Advanced

Genetic Determinants of Obesity in Relation to Diet, Weight Gain and Mortality

Rukh, Gull LU (2016) In Lund University Faculty of Medicine Doctoral Dissertation Series 2016:43.
Abstract (Swedish)
Popular Abstract in Swedish

Fetma är ett världsomfattande hälsoproblem som drabbar rika och fattiga länder i samma utsträckning och leder till minskad förväntad livslängd. Detta är inte bara ett problem i sig utan för med sig ytterligare följdsjukdomar så som diabetes, hjärt- kärlsjukdomar, vissa former av cancer och artros. Det är en allmän uppfattning att den oroväckande ökningen av fetma under de två senaste decennierna beror på ohälsosamma matvanor och fysisk inaktivitet, men trots samma levnadssätt drabbas inte alla av fetma. Studier i familjer och tvillingar visar att 40-70% av fetman förklaras av genetiska faktorer. De hittills identifierade genetiska varianterna förklarar dock enbart en liten del av den sammanlagda... (More)
Popular Abstract in Swedish

Fetma är ett världsomfattande hälsoproblem som drabbar rika och fattiga länder i samma utsträckning och leder till minskad förväntad livslängd. Detta är inte bara ett problem i sig utan för med sig ytterligare följdsjukdomar så som diabetes, hjärt- kärlsjukdomar, vissa former av cancer och artros. Det är en allmän uppfattning att den oroväckande ökningen av fetma under de två senaste decennierna beror på ohälsosamma matvanor och fysisk inaktivitet, men trots samma levnadssätt drabbas inte alla av fetma. Studier i familjer och tvillingar visar att 40-70% av fetman förklaras av genetiska faktorer. De hittills identifierade genetiska varianterna förklarar dock enbart en liten del av den sammanlagda genetiska risken. Den individuella risken att utveckla fetma beror således på både gener och miljön och möjliga interaktioner mellan dessa. I nuläget finns inte tillräckligt starka bevis för att kunna ge tydliga rekommendationer syftande till att förebygga fetma och visar att stora studier med tydliga sjukdomsdefinitioner behövs.

Att studera interaktioner mellan gener och miljö kan hjälpa till att identifiera grupper av människor där man kan skräddarsy förebyggande och behandling av fetma baserat på individens genetiska profil. I avhandlingen fokuserade vi på genetiska varianter med koppling till BMI och studerade dessa både individuellt och tillsammans i så kallad genetisk riskberäkning (GRS). GRS byggs upp genom att summera antal riskvarianter hos varje individ till ett individuellt score. Vi undersökte om matvanor kan förändra den sammanlagda genetiska risken för fetma. Vi utvärderade också huruvida den genetiska riskscoren påverkade viktuppgång vid olika tidpunkter i livet. Slutligen studerade vi om det finns ett orsakssamband mellan kardiometabola egenskaper och mortalitet, genom att använda en så kallad Mendeliansk randomiseringsmetod. Vi använde oss av data från två olika befolkningsbaserade prospektiva studier, MDCS som består av ca.30 000 individer från södra Sverige och GLACIER som består av ca.19 000 individer från norra Sverige.

I studie I såg vi att energigivande näringsämnen, fibrer och sammantaget energiintag inte påverkar styrkan i kopplingen mellan genetiska riskfaktorer och högre BMI och fetma. Å andra sidan observerade vi att vissa individuella genetiska varianter kan ha en effekt på mat- och energiintag och att effekten av vissa genetiska markörer kan förändras genom kosten. I studie II kunde vi se att individer som har en hög genetisk risk för fetma och dessutom konsumerar stora mängder av socker-sötade drycker hade högre BMI. I studie III, studerade vi genen för enzymet amylas som förekommer i saliv (AMY1) i förhållande till mängd stärkelse i kosten och fetma. Genen förekommer i flera kopior i vår arvsmassa och antalet kopior varierar mellan individer. Vi kunde konstatera att kvinnor med färre kopior av genen AMY1 hade högre BMI om deras kost innehöll lite stärkelse och vice versa, vilket tyder på att mängden stärkelse i kosten kan påverka den genetiska risken för fetma hos kvinnor. I studie IV kunde vi se att individer med högre genetisk risk för fetma ökar mer i vikt i tidig vuxenålder men därefter är förhållandet det motsatta. I studie V, observerade vi ett orsakssamband mellan HDL-kolesterol (”det goda kolesterolet”), triglycerider (en särskild typ av blodfetter) och mortalitet. Individer med högre genetisk risk för höga triglyceridnivåer och låga HDL-kolesterolnivåer har högre risk att dö i förtid, speciellt av hjärt-kärlsjukdomar.

Sammanfattningsvis så visar våra resultat att även om vi inte kan ändra våra gener så kan vi ändra deras effekt med våra livsstilsval. Genom att t.ex. minska konsumtion av sötade drycker kan man minska risken för fetma även hos individer med hög genetisk risk. Våra resultat tyder på att effekten av våra gener förändras under vår livstid och livsstilsanpassnig kan därför krävas. Speciellt individer med hög genetisk risk för fetma bör undvika stor viktuppgång tidigt i vuxenlivet för att inte drabbas av negativa konsekvenser senare i livet. Våra resultat pekar också på ett orsakssamband mellan högre nivåer av triglycerider, lägre nivåer av HDL-kolesterol och högre risk för ökad dödlighet, vilket kan hjälpa att utveckla nya behandlingsmetoder i kliniken. (Less)
Abstract
Obesity is one of the major health concerns that has reached epidemic proportions globally. It is generally believed to be a result of interactions between genetic and environmental factors. In this thesis we investigated the role of dietary factors in modifying the genetic susceptibility to obesity (papers I to III), studied the association between genetic susceptibility to obesity and weight gain at different time-points in life (paper IV) and tried to dissect the causality between cardiometabolic traits and mortality (paper V). The work in this thesis was conducted using data from the population based prospective Malmö Diet and Cancer Study (MDCS; N= ~30,000) and the Gene-Lifestyle interactions And Complex traits Involved in Elevated... (More)
Obesity is one of the major health concerns that has reached epidemic proportions globally. It is generally believed to be a result of interactions between genetic and environmental factors. In this thesis we investigated the role of dietary factors in modifying the genetic susceptibility to obesity (papers I to III), studied the association between genetic susceptibility to obesity and weight gain at different time-points in life (paper IV) and tried to dissect the causality between cardiometabolic traits and mortality (paper V). The work in this thesis was conducted using data from the population based prospective Malmö Diet and Cancer Study (MDCS; N= ~30,000) and the Gene-Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER; N= ~5000) cohorts. In paper I, we did not observe any evidence for macronutrient, fiber or total energy intake in modifying the genetic susceptibility to obesity when genetic susceptibility was represented as a Genetic Risk Score (GRS) based upon 13 BMI associated genetic variants. In individual SNP analyses, after correcting for multiple comparisons, some of the individual obesity loci such as NEGR1 rs2815752 associated with fat, carbohydrate and fiber intakes (P≤1x10-4 for all) and BDNF rs4923461 interacted with protein intake on BMI (Pinteraction=0.001). In paper II, pooled analyses of MDCS and GLACIER suggested 0.16 (SE=0.04) kg/m2 increase in BMI (P=8x10-5) in the lowest quartile of GRS (comprised of 30 BMI-associated genetic variants) for each increment in category of sugar-sweetened beverages (SSB) intake vs. 0.24 (SE=0.04) kg/m2 higher BMI in the highest GRS quartile (P=1x10-7). We also observed evidence for the role of SSB intake in modifying the genetic susceptibility to obesity (Pinteraction=0.049). In paper III, a copy number variant (CNV) in the salivary amylase gene (AMY1) did not associate with obesity traits neither in men nor in women (P>0.05 for all). However, upon stratification by dietary starch intake, BMI decreased with increasing AMY1 CNV in low starch intake group (P=0.035) and increased with increasing AMY1 CNV in the high starch intake group (P=0.04) among females. These results suggest a putative role of starch intake in modifying the association between AMY1 CNV and obesity in women (Pinteraction=0.041). In paper IV, a GRS based on 31 BMI-associated genetic variants was associated with increased annual weight change (β=0.003 kg; SE=0.01; P=7x10-8) and increased odds for substantial weight gain (OR=1.01; 95% CI= 1.00-1.02; P=0.013) per risk allele from young to middle age in MDCS. However, the GRS was associated with decreased annual weight change (β=-0.005 kg; SE=0.002; P=0.002) and decreased risk for substantial weight gain (OR=0.97; 95% CI= 0.96-0.99; P=0.001) per risk allele during and after middle-age in the pooled analyses of MDCS and GLACIER. These results suggest a paradoxical inversed relationship between genetic susceptibility to obesity and weight gain during and after middle age compared to increased weight gain in younger age. In paper V, observations from multivariable Mendelian randomization analyses suggest a direct causal association of TG (P=0.017 and P=0.028) and an inverse association of HDLC (P=0.049 and P=0.005) with total- and cardiovascular mortality, respectively. In conclusion, the results from this thesis suggest a role of specific dietary factors in modifying the genetic susceptibility to obesity and that genetic variation affect weight gain differently at different time-points in life but the underlying mechanisms need to be further understood. Additionally,our findings points towards causal associations between TG and HDLC and mortality which can help to devise better treatment strategies in clinical practice. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Assistant Professor Jensen, Majken Karoline, Harvard T.H. Chan School of Public Health, Harvard university, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
genetic variants, copy number variants, genetic risk score, BMI, gene-diet interactions, annual weight change, substantial weight gain, sugar-sweetened beverages, mortality, Mendelian randomization
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2016:43
pages
121 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Kvinnokliniken's Aula, 3rd Floor, Jan Waldenströms gata 47, Skåne university Hospital, Malmö
defense date
2016-04-15 09:00
ISSN
1652-8220
ISBN
978-91-7619-269-6
language
English
LU publication?
yes
id
1f8a8140-785b-4840-9d35-d98f139b8323 (old id 8862108)
date added to LUP
2016-03-22 11:52:57
date last changed
2016-09-19 08:44:51
@phdthesis{1f8a8140-785b-4840-9d35-d98f139b8323,
  abstract     = {Obesity is one of the major health concerns that has reached epidemic proportions globally. It is generally believed to be a result of interactions between genetic and environmental factors. In this thesis we investigated the role of dietary factors in modifying the genetic susceptibility to obesity (papers I to III), studied the association between genetic susceptibility to obesity and weight gain at different time-points in life (paper IV) and tried to dissect the causality between cardiometabolic traits and mortality (paper V). The work in this thesis was conducted using data from the population based prospective Malmö Diet and Cancer Study (MDCS; N= ~30,000) and the Gene-Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER; N= ~5000) cohorts. In paper I, we did not observe any evidence for macronutrient, fiber or total energy intake in modifying the genetic susceptibility to obesity when genetic susceptibility was represented as a Genetic Risk Score (GRS) based upon 13 BMI associated genetic variants. In individual SNP analyses, after correcting for multiple comparisons, some of the individual obesity loci such as NEGR1 rs2815752 associated with fat, carbohydrate and fiber intakes (P≤1x10-4 for all) and BDNF rs4923461 interacted with protein intake on BMI (Pinteraction=0.001). In paper II, pooled analyses of MDCS and GLACIER suggested 0.16 (SE=0.04) kg/m2 increase in BMI (P=8x10-5) in the lowest quartile of GRS (comprised of 30 BMI-associated genetic variants) for each increment in category of sugar-sweetened beverages (SSB) intake vs. 0.24 (SE=0.04) kg/m2 higher BMI in the highest GRS quartile (P=1x10-7). We also observed evidence for the role of SSB intake in modifying the genetic susceptibility to obesity (Pinteraction=0.049). In paper III, a copy number variant (CNV) in the salivary amylase gene (AMY1) did not associate with obesity traits neither in men nor in women (P>0.05 for all). However, upon stratification by dietary starch intake, BMI decreased with increasing AMY1 CNV in low starch intake group (P=0.035) and increased with increasing AMY1 CNV in the high starch intake group (P=0.04) among females. These results suggest a putative role of starch intake in modifying the association between AMY1 CNV and obesity in women (Pinteraction=0.041). In paper IV, a GRS based on 31 BMI-associated genetic variants was associated with increased annual weight change (β=0.003 kg; SE=0.01; P=7x10-8) and increased odds for substantial weight gain (OR=1.01; 95% CI= 1.00-1.02; P=0.013) per risk allele from young to middle age in MDCS. However, the GRS was associated with decreased annual weight change (β=-0.005 kg; SE=0.002; P=0.002) and decreased risk for substantial weight gain (OR=0.97; 95% CI= 0.96-0.99; P=0.001) per risk allele during and after middle-age in the pooled analyses of MDCS and GLACIER. These results suggest a paradoxical inversed relationship between genetic susceptibility to obesity and weight gain during and after middle age compared to increased weight gain in younger age. In paper V, observations from multivariable Mendelian randomization analyses suggest a direct causal association of TG (P=0.017 and P=0.028) and an inverse association of HDLC (P=0.049 and P=0.005) with total- and cardiovascular mortality, respectively. In conclusion, the results from this thesis suggest a role of specific dietary factors in modifying the genetic susceptibility to obesity and that genetic variation affect weight gain differently at different time-points in life but the underlying mechanisms need to be further understood. Additionally,our findings points towards causal associations between TG and HDLC and mortality which can help to devise better treatment strategies in clinical practice.},
  author       = {Rukh, Gull},
  isbn         = {978-91-7619-269-6},
  issn         = {1652-8220},
  keyword      = {genetic variants,copy number variants,genetic risk score,BMI,gene-diet interactions,annual weight change,substantial weight gain,sugar-sweetened beverages,mortality,Mendelian randomization},
  language     = {eng},
  pages        = {121},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Genetic Determinants of Obesity in Relation to Diet, Weight Gain and Mortality},
  volume       = {2016:43},
  year         = {2016},
}