ARTICLES. The potential role of biotin as dietary risk marker for hypertension in black South African children the THUSA BANA study

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1 The potentil role of iotin s dietry risk mrker for hypertension in lck South Africn children the THUSA BANA study A E Schutte, J M vn Rooyen, H W Huismn, H S Kruger, N T Mln Ojective. To determine whether iotin intke might contriute to the etiology of hypertension in lck children. Design. Cross-sectionl study. Setting. North West province, South Afric. Sujects. Children etween 10 nd 15 yers of ge were recruited from ech of 30 schools over period of 2 yers ( ). These children comprised 321 oys nd 373 girls from communities rnging from rurl to urnised. The hypertensive group included 40 oys nd 79 girls with highnorml to hypertensive lood pressure. The normotensive group consisted of 281 oys nd 294 girls. Min outcome mesures. Dietry intke, crdiovsculr prmeters. Results. Biotin intke in ll groups ws elow the dequte intke level of 20 µg/d. In the stepwise regression nlysis iotin ws significntly ssocited (p 0.05) with systolic nd distolic lood pressure long with rteril complince nd stroke volume of the hypertensive group. No significnt ssocitions were indicted for the normotensive group. Conclusions. This study is the first to show tht iotin might e possile risk mrker for the etiology of hypertension in lck children. Since dietry hits re potentilly modifile, the mnipultion of diet could hve significnt impct not only on lood pressure levels, ut lso on rise in lood pressure with ge. This mens tht there is need for further reserch concerning the effect of iotin on dults. 144 Smoking, oesity, hypertension nd physicl inctivity hve een identified s mjor risk fctors for crdiovsculr disese. However, recent scientific investigtions hve exmined dditionl fctors contriuting to development of this disese. 1 Diet hs een implicted s one of mny fctors influencing lood pressure (BP), 2 nd hypertension is n importnt risk fctor for crdiovsculr disese nd stroke. Biotin is wter-solule vitmin nd its richest dietry sources include liver, kidneys, hert, pncres, poultry, egg yolk nd milk. 3 Most iotin in mets nd cerels ppers to e protein-ound. However, the solute content of even the richest iotin sources is low when compred with the sources of most other wter-solule vitmins. 4 Biotin is lso synthesised y the microflor in the colon. Free iotin is sored in the proximl smll intestine y mens of oth fcilitted nd simple diffusion. Biotin cn lso e sored from the colon, which fcilittes the utilistion of the vitmin produced y hind gut microflor. 5 Despite incresing interest in iotin nutriture, considerle sic informtion on iotin iovilility nd nutritionl sttus remins unknown. 6 School of Physiology, Nutrition nd Consumer Science, Potchefstroom University, North West A E Schutte, PhD J M vn Rooyen, DSc H W Huismn, PhD H S Kruger, PhD N T Mln, DSc Both mrginl nd frnk iotin deficiencies occur rrely. 1,4,6 The only well-documented cses hve occurred in ssocition with totl or ner-totl intrvenous feeding without iotin supplementtion, chronic egg white feeding, or inorn errors of metolism tht led to iotin wsting. 7 A single cse tht does not fit ny of the three estlished ssocitions is tht of n infnt fed rice-sed formul tht ws presumly very low in iotin. 8 According to Mock, 9 however, reduced iotin sttus my e rre. Aprt from the ovementioned cses, iotin deficiency cn occur in ptients receiving long-term therpy with certin nticonvulsnts, 10,11 in children with severe protein energy mlnutrition 12 nd in sustntil proportion of pregnnt women with otherwise norml pregnncies. 9,13 Specultion tht the humn iotin requirement cn e produced y gut microflor 14 contrdicts report descriing n infnt who developed iotin deficiency while consuming iotin-free, elementl formul. 8 Humn iotin requirements in specific popultions nd t vrious ges remin uncertin nd scientific knowledge is insufficient to provide estimted verge requirements (EARs) nd recommended dietry llownces (RDAs), in prt ecuse indictors of iotin sttus hve not een vlidted. 4,9 Considerle sic informtion concerning iotin vilility nd nutritionl sttus lso remins unknown. 6 In cses such s this, dequte intkes (AIs) re provided. 15 Like RDAs, AIs re gols for the nutrient intke of individuls. The AI of iotin

2 rnges from 20 µg (in 9-13-yer-olds) to 30 µg (in persons older thn 19 yers). 16 In nimls iotin functions s moile croxyl crrier in four croxylses: pyruvte croxylse, cetyl-coa croxylse, propionyl-coa croxylse, nd 3-methylcrotonyl-CoA croxylse. These roles link iotin to the metolic roles of folic cid, pntothenic cid, nd vitmin B According to Ho nd Cordin 1 there my e sustntil link etween cerel grin intkes nd crdiovsculr diseses stemming from oth iotin nd essentil ftty cid insufficiencies. The urgent need for further reserch concerning the potentil role of iotin insufficiency s crdiovsculr risk fctor serves s motivtion for this study. Hypertension is common in the lck popultion of Afric. 17 Studies in South Afric hve shown tht 25% of dult Zulu spekers in Durn 18 nd % of pprently helthy Tswn-speking people in the North West were hypertensive. 19 By using rteril complince, pulse pressure nd totl peripherl resistnce in ddition to crdiovsculr prmeters such s systolic BP (SBP) nd distolic BP (DBP), comprehensive study of the crdiovsculr effects of iotin cn e performed. Vsculr complince is defined s the chnge in volume of the rtery per unit of pressure ( V/ P) 20 nd cn lso e estimted esily from the simpler pproch to stroke volume divided y pulse pressure. 21 As rteril complince decreses there is rise in SBP nd fll in DBP. 22 This indictes pulse pressure mplifictions. An increse in pulse pressure, cused y lrge rtery stiffening, is n independent crdiovsculr risk fctor. 23 Dietry fctors relted to crdiovsculr helth of lck children my e prticulrly importnt in this regrd ecuse BP levels hve een seen to trck from childhood to dulthood, 24,25 which mens tht high BP levels in childhood my led to hypertension in dulthood. It is lso known tht micronutrient deficiencies in prticulr re present in lck children in South Afric. 26 The THUSA BANA study (Trnsition nd Helth during Urnistion in South Afric, Bn = children) ws designed to ssess the reltionship etween the level of urnistion nd the helth sttus of children in the North West province of South Afric. The im of this prt of the study ws to determine whether iotin might contriute to the etiology of hypertension in lck children. Methods Study design Thirty schools were rndomly selected from list of schools in five regions in North West. These schools were visited during the weeks preceding the collection of dt, in order to otin permission from the relevnt school principls s well s from the prents of the children. Children t the vrious schools were rndomly selected from clss lists. Dt collection took plce during norml school hours. Sujects Children etween 10 nd 15 yers of ge were recruited from ech of the 30 schools over period of 2 yers ( ). These children comprised 321 oys nd 373 girls from communities rnging from rurl to urnised. The hypertensive group consisted of 40 oys nd 79 girls with highnorml to hypertensive BP. Hypertension in children is defined s n verge SBP or DBP greter thn or equl to the 90th percentile for ge nd sex. 27 Height percentiles were lso tken into considertion since ody size is the most importnt determinnt of BP in childhood nd dolescence. 27 The normotensive group consisted of 281 mle nd 294 femle sujects with BP lower thn the 90th percentile for ge nd sex (Tle I). The Ethics Committee of the University of Potchefstroom pproved the study, nd ll the prents of the sujects gve informed consent. Dt collection nd mesurements The sujects were ll introduced to the experimentl setup, fter which ech individul ws seprtely sujected to the following procedures. Crdiovsculr prmeters The sujects were connected to Finpres (finger-rteril pressure) pprtus 28,29 nd BP ws recorded continuously. After period of rest of t lest 10 minutes, resting BP vlues were otined. BP ws regrded s resting when the SBP did not chnge y more thn 10 mmhg during the lst minute of this period, otherwise the resting period ws extended. The resting BP ws then recorded continuously for 1 minute. The dt were stored on mgnetic tpe using Kyow RTP-50A four-chnnel dt recorder nd digitised for further nlysis y mens of the Fst Modelflo softwre progrm. 30 In this wy the SBP nd DBP, stroke volume (SV), pulse pressure (PP), totl peripherl resistnce (TPR) nd rteril complince (C) were otined. Dietry intke Dietry intke dt were collected y fieldworkers trined y registered dieticins. A 24-hour dietry recll ws collected fce-to-fce nd the dt collection interview method nd nutrient coding were the sme for ll reclls. Food models nd photo ooks for portion-size estimtes were used for the reclls. This type of dietry ssessment is widely used in interntionl epidemiologicl studies Mcronutrients 145 SAJCN

3 Tle I. Chrcteristics of sujects: ge, crdiovsculr prmeters nd dietry intkes Vrile N Normotensive* N Hypertensive Boys Age (yers) ± ± 1.5 SBP (mmhg) ± ± 11 DBP (mmhg) ± ± 8 C (ml/mmhg) ± ± 0.31 PP (mmhg) ± ± 11.3 TPR (mmhg.s/ml) ± ± 1.4 SV (ml) ± ± 11.3 Biotin intke (µg/d) ± ± 12.0 Totl protein (g/d) ± ± 25.9 Plnt protein (g/d) ± ± 15.8 Girls Age (yers) ± ± 1.9 SBP (mmhg) ± ± 9 DBP (mmhg) ± ± 8 C (ml/mmhg) ± ± 0.38 PP (mmhg) ± ± 9.1 TPR (mmhg.s/ml) ± ± 0.8 SV (ml) ± ± 14.5 Biotin intke (µg/d) ± ± 13.4 Totl protein (g/d) ± ± 23.0 Plnt protein (g/d) ± ± 13.3 *Normotensive defined y lood pressure lower thn the 90th percentile. Adjusted for ge, sex nd height. Hypertensive defined y lood pressure in the upper 10th percentile. Adjusted for ge, sex nd height. p 0.05 p Vlues re men ± stndrd devitions. N = numer of sujects; SBP = systolic lood pressure; DBP = distolic lood pressure; C = rteril complince; PP = pulse pressure; TPR = totl peripherl resistnce; SV = stroke volume. 146 (protein, ft, nd crohydrte), fire, minerls (such s clcium, mgnesium, sodium, potssium, nd phosphorus), vitmins (such s A, B 6, B 12, C, D, E, nd iotin) nd cholesterol were clculted in the pproprite units, using the FoodFinder computer progrm sed on the South Africn food composition tles. 34 Sttisticl nlysis All processed dt were trnsferred to Excel nd sttisticlly nlysed using the STATISTICA softwre computer pckge. 35 Owing to skewed distriutions ll dietry vriles were logrithmiclly trnsformed. Multivrite nlyses nd forwrd stepwise regression nlyses were used to ssess the ssocition etween SBP, DBP, SV, PP nd C s dependent vriles nd the following (log-trnsformed) independent vriles: dietry mcronutrients (totl protein, plnt protein, niml protein, totl ft, sturted ft, monounsturted ft, polyunsturted ft, totl crohydrtes, dded sugr, energy), dietry fire, dietry cholesterol, dietry minerls (clcium, mgnesium, potssium, sodium, zinc, iron, phosphorus, copper) nd dietry vitmins (vitmin A, thimine, rioflvin, nicotinic cid, iotin, pntothenic cid, vitmin B 6, folic cid, vitmin B 12, scoric cid, nd vitmin E). Stepwise regression nlyses were done to determine the most significnt (p 0.05) determinnts of SBP, DBP, SV, TPR, PP nd C in the four suject groups, nmely normotensive oys, hypertensive oys, normotensive girls nd hypertensive girls. Independent t-tests were used to determine if significnt differences existed etween the suject groups. Results The ge, crdiovsculr chrcteristics of prticipnts t seline nd dietry intke vlues for iotin nd totl protein for the four suject groups re shown in Tle I. As would e expected, the hypertensive nd normotensive mle groups showed significnt differences etween SBP (p 0.001), DBP (p 0.001), PP (p 0.05) nd TPR (p 0.5). The hypertensive nd normotensive femle groups showed significnt differences etween SBP (p 0.001), DBP (p 0.001), C (p 0.05) nd PP (p 0.05). Biotin intke nd protein intke showed no significnt differences etween the groups. The iotin intke for ll the groups ws well elow the AI level of 20 µg/d prescried for children ged 9-13 yers. 16 The protein intke,

4 however, ws higher thn the RDA vlues of g/d for children ged yers. 36 In the stepwise regression model (Tle II), with SBP, DBP, SV, C, PP nd TPR s the dependent vriles nd ll the dietry fctors used s independent vriles, iotin (β = 0.44) together with folic cid (β = 0.35), mgnesium (β = 0.43) nd dded sugr (β = 0.29) ccounted for 27.5% of the vrince in SBP (R 2 = 0.275) in hypertensive oys. Biotin (β = 0.79) together with pntothenic cid (β = 0.53), dded sugr (β = 0.24), zinc (β = 0.40) nd energy (β = 0.27) explined 28.9% of the vrince in DBP in hypertensive oys. Biotin (β = 0.31) with vitmin E (β = 0.18), nicotinic cid (β = 0.30), crohydrtes (β = 0.46), clcium (β = 0.33) nd mngnese (β = 0.21) ccounted for 34.4% of the vrince in C of hypertensive oys nd iotin ws the only independent vrile tht showed significnt (p 0.05) reltionship with C. In hypertensive girls iotin (β = 0.24) together with vitmin A (β = 0.28), energy (β = 0.44), iron (β = 0.58) nd folic cid (β = 0.30) ccounted for 22.3% of the vrince in DBP. No significnt dietry mrkers were indicted for either of the normotensive groups. Discussion The effects of comintion of dietry fctors on BP hve recently een recognised s importnt. This suject requires urgent ttention. 32 To determine the effects of iotin on the crdiovsculr prmeters, it ws necessry to include ll the other dietry fctors for the regression nlysis to e vlid, since the impct of n individul nutrient on BP is modified y the intke of other nutrients. 33 The dtset on the iotin content of foods in the South Africn Food Composition Tles is not complete. 34 However, the vlues of ll of the richest sources of iotin re included nd the food sources with sent vlues were those not normlly ingested y children in these prts of South Afric, for exmple gots milk, cheese, rost duck, venison, rye red nd some redy-to-et rekfst cerels. There were, however, lso missing dt for some chicken dishes nd soup powder. In these cses other food codes were used. A totl of 89 children (12.8%) te chicken dishes, which my hve cused n underestimtion of the children s iotin intke y 3 µg/100 g intke. Only 4 children (0.005%) te the soup powder dishes which might hve cused n underestimtion of their iotin intke of 0.01 µg/100 g. Becuse reduced lood concentrtions of iotin hve een oserved in children with severe protein energy mlnutrition, 12 it ws necessry to determine the protein intke of the sujects. According to the results in Tle I none of the groups showed indequte protein intke, ut deficient iotin intkes were oserved in ll the groups. In our sujects out hlf the totl protein intke ws from plnt sources (Tle I), which my lck essentil mino cids. 26 Biotin showed strong positive ssocitions with SBP, DBP, SV nd C, especilly in the hypertensive mle group, ut no significnt differences were indicted etween the iotin intkes of the normotensive nd hypertensive groups. This might e explined y genetic predisposition in the hypertensive group, ut since informtion on the determinnts of iotin remins unknown, 6 the origin for the positive reltionships in hypertensives is uncler. The positive ssocition of iotin with oth C nd SV is reflected in the eqution: C = SV/PP. 21 Biotin ws the only dietry fctor positively ssocited with rteril complince nd it seems tht iotin intke could possily ply preventive role in the etiology of hypertension in lck children. Low iotin intkes were oserved in oth the normotensive nd hypertensive groups, ut iotin only showed strong reltionship with crdiovsculr prmeters in the hypertensive group. A suoptiml iotin sttus might ccelerte or initite the development of hypertension in person who is predisposed to e hypertensive. The physiologicl mening of the positive reltionship etween BP nd iotin intke my e explined y the following mechnism. Tle II. Stepwise regression of SBP, DBP, SV, C, PP nd TPR s dependent vriles with ll dietry fctors s independent vriles, ut only iotin results re indicted. Regression coefficients et (β) nd level of significnce, p, re shown SBP DBP SV C PP TPR Boys Normotensive NS NS NS NS NS NS Hypertensive β = 0.44, β = 0.79, β = 0.30 β = 0.31 NS NS p = p = p = 0.04 p = Girls Normotensive NS NS NS NS NS NS Hypertensive NS β = 0.24, NS NS NS NS p = 0.02 NS = indictes not significnt (p > 0.05). Biotin intke is regrded s significnt mrker when p SBP = systolic lood pressure; DBP = distolic lood pressure; SV = stroke volume; C = rteril complince; PP = pulse pressure; TPR = totl peripherl resistnce. 147 SAJCN

5 148 A specific threshold for iotin intke is proposed nd could cuse n inversion of the crdiovsculr effect of iotin. This mens tht insufficient intke of iotin could cuse n increse in crdiovsculr risk for hypertension. Owing to the coenzymtic ctivity of iotin in the holocroxylse complexes, insufficient mounts of exogenous iotin could ffect elongtion nd desturtion of essentil ftty cids, contriuting to endothelil cell dysfunction. 1 A grdul increse in iotin intke could therefore result in higher risk until threshold vlue is reched. From this point, which could lso e sufficient iotin intke, the crdiovsculr risk could e lowered. Conclusion This study is the first to show tht iotin might e regrded s possile risk mrker for the etiology of hypertension in lck children. Despite the indequte iotin intkes of the children in this study, results indicted positive ssocition etween iotin intke nd crdiovsculr prmeters for hypertensive lck children. Diets, however, re mde up of multiple nutrients, nd one needs to tke into ccount comintions of nutrients to estimte the effects of dietry ptterns. Since dietry hits re potentilly modifile, the mnipultion of diet could hve significnt impct not only on BP levels, ut lso on the rise in BP with ge. This mens tht there is need for further reserch concerning the effect of iotin on dults. A diet rich in fruits, vegetles, nd non-ft dietry foods, nd low in sturted ft nd totl ft is proposed. Such diet will hve iotin content of out µg per dy. According to the DASH (Dietry Approches to Stop Hypertension) study such diet will decrese SBP nd it would e effective in the prevention nd control of high BP. 37 This study ws mde possile y grnts from the South Africn Sugr Assocition, the Medicl Reserch Council of South Afric, the Potchefstroom University for Christin Higher Eduction, the Hypertension Society of South Afric nd the Deprtment of Trde nd Industry through the Technology nd Humn Resources for Industry Progrmme (THRIP) system. The uthors re grteful to Professor H S Steyn for sttisticl consulttion. References 1. Ho RC, Cordin L. The potentil role of iotin insufficiency on essentil ftty cid metolism nd crdiovsculr disese risk. Nutr Res 2000; 20: Ntionl Reserch Council (NRC). Hypertension. In: Diet nd Helth. Implictions For Reducing Chronic Disese Risk. Wshington, DC: Ntionl Acdemy Press, 1989: Livniou E, Costopoulou D, Vssilidou I, et l. Anlyticl techniques for determining iotin. J Chromtogr A 2000; 881: Zempleni J, Mock DM. 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6 CONTINUING PROFESSIONAL DEVELOPMENT ACTIVITY FOR DIETITIANS SAJCN CPD ctivity No 24 Decemer 2003 You cn otin 3 CPD points for reding the rticle: "The potentil role of iotin s dietry risk mrker for hypertension in lck South Africn children: the Thus Bn study" nd nswering the ccompnying questions. This rticle hs een ccredited for CPD points for dietitins. (Ref numer: DT 04/3/001/12) HOW TO EARN YOUR CPD POINTS 1. Check your nme nd HPCSA numer. 2. Red the rticle nd nswer ll the questions. 3. Indicte your nswers to the questions y coloring the pproprite lock(s) in the cut-out section t the end of this questionnire. 4. You will ern 3 CPD points if you nswer more thn 75% of the questions correctly. If you score etween 60-75% 2 points will e llocted. A score of less thn 60% will not ern you ny CPD points. 5. Mke photocopy for your own records in cse your form is lost in the mil. 6. Send the cut-out nswer form y mil, NOT BY FAX to: SASPEN Secretrit, SAJCN CPD ctivity No 24, c/o Deprtment of Humn Nutrition, PO Box 19063, Tygererg, 7505 to rech the office not lter thn 5 Mrch Answer sheets received fter this dte will not e processed. 1. This study is the first to show tht might e regrded s possile risk mrker for the development of hypertension in lck children. [] iotin [] iotin nd proteins [c] proteins 2. There my e sustntil link etween cerel grin intkes nd crdiovsculr disese stemming from dietry indequcies of oth iotin nd. [] essentil mino cid [] essentil ftty cid [c] crohydrte 3. The mjority of iotin in mets nd cerels ppers to e: [] crohydrte ound [] ft ound [c] protein ound 4. Biotin is lso synthesised y the: [] microflor in the colon [] enzymes in the smll intestine [c] microflor in the smll intestine PLEASE ANSWER ALL THE QUESTIONS (There is only ONE correct nswer per question) 7. is the most importnt determinnt of lood pressure in childhood nd dolescence. [] Age [] Diet [c] Body size 8. Biotin intke of hypertensive children differed significntly from normotensive children. 9. In the stepwise regression model, iotin, together with folic cid, mgnesium nd dded sugr ccounted for 27.5% of the vrince in systolic lood pressure of normotensive mles. 10. The following dietry mrkers were significntly ssocited with crdiovsculr prmeters for the normotensive groups: [] iotin [] iotin, mgnesium, folic cid nd dded sugr [c] iotin, pntothenic cid, dded sugr, zinc nd energy [d] none of the ove 5. Dietry fctors relted to crdiovsculr helth of lck children my e prticulrly importnt ecuse lood pressure levels hve een seen to trck from childhood to dulthood. 6. The sujects of the study consisted of lck children etween the ges of: [] 5 nd 10 yers. [] 10 nd 15 yers. [c] 15 nd 18 yers. 11. Neither the mle nor femle hypertensive groups showed ny differences from the mle or femle normotensive groups regrding iotin intke. 12. Biotin nd protein intke were the only dietry fctors tht were positively ssocited with rteril complince. Cut long the dotted lines nd send to: SASPEN Secretrit, SAJCN CPD ctivity No 24, c/o Deprtment of Humn Nutrition, PO Box 19063, Tygererg, 7505 to rech the office not lter thn 5 Mrch 2004 HPCSA numer: DT Surnme s registered with HPCSA: Initils: Postl ddress: Code: Full memer of ADSA: yes no If yes, which rnch do you elong to? Full memer of SASPEN: yes no Full memer of NSSA: yes no "The potentil role of iotin s dietry risk mrker for hypertension in lck South Africn children: the Thus Bn study" AE Schutte, JM vn Rooyen, HW Huismn, HS Kruger, NT Mln Plese color the pproprite lock for ech question (e.g. if the nswer to question 1 is : 1) ) 149 1) c 2) c 3) c 4) 5) 6) c 7) c 8) 9) 10) 11) 12) c d c