Trans-Ethnic Mendelian-randomization Study Qhia Txog Kev Sib Raug Zoo Ntawm Cov Txheej Txheem Cardiometabolic Thiab Kab Mob Raum Ⅱ

Cov txiaj ntsig

Kev cuam tshuam ntawm kev pheej hmoo ntawm CKDFeem ntau ntawm 45 yam kev pheej hmoo muaj cov cuab yeej tshuaj caj ces muaj zog rau ob leeg poj koob yawm txwv (F-statistics> 10 rau 44 ntawm 45 qhov kev pheej hmoo ntawm cov neeg nyob sab Europe thiab 15 ntawm 17 qhov kev pheej hmoo ntawm cov neeg Esxias sab hnub tuaj; Cov Lus Qhia Ntxiv S2 thiab S3, muaj raws li cov ntaub ntawv ntxiv ntawm IB online). Txawm li cas los xij, cov cuab yeej tau muaj zog dua hauv cov neeg European piv nrog cov neeg Esxias sab hnub tuaj (Table Ntxiv S6, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Cov txiaj ntsig kwv yees rau cov45 yam tseem ceeb ntawm CKDHauv cov neeg European thiab 17 qhov kev pheej hmoo ntawm cov neeg Esxias sab hnub tuaj tau nthuav tawm hauv daim duab 2. Cov txiaj ntsig kwv yees rau lwm qhov kev ntsuam xyuas muaj txiaj ntsig tuaj yeem pom hauv Cov Lus Ntxiv S7–S12 (muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Cov kev ntsuam xyuas ntxaws ntxaws ntawm cov ntaub ntawv pov thawj hauv cov neeg European thiab cov neeg Esxias sab hnub tuaj tau nthuav tawm hauv Cov Lus Ntxiv S13A thiab S13B (muaj raws li cov ntaub ntawv ntxiv ntawm IJE online).

NYEEM NTXIV RAU HAUV HERBA CISTANCHE FOR KIDNEY

Cov xwm txheej txaus ntshai uas qhia txog cov pov thawj MR ntseeg tau Hauv European caj ces, yim yam muaj feem cuam tshuam nrog CKD. LUB SIJ HAWM [95% kev ntseeg siab ib ntus (CIs)] rau CKD ib 1-SD nce ntxiv hauv kev pheej hmoo pheej hmoo yog 1.78 (1.64 txog 1.94) rau BMI, 1.24 (1.12 txog 1.37) rau SBP, 1.13 (1.{{ 20}}7 txog 1.19) rau lipoprotein(a) qib, 0.93 ({27}}.90 rau 0.97) rau HDL -C thiab 0.96 (0.94 txog 0.98) rau apolipoprotein AI. Qhov OR (95% CI) ib ob npaug ntawm qhov tsis sib xws ntawm kev lav phib xaub rau binary muaj feem cuam tshuam yog 2.05 (1.59 txog 2.64) rau ntshav siab, 1.20 (1.09 txog 1.31) rau nephrolithiasis thiab 1.08 (1.05 txog 1.12) rau T2 Qhov cuam tshuam ntawm yim qhov kev pheej hmoo ntawm CKD tau zoo ib yam thoob plaws UK Biobank, CKDGen, thiab HUNT (Cov Duab Ntxiv S2A thiab Cov Lus Ntxiv S7A, S8A thiab S9A, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online).

Hauv cov neeg Esxias sab hnub tuaj, cov noob caj noob ces kwv yees siab dua BMI (LOSSIS ¼ 1.42, 95% CI ¼ 1.20 txog 1.69, P ¼ 6.49 10–5), nce nephrolithiasis (los yog ¼ 1.12, 95% CI ¼ 1.04 txog 1.101.1 ¼, P -3) thiab nce T2D txaus ntshai (LOSSIS ¼ 1.07, 95% CI ¼ 1.03 txog 1.10, P ¼ 1.66 10–4) yog tag nrho cov cuam tshuam nrog kev pheej hmoo ntawm CKD (Cov Duab Ntxiv S2B, muaj nyob rau hauv cov ntaub ntawv ntxiv ntawm IJE online). Cov txiaj ntsig ntawm T2D ntawm CKD tau zoo ib yam thoob plaws peb qhov kev tshawb fawb East Asian. Txawm li cas los xij, qhov cuam tshuam ntawm BMI thiab nephrolithiasis ntawm CKD tsis tau pom nyob rau hauv Tuam Tshoj Kadoorie Biobank - qhov no yuav yog vim muaj tsawg tus neeg mob CKD hauv cov peev txheej no (Cov Lus Qhia Ntxiv S10A-S12, muaj raws li Cov ntaub ntawv ntxiv ntawm IJE online).

Daim duab 3 Forest plot forua rau muaj kev cuam tshuam ntawm plaub cov ntshav siab phenotypesntawm cov kab mob raum mob ntev. Cov subplots sawv cev rau Mendelian-randomization tshwm sim ntawm txawv ntshav-siab phenotypes. CKD, mob raum mob.

Peb kuj tau ua ntau qhov kev ntsuam xyuas rhiab heev. Qhov kev tshuaj ntsuam MR bidirectional pom muaj qhov cuam tshuam zoo ntawm CKD qhov kev pheej hmoo ntawm kev pheej hmoo siab kub siab hauv European poj koob yawm txwv (Table Ntxiv S14, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Cov txiaj ntsig MR sib txawv rau T2D, BMI, thiab kub siab ntawm CKD suav nrog hauv Cov Lus Ntxiv S15A-C, muaj nyob rau hauv cov ntaub ntawv ntxiv ntawm IJE online. MR tsom xam siv eGFR raws li cov txiaj ntsig tau pom zoo ib yam rau cov CKD (Cov Lus Qhia Ntxiv S7B-S10B, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online).

Cov yam tseem ceeb uas qhia txog cov pov thawj tsis muaj zog MR

Muaj cov pov thawj tsis muaj zog los txhawb kev cuam tshuam rau CKD ntawm qhov seem 37 qhov kev pheej hmoo uas tau txiav txim siab hauv European poj koob yawm txwv kev txheeb xyuas (Cov Lus Qhia Ntxiv S7–S9, muaj nyob rau hauv cov ntaub ntawv ntxiv ntawm IJE online) thiab 14 qhov kev pheej hmoo uas tau txiav txim siab hauv East Asian poj koob yawm txwv tshuaj ntsuam xyuas ( Cov Lus Qhia Ntxiv S10–S12, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Qee qhov tsim muaj kev pheej hmoo, xws li haus luam yeeb thiab se rum uric acid, yog cov pov thawj tsis muaj zog. Tsis tas li ntawd, lub sijhawm pw tsaug zog luv dua tau pom cov pov thawj los txhawb kev koom tes nrog CKD hauv Nyij Pooj-Kidney-Biobank / ToMMo (Table Ntxiv S11, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online) thiab hauv UK Biobank (Table Ntxiv S7A, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online), uas tsis tau luam tawm hauv lwm cov kev tshawb fawb.

Ua raws li MR tshuaj ntsuam xyuas cov kev tshawb pom tseem ceeb

Cov txiaj ntsig ntawm cov ntshav siab phenotypes ntawm CKD thoob plaws cov pej xeem Daim duab 3 qhia tau hais tias cov ntshav siab phenotypes, suav nrog kev ua txhaum ntawm caj ces ntawm ntshav siab thiab caj ces kwv yees SBP thiab PP, tau pom muaj kev cuam tshuam loj heev ntawm CKD hauv European kev tshawb fawb tab sis tau tshwm sim los qhia qhov tshwm sim tsis zoo. nyob rau hauv cov kev tshawb fawb East Asian sib raug zoo (LOSSIS rau kev lav phib xaub ntawm kev kub siab ntawm CKD xws li 1.46 txog 1.77 hauv Europeans tab sis tsuas yog los ntawm 0.99 rau 1.07 hauv East Asians). Txhawm rau kom ntseeg tau cov txiaj ntsig MR no, peb thawj zaug kuaj xyuas lub zog ntawm cov cuab yeej tshuaj caj ces rau plaub lub phenotypes ntshav siab thiab pom tias cov cuab yeej muaj zog tau zoo tshaj qhov F-statistics pib ntawm 10 rau tag nrho plaub phenotypes hauv Europeans thiab East Asians (Table Ntxiv S6. , muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Txhawm rau txhawb zog ntxiv, peb tau siv cov cuab yeej tshuaj caj ces rau ntshav siab, SBP, DBP, thiab PP los ntawm 100 641 Tuam Tshoj Kadoorie Biobank cov neeg koom [uas tau txais txiaj ntsig zoo dua li cov ntaub ntawv kub siab nyob sab Europe (F-statistics ¼ 61.11 hauv Europeans vs 330.85 hauv East Asians); Cov Lus Qhia Ntxiv S2 thiab S3, muaj nyob rau hauv cov ntaub ntawv ntxiv ntawm IJE online] thiab tseem tau pom cov txiaj ntsig tsis zoo hauv East Asians (Table Ntxiv S16A, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Qhov thib peb, peb tau ua MR tsom xam siv European SBP thiab DBP cov cuab yeej muab rho tawm los ntawm East Asian cov kev tshawb fawb (Table Ntxiv S5, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online), uas pom cov txiaj ntsig zoo sib xws (Table Ntxiv S16B, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Thaum kawg, peb kwv yees qhov sib txawv ntawm cov kev cuam tshuam ntawm caj ces ntawm kev kub siab thoob plaws cov neeg European thiab cov neeg Esxias sab hnub tuaj thiab pom tias 20.9% ntawm cov cuab yeej tau pom qhov txawv txav ntawm ob pawg poj koob yawm txwv (Cov Lus Qhia Ntxiv S17, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Sensitivity MR tsom xam tsis suav nrog cov cuab yeej sib txawv, tswj hwm cov kab ke sib txawv ntawm BP thoob plaws cov poj koob yawm txwv, pom cov txiaj ntsig zoo sib xws MR (Table Ntxiv S18, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Cov kev ntsuam xyuas no muab pov thawj ntxiv tias ntshav siab muaj lub luag haujlwm tshwj xeeb hauv cov pej xeem hauv CKD etiology.

Cov teebmeem ntawm glycemic phenotypes thiab CKD

Txawm hais tias cov ntaub ntawv pov thawj rau kev cuam tshuam ntawm T2D ntawm CKD tau ntseeg tau, peb tau tshawb pom cov pov thawj me me los txhawb kev cuam tshuam ntawm yim glycemic phenotypes [fasting insulin (FI), yoo mov qabzib (FG), 2- teev piam thaj (2hGlu), yoo mov. proinsulin (FP), hemoglobin A1c (HbA1c), HOMA-B, insulin-zoo li kev loj hlob yam cuam tshuam rau cov protein 3 thiab insulin-zoo li kev loj hlob yam I] ntawm CKD (Cov Duab Ntxiv S3, muaj nyob rau hauv cov ntaub ntawv ntxiv ntawm IJE online) thiab eGFR (Sab Ntxiv Daim duab S4, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Kev soj ntsuam tom qab tau pom tias: (i) cov txiaj ntsig zoo sib xws tau pom tom qab kev tswj xyuas qhov ua tau rov qab ua rau cov cuab yeej thiab cov peev txheej muaj peev xwm (Sab Ntxiv Table S19A, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online); (ii) Cov pov thawj me me tau pom tias kev lav phib xaub ntawm caj ces rau T1D tau cuam tshuam nrog CKD kev pheej hmoo hauv ib qho ntawm peb qhov txiaj ntsig kev tshawb fawb los ntawm European poj koob yawm txwv (Cov Lus Ntxiv S19B, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online), uas ntxiv txhawb qhov tsis muaj zog ntawm cov piam thaj ntawm CKD; (iii) rau MR tsom xam siv stratified eGFR nyob rau hauv cov teb chaws Europe, me ntsis cuam tshuam ntawm glycemic phenotypes ntawm eGFR tau pom nyob rau hauv ob qho tib si mob ntshav qab zib thiab tsis mob ntshav qab zib cov qauv (Sab Ntxiv Table S19C, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online), uas qhia tias qhov tsis muaj zog ntawm cov tshuaj. qabzib ntawm CKD tuaj yeem ua tsis tau ntawm dia betes; (iv) yoo mov qabzib thiab caj ces lav rau T2D tau cuam tshuam nrog ntshav qab zib retinopathy (Sab Ntxiv Table S19D, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online), sug gesting hais tias cov noob caj noob ces ntawm glycemic phenotypes siv rau lub ntsiab MR tshuaj ntsuam xyuas tau ntseeg tau.

Cov teebmeem ntawm cov ntshav lipids thiab CKD

Rau MR kev tshawb pom ntawm lipids, peb cov kev soj ntsuam tom qab tau pom qee qhov kev soj ntsuam tshiab. Ua ntej, peb tau soj ntsuam cov pov thawj MR sib txawv rau kev kwv yees cov noob caj noob ces HDL-C ntawm CKD thoob plaws Europeans thiab East Asians. Hauv cov neeg European, cov pov thawj MR zoo tau pom los txhawb qhov cuam tshuam ntawm HDL-C thiab apolipoprotein AI ntawm CKD (Cov Lus Qhia Ntxiv S7-S9, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online), thaum muaj cov pov thawj MR tsis muaj zog rau cov txiaj ntsig ntawm HDL-C. ntawm CKD hauv East Asians (Cov Lus Qhia Ntxiv S1{{10}}}-S12, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Txhawm rau ntsuas qhov muaj peev xwm cuam tshuam ntawm lub zog ntawm HDL-C cuam tshuam rau CKD hauv East Asians (OR¼ {{20}}.94, 95% CI ¼ 0.87 rau 1.{{ 42}}2), peb tau ua MR siv cov cuab yeej European HDL-C zoo dua uas tau muab rho tawm los ntawm East Asian cov kev tshawb fawb (Table Ntxiv S5, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Siv txoj hauv kev no, peb pom cov pov thawj MR txhim khu kev qha (OR¼ 0.89, 95% CI ¼ 0.83 txog 0.96; Cov Table Ntxiv S16C, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Qhov no qhia tias HDL-C tuaj yeem cuam tshuam rau CKD hauv ob tus neeg. Thib ob, siv cov ntaub ntawv nyob sab Europe, ntau qhov sib txawv MR xav txog HDL-C thiab apolipoprotein AI hauv tib tus qauv tau ua. Qhov no qhia tau hais tias cov nyhuv ntawm HDL-C ntawm CKD yog ywj siab ntawm apolipoprotein AI (Sab Ntxiv Table S15D, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Thib peb, tom qab qhov kev tshawb pom HDL-C, peb pom muaj qhov cuam tshuam ntawm cov roj cholesterol hloov pauv cov qib protein ntawm CKD hauv CKDGen (OR¼ 1.06, 95% CI ¼ 1.01 txog 1.11, P ¼ 0.01; Supplementary Table S20, muaj raws li cov ntaub ntawv ntxiv ntawm IB online). Thaum kawg, peb tau tshawb xyuas qhov muaj peev xwm cuam tshuam ntawm apolipoprotein(a) loj ntawm CKD tab sis pom muaj pov thawj me me rau qhov ua rau muaj txiaj ntsig. Qhov no qhia tau hais tias qhov cuam tshuam ntawm lipoprotein (a) qib ntawm CKD tuaj yeem ywj pheej ntawm apolipoprotein(a) loj (Sab Ntxiv Table S21, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online).

Tsis yog-linear cuam tshuam ntawm BMI thiab yoo mov qabzib ntawm CKD Peb tau pom qhov kev sib raug zoo ntawm caj ces kwv yees BMI thiab CKD (Table Ntxiv S22, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Cov duab nkhaus ntawm qhov kev sib raug zoo no qhia tias muaj kev pheej hmoo siab dua ntawm CKD hauv cov neeg rog rog lossis rog rog, nrog rau qhov pom zoo BMI qhov pib ntawm 25 kg / m2 hauv UK Biobank thiab HUNT (Daim duab 4). Stratified analyses cais los ntawm kev sib deev (Cov Duab Ntxiv S5, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online) thiab hnub nyoog (Cov Duab Ntxiv S6, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online) qhia txog cov teebmeem zoo sib xws rau kev kwv yees caj ces BMI ntawm CKD. Kev kwv yees kev noj qab haus huv ntawm noob caj noob ces tau pom tias muaj pov thawj tsis muaj zog rau kev sib raug zoo nrog CKD (Cov Duab Ntxiv S7 thiab Cov Lus Ntxiv S22, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online). Qhov kev tshawb pom no tau zoo ib yam ntawm cov txiv neej thiab poj niam (Cov Duab Ntxiv S8, muaj nyob rau hauv cov ntaub ntawv ntxiv ntawm IJE online) thiab pab pawg hnub nyoog sib txawv (Cov Duab Ntxiv S9, muaj raws li cov ntaub ntawv ntxiv ntawm IJE online).

Raws li cov ntsiab lus, peb tau muab piv rau MR qhov kev tshawb pom nrog cov pov thawj kho mob uas twb muaj lawm hauv KDIGO cov lus qhia thiab tau teev cov kev cuam tshuam txog kev kho mob hauv Table 1.

Daim duab 4 Non-linear Mendelian randomization ntawm lub cev qhov ntsuas ntawm cov kab mob raum ntev. Qhov koob tshuaj- teb nkhaus ntawm lub cev qhov ntsuas qhov ntsuas thiabmob raum mob txaus ntshairau (A) UK Biobank thiab (B) HUNT Study. Qhov gradient ntawm txhua lub ntsiab lus ntawm qhov nkhaus yog qhov nruab nrab qhov nruab nrab qhov tshwm sim. Cov chaw ntxoov ntxoo sawv cev rau 95% kev ntseeg siab ib ntus.CKD,mob raum mob.

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