Eu J Clin In es . 2024;54:e14101.
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1 o 11
h ps://doi.o g/10.1111/eci.14101
wileyonlinelib a y.com/jou nal/eci
Recei ed: 27 July 2023
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Accep ed: 23 Sep embe 2023
DOI: 10.1111/eci.14101
ORIGINAL ARTICLE
Associa ion be ween exposu e o ai pollu ion and blood
lipids in he gene al popula ion o Spain
Se gioValdés1,2
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ViyeyDoula am- Gamga am1
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C is inaMaldonado- A aque1,2
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E aGa cía- Escoba 1,2
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Sa aGa cía- Se ano1,2
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WasimaOualla- Bachi i1,2
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Ma aGa cía- Vi anco3
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Juan LuisGa ido3
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Vic o iaGil3
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Fe nandoMa ín- Llo en e3
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Al onsoCalle- Pascual2,4
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LuisCas año2,5,6
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ElíasDelgado7
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Edelmi oMenéndez7
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JosepF anch- Nadal2,8
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SoniaGaz ambide2,6,9
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JoanGi bés10
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F. Ja ie Cha es2,11
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José L.Galán- Ga cía12
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Gab ielAguile a- Venegas12
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Joan Ca lesVall é2,13
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Nú iaAmigó2,14,15
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Mon seGua diola2,13
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JosepRibal a2,13
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GemmaRojo- Ma ínez1,2
1Depa men o Endoc inology and Nu i ion, Hospi al Regional Uni e si a io de Málaga/Uni e sidad de Málaga, Ins i u o de In es igación
Biomedica de Málaga- IBIMA, Málaga, Spain
2Cen o de In es igación Biomédica en Red de Diabe es y En e medades Me abólicas Asociadas (CIBERDEM), Ins i u o de Salud Ca los III, Mad id,
Spain
3Cen o de In es igaciones Ene gé icas, Medioambien ales y Tecnológicas (CIEMAT) – Di isión de Con aminación A mos é ica, Mad id, Spain
4Depa men o Endoc inology and Nu i ion and Ins i u o de In es igación Sani a ia Uni e si y Hospi al S. Ca los (IdISSC), Depa men Medicine
II, Uni e sidad Complu ense (UCM), Mad id, Spain
5Hospi al Uni e si a io C uces, BioC uces, UPV/EHU, Ba akaldo, Spain
6Cen o de In es igación Biomédica en Red de En e medades Ra as (CIBERER), Ins i u o de Salud Ca los III, Mad id, Spain
7Depa men o Endoc inology and Nu i ion, Hospi al Uni e si a io Cen al de As u ias/Uni e si y o O iedo, Ins i u o de In es igación Sani a ia
del P incipado de As u ias (ISPA), O iedo, Spain
8EAP Ra al Sud, Ins i u Ca alà de la Salu , Red GEDAPS, P ima y Ca e, Uni a de Supo a la Rece ca (IDIAP – Fundació Jo di Gol), Ba celona,
Spain
9Depa men o Endoc inology and Nu i ion, Hospi al Uni e si a io C uces – BioC uces Bizkaia – UPV- EHU, Ba acaldo, Ba celona, Spain
10Diabe es Uni , Hospi al A nau de Vilano a, Valencia, Spain
11Genomic S udies and Gene ic Diagnosis Uni , Fundación de In es igación del Hospi al Clínico de Valencia – INCLIVA, Valencia, Spain
12Depa men o Applied Ma hema ics, Uni e si y o Málaga, Málaga, Spain
13Resea ch Uni on Lipids and A he oscle osis, San Joan Uni e si y Hospi al, Ro i a i Vi gili Uni e si y, IISPV, Reus, Spain
14Me abolomics Pla o m, Uni e si a Ro i a i Vi gili, IISRV, Reus, Spain
15Bios e Teslab, Reus, Spain
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial License, which pe mi s use, dis ibu ion and ep oduc ion in any
medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o comme cial pu poses.
© 2023 The Au ho s. Eu opean Jou nal o Clinical In es iga ion published by John Wiley & Sons L d on behal o S ich ing Eu opean Socie y o Clinical In es iga ion
Jou nal Founda ion.
Valdés Se gio and Doula am- Gamga am Viyey ha e con ibu ed equally o his wo k and sha e i s au ho ship.
Josep Ribal a and Gemma Rojo- Ma ínez ha e con ibu ed equally o his wo k and sha e las au ho ship.
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VALDÉS e al.
1
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BACKGROUND
The Wo ld Heal h O ganiza ion (WHO) has iden i ied
ai pollu ion as he la ges single en i onmen al heal h
isk wo ldwide, wi h ou doo ai pollu ion accoun ing
o mo e han 4.2 million dea hs e e y yea .1 Nea ly hal
o ou doo ai pollu ion- ela ed p ema u e dea hs a e
due o ischaemic hea disease and s oke.1 Ai pollu ion
can impac he ca dio ascula sys em h ough a numbe
o mechanisms, including endo helial dys unc ion, sys-
emic and pulmona y oxida i e s ess and in lamma ion,
au onomic ne ous sys em dys unc ion and epigene ic
changes.2– 5 Al e a ions in lipid me abolism could be
ano he po en ial pa hway in he associa ion be ween
ai pollu ion and a e ioscle osis. In his ega d, se -
e al p e ious epidemiological s udies ha e explo ed he
ela ionships be ween he exposu e o se e al ambien
ai pollu an s and blood lipid le els and he p esence o
dyslipidaemia.6– 24 Howe e , mos o his e idence has
elied on s anda d lipid measu es. S anda d lipid pan-
els measu e he choles e ol o iglyce ide con en (in
concen a ion pe decili e) ca ied by each lipop o ein
class, a he han he numbe s o hese pa icles. In con-
as , NMR spec oscopy p o ides a di ec assessmen o
he numbe and size o lipop o ein pa icles, p o iding
addi ional in o ma ion abou ca dio ascula disease
(CVD) isk.25– 29
Acco dingly, in he p esen s udy, we aimed o assess
he associa ions be ween he exposu e o ai pollu an s
[pa icles wi h an ae odynamic diame e o less han 10
mic ons (PM10), pa icles wi h an ae odynamic diame-
e o less han 2.5 mic ons (PM2.5) and ni ogen dioxide
(NO2)], wi h bo h he blood lipid le els o a s anda d lipid
p o ile as well as he pa icle concen a ions o lipop o-
eins, in a na ionwide sample ep esen a i e o he adul
popula ion o Spain.
Co espondence
Se gio Valdés, Depa men o
Endoc inology and Nu i ion, Hospi al
Uni e si a io Regional de Málaga Plaza
del Hospi al Ci il s/n, 29009 Málaga,
Spain.
Email: se gio. [email p o ec ed]
Funding in o ma ion
Conseje ía de Salud y Bienes a Social,
Jun a de Andalucía, G an /Awa d
Numbe : RC- 0006- 2016; Ins i u o de
Salud Ca los III, G an /Awa d Numbe :
CM21/00214, INT21/00037, PI17/02136
and PI20/01322
Abs ac
Backg ound and Aims: We aimed o assess he associa ions o exposu e o ai
pollu an s and s anda d and ad anced lipop o ein measu es, in a na ionwide
sample ep esen a i e o he adul popula ion o Spain.
Me hods: We included 4647 adul s (>18 yea s), pa icipan s in he na ional,
c oss- sec ional, popula ion- based [email p o ec ed] s udy, conduc ed in 2008– 2010.
S anda d lipid measu emen s we e analysed on an A chi ec C8000 Analyze
(Abbo Labo a o ies SA). Lipop o ein analysis was made by an ad anced 1H-
NMR lipop o ein es (Liposcale®). Pa icipan s we e assigned ai pollu ion con-
cen a ions o pa icula e ma e <10 μm (PM10), <2.5 μm (PM2.5) and ni ogen
dioxide (NO2), co esponding o he heal h examina ion yea , ob ained by mod-
elling combined wi h measu emen s aken a ai quali y s a ions (CHIMERE
chemis y- anspo model).
Resul s: In mul i a ia e linea eg ession models, each IQR inc ease in PM10,
PM2.5 and NO2 was associa ed wi h 3.3%, 3.3% and 3% lowe le els o HDL- c and
1.3%, 1.4% and 1.1% lowe HDL pa icle (HDL- p) concen a ions (p < .001 o all
associa ions). In mul i a ia e logis ic eg ession, he e was a signi ican associa-
ion be ween PM10, PM2.5 and NO2 concen a ions and he odds o p esen ing
low HDL- c (<40 mg/dL), low HDL- p (<p25) and highe LDL pa icle (LDL- p)
concen a ions (≥p75). In subg oup analyses he e we e s onge associa ions be-
ween PM10 and NO2 and low HDL- p in men (p o in e ac ion .008 and .034), and
be ween NO2 and low HDL- p in indi iduals wi h obesi y (p o in e ac ion .015).
Conclusions: Ou s udy shows an associa ion be ween he exposu e o ai pol-
lu an s and blood lipids in he gene al popula ion o Spain, sugges ing a link o
a he oscle osis.
KEYWORDS
ai pollu ion, choles e ol, HDL, lipids, lipop o ein, iglyce ide
13652362, 2024, 2, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/eci.14101 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [13/03/2024]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
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VALDÉS e al.
2
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METHODS
2.1
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S udy design, se ing and
popula ion
The [email p o ec ed] s udy is a na ional, c oss- sec ional,
popula ion- based su ey conduc ed in 2008– 2010.30 A
clus e sampling design was used o selec pa icipan s o
o m a ep esen a i e andom sample o he Spanish pop-
ula ion. One hund ed heal h cen es o hei equi alen
om all a ound he coun y we e selec ed a andom, wi h
a p obabili y o selec ion p opo ional o hei a ge pop-
ula ion size, a e which 100 indi iduals aged ≥18 yea s
we e andomly selec ed om each heal h cen e. O he
eligible adul s, 55.8% came o examina ion, o which 9.9%
we e excluded (ins i u ionalized, se e e disease, p eg-
nancy o ecen deli e y), esul ing in a inal sample o
5072 indi iduals.
The p esen s udy ocuses on 4647 indi iduals (92% o
he s udy sample), in whom comple e da a on concen a-
ions o ai pollu an s and blood lipids we e a ailable o
analyses.
This esea ch was ca ied ou in acco dance wi h he
Decla a ion o Helsinki o he Wo ld Medical Associa-
ion.31 W i en in o med consen was ob ained om all
he pa icipan s. The s udy was app o ed by he E hics
and Clinical In es iga ion Commi ee o he Hospi al
Regional Uni e si a io de Málaga (Málaga, Spain) in ad-
di ion o o he egional e hics and clinical in es iga ion
commi ees all o e Spain.
2.2
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Va iables and p ocedu es
The pa icipan s we e in i ed o a end a single examina-
ion isi a hei heal h cen e. In o ma ion was collec ed
by means o an in e iewe - adminis e ed s uc u ed
ques ionnai e, ollowed by a physical examina ion and
blood sampling. In o ma ion on age, gende , educa ional
le el (none/basic/high school/college), smoking habi
(cu en , o me o ne e smoke s) and alcohol in ake
(<30/30– 60/>60 se ings pe mon h), was ob ained by
ques ionnai e. Food consump ion was de e mined by a
ood equency ques ionnai e and adhe ence o he Medi-
e anean die was es ima ed by an adap a ion o a 14- i em
Medi e anean die sco e (MedSco e).32 The le el o daily
physical ac i i y was es ima ed by he sho o m o he
In e na ional Physical Ac i i y Ques ionnai e (IPAQ).33
Weigh and heigh we e measu ed and he body mass
index (BMI) was calcula ed as weigh (kg)/heigh (m)2.
Medical his o y and medica ions we e also eco ded.
Blood samples, ob ained in as ing condi ions, we e
immedia ely cen i uged and he se um was ozen un il
analysis. Samples we e managed by he biochemis y lab-
o a o y o he Hospi al Regional Uni e si a io de Málaga,
he IBIMA Biobank and by he CIBERDEM Bio eposi o y
(IDIBAPS Biobank).
2.3
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Lipid measu emen s
S anda d lipid measu emen s Se um le els (mg/dL)
o iglyce ides (TG), o al choles e ol (TC) and high-
densi y lipop o ein choles e ol (HDL- c) we e measu ed
on an A chi ec C8000 Analyze (Abbo Labo a o ies
SA). Low- densi y lipop o ein choles e ol (LDL- c) was
es ima ed by he F iedewald o mula. ‘High o al choles-
e ol’ was de ined as TC ≥ 240 mg/dL; ‘high LDL- c’ was
de ined as LDL- c ≥ 160 mg/dL; ‘low HDL- c’ was de ined
as HDL- c < 40 mg/dL; and hype iglyce idaemia was de-
ined as TG ≥ 200 mg/dL.34
Lipop o ein analysis Lipop o ein analysis was pe -
o med by using Liposcale® Tes (CE, ISO 13.485
app o ed), an ad anced lipop o ein es based on wo-
dimensional (2D) di usion- o de ed 1H- NMR (P o on nu-
clea magne ic esonance) spec oscopy.35 Be o e 1H- NMR
analysis, 200 μL o se um we e dilu ed wi h 50 μL deu e -
a ed wa e and 300 μL o 50 mM phospha e bu e solu ion
a pH 7.4. 1H- NMR spec a we e eco ded a 306K on a
B uke A ance III 600 spec ome e ope a ing a a p o on
equency o 600.20 MHz. The me hyl signal was decon o-
lu ed by using Lo en zian unc ions o de e mine he lipid
concen a ion o he main lipop o ein classes (VLDL, LDL
and HDL), and hei size associa ed di usion coe icien s.
Then, he lipid concen a ions we e combined wi h hei
associa ed pa icle olume in o de o quan i y he num-
be o pa icles equi ed o anspo he measu ed lipid
concen a ion o each lipop o ein subclass calcula ing he
pa icle concen a ions o VLDL (VLDL- p), LDL (LDL- p)
and HDL (HDL- p). The a ia ion coe icien s o pa icle
numbe we e be ween 2% and 4%, and o he pa icle sizes
we e lowe han 0.3%. These analyses we e pe o med
a he Bios e Teslab acili ies. We classi ied pa icipan s
as ha ing no mal o abno mal le els o LDL- p, VLDL- p
and HDL- p, using he equi alen s o he 75 h (LDL- p and
VLDL- p) and 25 h (HDL- p) pe cen iles (p) o pa icle con-
cen a ions wi hin ou s udy popula ion.
2.4
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Exposu e assessmen
Modelled mean annual PM10, PM2.5 and NO2 concen a-
ions in Spain o he pe iod 2008– 2010 we e calcula ed
wi h he CHIMERE chemis y- anspo model.36 This
model calcula es he concen a ion o gaseous species
and bo h ino ganic and o ganic ae osols o p ima y and
13652362, 2024, 2, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/eci.14101 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [13/03/2024]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
4 o 11
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VALDÉS e al.
seconda y o igin, including p ima y pa icula e ma e ,
mine al dus , sulpha e, ni a e, ammonium, seconda y
o ganic species and wa e . This model has been b oadly
e alua ed in Spain by compa ison wi h measu ed ai pol-
lu an s a a la ge se o moni o ing si es.37,38 The model
was applied o a domain co e ing he Ibe ian Peninsula a
a ho izon al esolu ion o 0.1 × 0.1°. The modelled concen-
a ions we e co ec ed wi h obse ed alues, by conside -
ing a me hodology desc ibed by Ma ín e al.39 in which (1)
a bias is calcula ed wi h ega d o he obse a ions in he
Spanish ai quali y ne wo k o moni o ing si es, (2) hese
biases a e spa ially in e pola ed using a k iging me hodol-
ogy o ob ain a g idded bias and (3) his g idded bias is
applied o he modelled concen a ion g id. This me hod-
ology conside s a di e en bias g id o u al and u ban
si es ha a e hen combined and weigh ed by popula ion
densi y. We assigned he a e age annual exposu e o ai
pollu an s co esponding o he heal h examina ion yea
o each pa icipan by in e pola ing he es ima ed concen-
a ions o he cen oid o hei esiden ial pos al codes.
Da a on mean annual empe a u e (°C) om each mu-
nicipali y o esidence we e ob ained om he Spanish
Na ional Me eo ological Agency.40
2.5
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S a is ical analysis
We applied linea eg ession models o assess associa-
ions be ween ai pollu an and lipid measu emen s,
which we e log ans o med o no malize dis ibu ions
and also o limi he in luence o ex eme alues. Asso-
cia ion es ima es we e p esen ed as pe cen changes wi h
co esponding 95% con idence in e als (calcula ed by
100 × [exp(b) − 1]), pe each in e qua ile ange (IQR) in-
c ease in ai pollu an concen a ions which equa ed o
7.7 μg/m3 PM10, 4.8 μg/m3 PM2.5 and 12.1 μg/m3 NO2.
We also used logis ic eg ession models o in es iga e
he associa ions o ambien ai pollu an s wi h high o al
choles e ol (TC ≥ 240 mg/dL); high LDL- c (LDL- c ≥ 160 mg/
dL); low HDL- c (HDL- c < 40 mg/dL); and hype iglyce-
idaemia (TG ≥ 200 mg/dL) as de ined by he s anda d
lipid measu emen s, and wi h high LDL- p and VLDL- p
concen a ions (≥p75), and low HDL- p concen a ions
(<p25), measu ed by he Liposcale® es . These esul s a e
p esen ed as odds a ios (ORs) wi h co esponding 95%
CIs again pe each IQR inc ease in ai pollu an s.
All hese models we e con olled o possible con ound-
e s such as age, sex, BMI, educa ion le el, smoking s a us,
alcohol in ake, municipali y popula ion, MedSco e, IPAQ,
mean ambien empe a u e o he municipali y and lipid
lowe ing medica ion.
In addi ion, we in es iga ed po en ial e ec modi-
ica ion o he associa ions by sex (male/ emale), age
(<40/40– 60 o ≥60 yea s) and BMI (<30 o ≥30 kg/m2).
Each po en ial modi ie was examined in a sepa a e model
by adding an in e ac ion e m.
All he s a is ical analyses we e pe o med wi h IBM
SPSS s a is ics 23.0. Repo ed p alues we e based on wo-
sided es s wi h s a is ical signi icance se a .05. Bon e -
oni co ec ion o mul iple compa isons was applied a a
le el o alpha =.05/7 = .007.
3
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RESULTS
A o al o 4647 indi iduals we e included in he analysis
(Table1). The sample was composed o 1976 men (42.5%)
and 2671 women (57.5%). Mean age o he popula ion was
50.5 ± 17.0 yea s ( ange: 18– 93 yea s). The cha ac e is ics
o he s udy popula ion ollowed a dis ibu ion as ex-
pec ed in he Spanish gene al popula ion. Dis ibu ions o
s anda d lipids and NMR pa icle concen a ions a e also
displayed in he able.
Table2 summa izes esiden ial es ima es o ou doo
ai pollu ion concen a ions assigned o he s udy pa ici-
pan s in he yea o examina ion. The median (25 h– 75 h
pe cen ile) PM10, PM2.5 and NO2 exposu e le els we e 23.7
(19.6– 27.3), 12.2 (10.5– 15.3) and 16.6 (12.5– 24.6) μg/m3,
espec i ely. Mos alues we e wi hin he cu en Eu o-
pean Ambien Ai Quali y Di ec i e a ge alues (Di ec-
i e 2008/50/EC).41
Table3 shows he esul s o he linea co ela ions
be ween ai pollu an concen a ions and s anda d lipid
bioma ke s (TC, LDL- c, HDL- c and TG) and NMR pa -
icle concen a ions (LDL- p, VLDL- p and HDL- p), in
c ude, and mul i a ia e adjus ed linea eg ession mod-
els. G ea e ai pollu an exposu es we e associa ed wi h
lowe TC and LDL- c concen a ions in c ude models, bu
hese associa ions we e a enua ed a e mul i a ia e ad-
jus men . This end was no obse ed by NMR analyses.
In ac he associa ion be ween ai pollu an s and LDL- p
al hough no signi ican ended o be posi i e. The h ee
pollu an s es ed showed a s ong and highly signi ican
nega i e associa ion wi h HDL- c concen a ions in bo h
c ude and mul i a ia e models. In he ully adjus ed
model, an IQR inc ease in PM10, PM2.5 and NO2 was as-
socia ed wi h 3.3%, 3.3% and 3% lowe le els o HDL- c,
espec i ely. The same end was obse ed ega ding he
associa ion be ween con aminan s and he concen a ion
o HDL pa icles measu ed by NMR. In he mul i a ia e
analysis, each IQR inc ease in PM10, PM2.5 and NO2 was
associa ed wi h 1.3%, 1.4% and 1.1% lowe HDL- p. PM2.5
concen a ions also showed a posi i e associa ion wi h TG
le els in mul i a ia e analyses.
Table4 shows he c ude and mul i a ia e- adjus ed ORs
o p esen ing lipid abno mali ies in he s anda d lipid
13652362, 2024, 2, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/eci.14101 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [13/03/2024]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
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5 o 11
VALDÉS e al.
p o ile and NMR, pe each IQR inc ease in ai pollu an
concen a ions. Replica ing wha was seen in he linea
model, he e was a s ong nega i e associa ion be ween
he h ee ai pollu an s es ed, and HDL- c. In he ully ad-
jus ed model, he odds o p esen ing low HDL- c (<40 mg/
dL), we e 1.36 (95% CI 1.21– 1.54) p < .001, 1.41 (95% CI
1.25– 1.59) p < .001 and 1.31 (95% CI 1.18– 1.44) p < .001
pe each IQR inc ease in PM10, PM2.5 and NO2. Again,
his same end was obse ed o he associa ion be ween
ai pollu an s and HDL- p, wi h mul i a ia e ORs o p e-
sen ing low HDL- p (<p25) o 1.23 (95% CI 1.09– 1.37)
p < .001, 1.23 (95% CI 1.10– 1.37) p < .001 and 1.18 (95% CI
1.07– 1.29) p = .001 pe each IQR inc ease in PM10, PM2.5
and NO2, espec i ely. In he logis ic eg ession models,
he e was also a posi i e associa ion be ween PM10 and
PM2.5 concen a ions and he odds o p esen ing highe
LDL- p, wi h mul i a ia e ORs o p esen ing LDL- p con-
cen a ions ≥p75 o 1.24 (95% CI 1.11– 1.39) p < .001 and
1.16 (95% CI 1.04– 1.29) p = .007, pe each IQR inc ease,
espec i ely.
In he subg oup analysis, we ound a signi ican in-
e ac ion be ween sex and he associa ion be ween PM10
and NO2 and low HDL- p (p o in e ac ion .008 and .034,
espec i ely), wi h s onge associa ions in men. We
also ound a s onge associa ion be ween NO2 and low
HDL- p in indi iduals wi h obesi y (p o in e ac ion .015)
(Figu e1).
4
|
DISCUSSION
In his na ionwide sample ep esen a i e o he adul
popula ion o Spain we ound signi ican associa ions
be ween exposu e o a ious ai pollu an s and se e al
s anda d and no el blood lipop o ein measu es, poin -
ing o a p o- a he ogenic lipid p o ile in subjec s exposed
o a highe deg ee o pollu ion. In pa icula we ound
s ong nega i e associa ions be ween PM10, PM2.5 and
NO2 exposu es, and bo h HDL- c and HDL- p concen-
a ions bo h in linea and in logis ic mul i a ia e e-
g ession models. Addi ionally, we ound a signi ican
associa ion be ween exposu e o PM10 and PM2.5, and
TABLE 1 Clinical cha ac e is ics and lipid alues o he s udy
sample (n = 4647).
% Mean ± SD Range
Age (yea s) 50.5 ± 17.0 18– 93
Women 57.5
Smoking
Cu en 23.8
Fo me 26.0
Ne e 50.2
Alcohol in ake (se ings- mon h)
<30 73.9
30– 60 14.9
>60 11.3
Municipali y popula ion
<10,000 18.4
10,000– 50,000 27.8
>50,000 53.8
Educa ion le el
No s udies 12.8
Basic 47.6
High school- college 39.6
BMI (kg/m2) 28.0 ± 5.2 12.2– 61.3
Med die sco e 7.8 ± 1.8 1– 13
Physical ac i i y (IPAQ)
Low 42.0
Medium 34.5
High 23.5
Lipid lowe ing medica ion 13.3
S anda d lipid bioma ke s (mg/dL)
TC 196 ± 40 58– 395
LDL- C 105 ± 30 21– 254
HDL- C 52 ± 13 7– 14
TG 121 ± 88 17– 2095
Pa icle concen a ion (1H- NMR) (nmol/L)
LDL- p 1392 ± 278 358– 2702
VLDL- p 53 ± 40 12– 619
HDL- p 28 ± 5 6– 56
Abb e ia ions: HDL- C, high- densi y lipop o ein choles e ol; HDL- p, HDL
pa icles; LDL- C, low- densi y lipop o ein choles e ol; LDL- p, LDL pa icles;
TC, o al choles e ol; TG: iglyce ides; VLDL- p, VLDL pa icles; 1H- NMR,
p o on nuclea magne ic esonance.
TABLE 2 Desc ip i e s a is ics o ai pollu an s concen a ions (μg/m3) in he s udy sample.
Pollu an
Pe cen ile
IQR Mean Minimum Maximum5 h 25 h 50 h 75 h 95 h
PM10 14.4 19.6 23.7 27.3 33.1 7.7 23.2 4.0 42.3
PM2.5 8.1 10.5 12.2 15.3 20.0 4.8 12.7 3.4 22.3
NO26.6 12.5 16.6 24.6 50.3 12.1 20.2 3.6 51.4
Abb e ia ions: IQR, in e qua ile ange; NO2, ni ogen dioxide; PM10, pa icles wi h an ae odynamic diame e o less han 10 mic ons; PM2.5, pa icles wi h an
ae odynamic diame e o less han 2.5 mic ons.
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TABLE 3 Associa ions be ween ai pollu an s (pe IQR concen a ions inc ease) and blood lipid le els.
S anda d lipid bioma ke s
TC LDL- C HDL- C TG
% change (95%
CI) p
% change (95%
CI) p
% change (95%
CI) p
% change (95%
CI) p
PM10
C ude −1.7 (−2.5, −1.0) <.001 −1.6 (−2.7, −0.5) .004 −3.2 (−4,1, −2.3) <.001 0.4 (−1.4, 2.0) .667
Mul i a ia e −1.1 (−1.9, −0.2) .013 −0.3 (−1.6, 0.9) .590 −3.3 (−4.3, −2.3) <.001 2.0 (0.1, 3.9) .037
PM2.5
C ude −1.1 (−1.9, −0.3) .01 −0.8 (−2.0, 0.4) .190 −3.0 (−4.0, −2.1) <.001 1.0 (−1.0, 2.9) .323
Mul i a ia e −0.6 (−1.4, 0.3) .215 −0.3 (−1.0, 1.5) .628 −3.3 (−4.3, −2.3) <.001 2.8 (0.9, 4.7) .003
NO2
C ude −1.8 (−2.5, −1.2) <.001 −1.8 (−2.7, −0.9) <.001 −2.7 (−3.4, −1.9) <.001 −1.5 (−2.9, 0.0) .053
Mul i a ia e −1.4 (−2.2, −0.7) <.001 −0.9 (−1.9, 0.2) .118 −3.0 (−3.8, −2.2) <.001 −0.5 (−1.2, 2.1) .570
Pa icle concen a ion (1H- NMR)
LDL- p VLDL- p HDL- p
% change (95% CI) p% change (95% CI) p% change (95% CI) p
PM10
C ude 0.2 (−0.6, 0.9) .703 1.1 (−1.0, 3.2) .324 −0.7 (−1.3, 0.0) .049
Mul i a ia e 0.6 (−0.3, 1.4) .205 1.9 (−0.3, 4.1) .091 −1.3 (−2.0, −0.6) <.001
PM2.5
C ude 0.4 (−0.4, 1.2) .364 1.0 (−1.3, 3.2) .391 −0.8 (−1.5, −0.1) .018
Mul i a ia e 0.6 (−0.2, 1.5) .159 1.9 (−0.3, 4.1) .089 −1.4 (−2.1, −0.7) <.001
NO2
C ude 0.6 (0.0, 1.2) .068 0.3 (−1.3, 2.0) .703 −0.5 (−1.1, 0.0) .040
Mul i a ia e 0.5 (−0.2, 1.3) .155 1.8 (−0.1, 3.6) .059 −1.1 (−1.6, −0.5) <.001
No e: % changes and p alues calcula ed by linea eg ession pe in e qua ile ange (IQR) inc ease in ai pollu an s concen a ions (PM10: 7.7 μg/m3, PM2.5: 4.8 μg/m3, NO2: 12.1 μg/m3). Mul i a ia e model: adjus ed
o age, sex, BMI, smoking s a us, alcohol in ake, educa ion le el, MedSco e, IPAQ, municipali y popula ion, ambien empe a u e and lipid lowe ing medica ion. In bold: % changes wi h p alues < .007 (alpha .05
co ec ed by Bon e oni = .05/7).
Abb e ia ions: HDL- C, high- densi y lipop o ein choles e ol; HDL- p, HDL pa icles; LDL- C, low- densi y lipop o ein choles e ol; LDL- p, LDL pa icles; NO2, ni ogen dioxide; PM10, pa icles wi h an ae odynamic
diame e o less han 10 mic ons; PM2.5, pa icles wi h an ae odynamic diame e o less han 2.5 mic ons; TC, o al choles e ol; TG, iglyce ides; VLDL- p, VLDL pa icles; 1H- NMR, p o on nuclea magne ic esonance.
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VALDÉS e al.
highe LDL- p concen a ions (≥p75), al hough he asso-
cia ions be ween ai pollu an s and he s anda d LDL- c
measu es we e null.
These indings a e in line wi h p e ious s udies sug-
ges ing ha ai pollu ion migh nega i ely impac blood
lipids in he gene al popula ion,6– 24 and may be a po en-
ial con ibu o o ai pollu ion- ela ed CVD isk. In ac ,
low HDL- c is a well- es ablished a he oscle o ic CVD isk
ac o ,34 whe eas lowe HDL and highe LDL pa icle
numbe s ha e also been associa ed wi h inc easing ca -
dio ascula e en s.42– 44
In e es ingly, al hough he ela ionship o he ex-
posu e o di e en ai pollu an s wi h s anda d lipid
bioma ke s has been widely s udied, o he bes ou
knowledge, only wo p e ious s udies ha e assessed as-
socia ions wi h pa icle concen a ion measu es. Bell
e al.9 examined he ela ionship be ween ai pollu ion
and bo h HDL- c and HDL- p, in 6654 men and women
ee o p e alen clinical CVD, pa icipan s in he Mul i-
E hnic S udy o A he oscle osis Ai Pollu ion s udy
(MESA Ai ). A 5 μg/m3 highe PM2.5 was associa ed wi h
lowe HDL- p (−0.64 μmol/L [95% CI −1.01, −0.26]),
bu no HDL- c (−0.05 mg/dL [95% CI −0.82, 0.71]). Mc-
Guinn e al.13 s udied linea associa ions o es ima e
change in lipop o ein le els wi h each μg/m3 inc ease in
annual a e age PM2.5 in 6587 pa ien s who had a ca diac
ca he e iza ion in Duke Uni e si y be ween 2001 and
2010 (CATHGEN s udy). The pe cen change om he
mean ou come le el was 2.00% (95% CI 1.38%, 2.64%)
o o al LDL- p. Howe e , he associa ions be ween ai
pollu ion and HDL pa icle concen a ions in his s udy
we e inconsis en . This is in con as o he indings
TABLE 4 Odd a ios (OR) o p esen ing lipid abno mali ies pe in e qua ile ange (IQR) inc ease in ai pollu an s concen a ions.
S anda d lipid bioma ke s
TC ≥ 240 mg/dL LDL- C ≥ 160 mg/dL HDL- C < 40 mg/dL
T iglyce ides ≥ 200
mg/dL
OR 95% CI pOR 95% CI pOR 95% CI pOR 95% CI p
PM10
C ude 0.94 0.85– 1.05 .282 0.99 0.82– 1.20 .952 1.29 1.17– 1.43 .000 0.96 0.85– 1.08 .489
Mul i a ia e 1.02 0.90– 1.16 .718 1.10 0.87– 1.37 .428 1.36 1.21– 1.54 .000 0.97 0.83– 1.12 .655
PM2.5
C ude 1.00 0.89– 1.13 .958 1.07 0.87– 1.31 .521 1.33 1.20– 1.47 .000 0.94 0.82– 1.07 .353
Mul i a ia e 1.07 0.94– 1.22 .314 1.16 0.92– 1.46 .198 1.41 1.25– 1.59 .000 0.95 0.82– 1.11 .542
NO2
C ude 0.93 0.85– 1.02 .139 0.97 0.83– 1.14 .975 1.23 1.14– 1.32 .000 0.91 0.82– 1.01 .073
Mul i a ia e 0.99 0.88– 1.11 .853 1.11 0.91– 1.36 .285 1.31 1.18– 1.44 .000 0.96 0.84– 1.10 .558
Pa icle concen a ion (1H- NMR)
LDL- p ≥ p75 VLDL- p ≥ p75 HDL- p < p25
OR 95% CI pOR 95% CI pOR 95% CI p
PM10
C ude 1.15 1.06– 1.26 .002 1.03 0.94– 1.12 .578 1.12 1.03– 1.23 .011
Mul i a ia e 1.24 1.11– 1.39 .000 1.08 0.96– 1.21 .188 1.23 1.09– 1.37 .000
PM2.5
C ude 1.12 1.02– 1.23 .016 1.02 0.93– 1.12 .631 1.13 1.03– 1.24 .007
Mul i a ia e 1.16 1.04– 1.29 .007 1.09 0.97– 1.21 .144 1.23 1.10– 1.37 .000
NO2
C ude 1.08 1.01– 1.16 .023 0.99 0.92– 1.06 .741 1.10 1.03– 1.17 .007
Mul i a ia e 1.11 1.02– 1.22 .018 1.05 0.95– 1.15 .334 1.18 1.07– 1.29 .001
No e: ORs. 95% CI and p alues we e calcula ed by logis ic eg ession pe in e qua ile ange (IQR) inc ease in ai pollu an s concen a ions (PM10: 7.7 μg/m3,
PM2.5: 4.8 μg/m3, NO2: 12.1 μg/m3). In bold: % changes wi h p alues < .007 (alpha .05 co ec ed by Bon e oni = .05/7). Mul i a ia e model: adjus ed o age, sex,
BMI, smoking s a us, alcohol in ake, educa ion le el, MedSco e, IPAQ, municipali y popula ion, ambien empe a u e and lipid lowe ing medica ion.
Abb e ia ions: HDL- C, high- densi y lipop o ein choles e ol; HDL- p, HDL pa icles; LDL- C, low- densi y lipop o ein choles e ol; LDL- p, LDL pa icles; NO2,
ni ogen dioxide; PM10, pa icles wi h an ae odynamic diame e o less han 10 mic ons; PM2.5, pa icles wi h an ae odynamic diame e o less han 2.5
mic ons; TC, o al choles e ol; TG, iglyce ides; VLDL- p, VLDL pa icles; 1H- NMR, p o on nuclea magne ic esonance.
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VALDÉS e al.
epo ed by Bell e al. in he MESA Ai s udy9 and o
ou esul s in [email p o ec ed], which indica e s ong nega i e
associa ions be ween ai pollu an s and HDL ma ke s.
O no e, he CATHGEN s udy sample consis ed o pa-
ien s who unde wen ca diac ca he e iza ion, who may
ep esen a highly selec i e popula ion, while he MESA
Ai and he [email p o ec ed] s udy popula ions may be mo e
gene alizable o he gene al backg ound popula ion.
Al hough he obse ed di e ences in blood lipids
ound in ou s udy may seem small, i is o no e ha , as
FIGURE 1 Logis ic eg ession analyses be ween PM2.5, PM10 and NO2 exposu es and HDL- c <40 mg/dL, HDL- p <p25 and LDL- p ≥p75
in di e en popula ion subg oups.
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VALDÉS e al.
poin ed ou by Bell e al.,9 he magni ude o he dec ease
o HDL- c and HDL- p we ha e obse ed (be ween −3.0%
and −3.3% dec ease in HDL- c and − 1.1% o −1.4% de-
c ease in HDL- p pe IQR inc ease in ai pollu an s con-
cen a ion), can be compa ed o he e ec o smoking on
hese measu emen s as obse ed in smoking cessa ion
s udies (2.4 mg/dL and 1.0 μmol/L change on HDL- c and
HDL- p, espec i ely).45
On he o he hand, exposu e o ai pollu ion has also
been shown o induce he de elopmen o dys unc ional
HDL esul ing in al e a ion o i s a he op o ec i e capaci-
ies,46,47 which may con ibu e o a he oscle osis p og es-
sion beyond he o al lipop o ein concen a ions measu ed
in ou s udy.
The appa en ly coun e in ui i e nega i e associa ion
be ween ai pollu an s and TC obse ed is o small magni-
ude and could be explained by he con ibu ion o HDL- c
o he TC le els, which was signi ican ly educed when as-
socia ed wi h highe exposu es. In line wi h his, no associ-
a ions wi h LDL- c le els in he mul i a ia e analyses we e
ound. This appa en ly benign e ec o ai pollu an s in
he s anda d LDL- c measu es was howe e accompanied
by a signi ican associa ion be ween highe exposu es o
PM10 and PM2.5, and highe LDL- p concen a ions (≥p75).
LDL- p has been ound o be a be e p edic o o CVD
han LDL- c, especially in indi iduals wi h LDL- p/LDL- c
disco dance.28,29,48 So again, hese associa ions could be
ega ded as p o- a he ogenic. In subg oup analyses, we
ound s onge associa ions be ween PM10 and NO2 and
low HDL- p in men, and be ween NO2 and low HDL- p in
indi iduals wi h obesi y, sugges ing ha hese subg oups
may be mo e suscep ible. A s onge suscep ibili y in
o e weigh – obese indi iduals is consis en wi h Sø ensen
e al.,6 Yang e al.,10 Kim e al.,12 Mao e al.,16 Zhang e al.22
and Kim e al.19 among o he s. Bo h ai pollu ion expo-
su e and o e weigh /obesi y a e associa ed wi h highe
sys emic in lamma ion2,49 which may explain an in e play
o hese ac o s. The modi ica ion e ec s o sex in p e ious
s udies ha e been mixed and ha de o in e p e .
The unde lying mechanisms explaining he e ec o
ai pollu an s on lipids ha e no been ully elucida ed.
The main hypo hesis is ha he oxida i e s ess and sys-
emic in lamma ion caused by inhaled ai pollu ion could
induce ad e se lipid me abolism and lipid oxida ion.50,51
Ai pollu an s ha e also been ound o cause DNA me h-
yla ion o genes ela ed o lipid me abolism.52 Fu he
s udies a e wa an ed o cla i y he ull spec um o hese
mechanisms.
Ou s udy has se e al s eng hs, including he la ge
popula ion- based design and he inclusion o ad anced li-
pop o ein measu es, as well as o he ex ensi e indi idual-
le el da a o clinical, demog aphic and li es yle a iables,
which allowed us o pe o m a comple e mul i a ia e
adjus men o he da a. Ou na ionwide pe spec i e, al-
lows us o ex apola e ou esul s mo e widely han local
o egional s udies, inc easing he public heal h implica-
ions o he indings.
The limi a ions o ou s udy include i s obse a ional
c oss- sec ional na u e; so ha we canno es ablish causal
associa ions o exclude esidual con ounding in he e-
la ion be ween ai pollu an s and lipids. Also, we used
ambien ou doo measu emen s modelled a he esiden-
ial add esses o he pa icipan s as a p oxy o exposu e
o ai pollu ion, whe eas no o he ele an in o ma ion
such as ime– ac i i y pa e ns, p oximi y o main oads,
occupa ional exposu es o pe sonal moni o ing da a was
a ailable. Exposu e measu emen e o is possible when
using modelled pollu an le els and his could, in ac ,
ha e a enua ed ou e ec es ima es. Finally, ou exposu e
models we e de eloped based on yea ly exposu es o ai
pollu an s, whe eas mo e e ined measu es o look a di -
e en lags we e no a ailable.
5
|
CONCLUSIONS
In summa y, ou s udy, in keeping wi h p e ious da a,
sugges s a dele e ious e ec o he exposu e o ai pollu -
an s on blood lipids, in he gene al popula ion o Spain.
Ou esul s ein o ce he need o imp o ing ai quali y as
much as possible o dec ease he isk o a he oscle osis in
ou popula ion, as he lipid changes obse ed in ou s udy
may be a po en ial con ibu o o ai pollu ion- ela ed
CVD isk.
AUTHOR CONTRIBUTIONS
Concep ion and design: G.R.M and J.R. Acquisi ion o
epidemiological da a: C.M.A., E.G.E., S.G.S., A.C.P.,
L.C., E.D., E.M., J.F.N., S.G., J.G., F.J.C., S.V. and G.R.M.
anda d biochemical samples managemen : W.O.B. and
G.R.M. Liposcale® samples managemen and analyses:
J.R., N.A. and M.G. Ai pollu ion modelling: M.G.V.,
J.L.G., M.T., V.G. and F.M.L. C ea ion o new so wa e
used in he wo k: J.L.G.G and G.A.V. Analysis and in e -
p e a ion o da a: S.V. J.C.V. and G.R.M. D a ing he a -
icle: S.V., V.K.D.G. and G.R.M. All au ho s e ised and
app o ed he inal manusc ip .
ACKNO WLE DGE MENTS
The [email p o ec ed] p ojec is a collabo a i e s udy wi h a ious
phases and sub- p ojec s in which a la ge numbe o esea ch-
e s and echnicians ha e collabo a ed, o whom we a e in-
deb ed. Ou p o ound app ecia ion goes o he p ima y ca e
manage s and pe sonnel o he pa icipa ing heal h cen es,
o all he ieldwo ke s, nu ses and echnicians and o he
s udy pa icipan s o hei al uis ic pa icipa ion.
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