"rvG ¡){g|.t_Iu«Á. rs;¶ ©;{Z´-r2{!rIudrs"rv; {` cy¥« ®Yr1s"¶ r1 ¨Z_pirb /¢1yIuRrIuR_Iu us u¶ {s ¡){g|t;IudÁ¼)Ë("uR u|-{Gy}s8 ¶u`u1¢
(233) Ðu¶ir$rÕ;,´"rv!t-u. ≤. ż Å"Ÿr2uL -y. . s {Zs Ër©v uÌÁ$¼1¡)y"(t" -y_ /uÕy¥¬¢1ypc;r2{!s_|cG;uÕ u ¨t;v! . y¥R©{´;r {!ru?rs;¶ t"s;{!´"r {Gr
(234) ÐuUrs"rvZ- u Ì`;uU2u /t;vZ` _Iu´;{Gyt" v^y©`r{s;u¶E¥,2yp v,{!s_.r|-uÉrs"rvZ- {, y¥_`8uÉr ¨G_pirl ¢y uÉrIufr1v` yc /"y Ë(;uIu. Ë+r©;vGu¤Á. É
(235) «Í¼ ±Å. . r /t"||;u Ð{Z´-u.
(236). u
(237) ´{G¶us-¢u. sx{ZsËr©;vGu«Á°¼. ¥Iy vG{gs".r1|.u. y}¥ pdrÐ{gs"|"rv,uO u {!¶t"rv, `y. Í%"¹°Í.
(238)
(239) r1¶"¶"{! {Gys_rv$v,{!s"r1|.u {G|}s;rv r' Éy©; /uдu1¶R{sd`"udͳ ͹q2u|;{!ys g É
(240) Uͼ Á$Ír$dÍ%³°-±Å;
(241) Å_¼Å.Å"²¨¼8Õ u1us ¥IIyp r©"v,ucÁ;_`"ud¸Í
(242) ¹er1s-¶¿Í%³ ͹b u|-{Gy}s; {s;¢1v!t"¶.u1¶erv, /y v,{s_.r|-ud {G|s"rvG ¥Iy;ufr1 `"pqrl ¢yIu g É
(243) «Í¼ÁÁirͳi¢ u1vGypiu2{G¢Ì¥` ypEi¸".³"Á³;} d
(244) ż Å"ŲLr1s-¶Ì É
(245) ͼ Á-ÅerRͳ±Å"°
(246) Cż Å"Ų {GvGux"ueÍ1À$ÍÍi2u|"{Gyse`"rÈvGu1¶»`y»`-uq;{g|;u ¨Èu
(247) ´;{G¶.us"¢1ui¥ y v,{!s_.r|-u¤yÌ`;{G 6 ¢y2u , É R
(248) Á°¼ ³;Å"1 b
(249) ż Å"Åų $ ¶"{G¶Ls-y}$ ;y rsv,{Gs"r1|.ul {Z|.s"r1vy¾ ®¼ ª$ {Gy"(Iyc,-uÌ©8{´;r2{!ruL|;us"y"piu1 {!¶_uvg{!s""r|.uLrs"r'v {` fy¥°"uLpir1,Ð{!s_|.r1vGuL2u1 {G¶t_rvG Érs"¶ r1 ¨pir ¨¢yIu}j" {!s;¢1{!"rvl¢ypc;ys"us¾r1s"rvZ- {! r dr.vG{Gu¶Äy ,-u ¨u y ;us-y},8u Rrs;¶ ¨"y u¶»`"r6`-ud¥ {,2 Èr1s;¶ ¨u¢ys;¶e" {!s-¢}{!"rv6¢y}pc-ys"us ¢1y}s"` {©"tÐu¶ Iu1 ;u1¢ I{!´-u1vZbIy ±°Í rRdÍ.Á-±"²±"c $Å_¼ ÅÅ"¹. . . t"s;{!´"r {Gr
(250) Ðu. rs"¶ ¸ °Í
(251) ¹ g É 6ͼÀ'± rRi¸""³Á.³L $Å_¼Å"ÅÁ ¨¼fs. . ÍÁ.
(252) rs;¶iÁ"² Ê y¥°"uy-´-uIrv,v""us;y},.;{G¢Ì´"rI{grs;¢u}¼.¡$y("uL¥I{GI ¨¢ypc-y}s;usI`"u¢1yu¥I¥I{,¢{,us` f¥y ® r1s"¶Cr ¨G_pir /¢yIu HAL author manuscript. . ¢y"u¥I¥I{,¢{,us` . . . u1Iu ur¢
(253) u t"rv¤y¯Å_¼±Í. . ;{`vGu1«¥IyL -u u1¢y}s;¶C¢1ypc;y}s;usI6`;u. uIufÅ_¼±Í ¥ y"_ ®¯rs;¶cIÅ_¼ ±Í ¥Iy$r "pcrl ¢y u}¼. Ë(;u»©8{´;r2{!ru v`{s;r|"u rs"rv; {, dy¥Õpir,I{!s;|rv,u Iu1 {g¶t_rv, drs-¶Är' 2`"pir /¢1y2u vGu¶ yÄr. inserm-00139064, version 1. u t"rv`yeͽ_¼ ²"}
(254) bż Å"ÅÅ.Å"±$r_`;uÕ /r1piufpirI"u("y. {I{Gy}s , i¸"³.Á"³(¥Iyt"s"¶ivG{!s""u¶L yL ®¯©" ts8{ ´;r2{Zr uÕrs"r1v!" {` g¡){g|.t_IuÕ¹ir1s"¶iËr©;vGufÁ ¼-Ë(;{, « u tv)"Iy}´;{G¶.u} /{g|s;{G¥I{g¢1rs¬u
(255) ´;{G¶us"¢1uÕ¥ yr ;vgu{Zy} y;{!¢ f Ë(Y{Zs"¥Iv!t8u
(256) s-¢{s_| ©"y1,C´"r2{gr©;{,v,{`¯{s Ð{Zp u»y r `"pqr y}s; /uÕrs;¶ ´;r2{Zr {Gys?{!s r1 ¨pirb¢1v,{s{!¢1rv«u." u /{gysC ¢yIue{!s ,;{G cIu1|"{`y}s¼)Ë"u2u r crvG y {s;¶"{G¢r
(257) Ð{Gy}s ¥yl;y}u
(258) s"{grv ;vgu{gy}Iy};{`¢ u¥I¥ u¢
(259) ¾y¥dÍ1³ ͹CIu|;{!ys¯ysÄG;u ud y -us"yG"-u1 , a
(260) ż Å"Å.½ 6rvZ"yt_|CG;u ¨t©; ¨`rsI{!rvj{!pc_Iy´-upius¤y"¥¤`;uRvG{!s"r1|-uR {!|s"rv6ysC¸ ͹ I¢y"pc©;{!s"u¶ u ¨ rI{, Ð{g¢ Ë?©;u1{s;|. ¡){!|"t"2u ¹. {gs"¢ ur' ¨u {!s u
(261) ´;{G¶.us"¢1uc¥IylvG{gs".r1|"uir1 c¢ypc;r2u¶»y»`"uqt"s;{´;r {!ru v,{!s"r1|.uirs;r1v!- u1 Õy¥ u1r¢ ;us"yg-"u. . . r1 C uvgrI{´8uvZ pqrv,v g"u?;,´"rvgt"u Är y¢{!r`u¶. . . {g|s;r1v` ©"u1{!s"| ur¢Eu t"r1vLy Å_¼ ÅÅ.² ¼¾ÕvZÐu s;r
(262) Ð{ ´u1v-Ì ;u1 u. . . {!,E`"u?ts8{´;r2{!runv,{s;r|;u r1 s;ynu´;{G¶"u
(263) s;¢uU¥yb /"r1Iu1¶. ¶u`u1 p {gs"rs © ® rs-¶xr' `pir ¢y2uÕy}sxu}{`"u1«Í;¹Í "y`usÐ{!rvGvZxv,{!s_.u¶L yLÐ{ZpxuÉ ycr ¨G;pqr y}s; uy6ÍÀ1$Í"Í ¥ y"ts-¶cv,{Gs"u¶Ì`yÌ`;uÉr' `"pirf ¢y2u}¼. ͹.
(264) Ã t"2usÐvZ--"u1Iu{, «r¶u©"ruLysd`"uÕ¶;{g ur uf;us"yG"-u1 ¤G;r$s;uu¶qyc©"u¢1y}s; {!¶"u u¶xy HAL author manuscript. . . " y|"u} / l{ZsdZ;uÌt.s"¶;u rs-¶_{s;| y¥°"uLpiu¢"rs;{G /pd «t.s;¶u1IvZ-{gs"| r1 ¨Z_pir ,fs8y}s"p yt" «Á;ÅÅ.½ ¼ Ä`yCs;y. . 6|-us"u
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