Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization.
Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.
Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
Caren E
CE
Smith
Department of Computer Languages and Systems, School of Technology and Experimental Sciences. University Jaume I, Castellón, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
Oscar
O
Coltell
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, Spain.
Jose V
JV
Sorlí
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Department of Internal Medicine, Hospital Clinic, IDIBAPS, Barcelona, Spain.
Ramón
R
Estruch
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Department of Preventive Medicine and Public Health, University of Navarra-Navarra Institute for Health Research (IdisNa), Pamplona, Navarra, Spain.
Miguel Ángel
MÁ
Martínez-González
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Human Nutrition Unit, Biochemistry and Biotechnology Department, IISPV, University Rovira i Virgili, Reus, Spain.
Jordi
J
Salas-Salvadó
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Cardiovascular Epidemiology Unit, Municipal Institut for Medical Research (IMIM), Barcelona, Spain.
Montserrat
M
Fitó
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Department of Cardiology, Hospital Txagorritxu, Vitoria, Spain.
Fernando
F
Arós
Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
Hassan S
HS
Dashti
Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
Chao Q
CQ
Lai
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Department of Family Medicine, Research Unit. Distrito Sanitario Atención Primaria Sevilla, Spain.
Leticia
L
Miró
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Lluís
L
Serra-Majem
Department of Epidemiology, School of Medicine, University of Malaga, Malaga, Spain.
Enrique
E
Gómez-Gracia
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Palma Institute of Health Research (IdISPa). Hospital Son Espases. Palma de Mallorca, Spain.
Miquel
M
Fiol
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Lipid Clinic, Endocrinology and Nutrition Service, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain.
Emilio
E
Ros
Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, Alabama, USA.
Stella
S
Aslibekyan
Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, Alabama, USA.
Bertha
B
Hidalgo
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Marian L
ML
Neuhouser
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Chongzhi
C
Di
Department of Clinical Laboratory &Nutritional Sciences, University of Massachusetts Lowell, Massachusetts, USA.
Katherine L
KL
Tucker
Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, Alabama, USA.
Donna K
DK
Arnett
Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.|Department of Epidemiology and Population Genetics, Centro Nacional Investigación Cardiovasculares (CNIC), Madrid, Spain.|Instituto Madrileño de Estudios Avanzados en Alimentación, Madrid, Spain.
José M
JM
Ordovás
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.|Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, Spain.
Dolores
D
Corella
D000368:Aged; D000483:Alleles; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000401:mortality; D038441:Diet, Mediterranean; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D019083:Mediterranean Region; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D008892:Milk; D064151:Minichromosome Maintenance Complex Component 6 / Q000235:genetics*; D012737:Sex Factors; D014481:United States
D005819:Genetic Markers; C103258:MCM6 protein, human; D064151:Minichromosome Maintenance Complex Component 6