Magnesium, Genetic Risk, and Risk Factors for Diabetes and Heart Disease.
Magnesium (Mg) is a vital but chronically under-consumed nutrient and low intake has
been linked to type 2 diabetes (T2D) and cardiovascular disease (CVD). Recent, novel
genetic findings related to fasting glucose (FG) and insulin (FI) have pointed to a
diverse set of single nucleotide polymorphisms (SNPs) that elevate risk of disordered
glycemic homeostasis or Mg status. ... read moreThe extent to which genetic variation affects Mg's
associations with these traits is largely unknown. Further, Mg's long-term associations
with progression of metabolic impairment (i.e., prediabetes or insulin resistance (IR))
merits further investigation. Meanwhile, arterial calcification--the "hardening" of the
arteries--has been quantified in the last decade via computed tomography (CT) in the
coronary arteries (CAC) and abdominal aorta (AAC), and experimental evidence points to a
protective benefit of Mg in arterial health. IR and T2D are significant risk factors for
calcification, and these disorders as well as CAC and AAC elevate risk of CVD morbidity
and mortality. Aims: The aims of this dissertation included analyses of: Aim 1:
interactions between Mg intake and SNPs related to elevated FG and FI, and lower serum
Mg, on FG and FI concentrations; Aim 2: Mg intake and risk of incident prediabetes/IR in
those with normal glycemic status, and risk of progressing to T2D in those with
prediabetes/IR; and Aim 3: cross-sectional associations of Mg intake with CAC and AAC.
Methods: Aim 1: 15 studies from the Cohorts for Heart and Aging Research in Genomic
Epidemiology Consortium provided data from up to 52,684 participants of European descent
without diabetes. In fixed-effect meta-analyses, quantified were (1) associations of
dietary Mg with FG and FI, and (2) interactions between Mg and SNPs related to FG (16
SNPs), FI (2 SNPs), or serum Mg (8 SNPs) on FG and FI. Aim 2: relative risks of
developing prediabetes/IR among those normal at baseline, and developing T2D in those
impaired at baseline, were estimated over 7 years of follow-up in 2,576 participants of
the Framingham Heart Study (FHS). Aim 3: cross-sectional associations of Mg intake on
CAC and AAC were assessed in 2,695 individuals free of CVD who participated in the FHS
CT sub-study using CT-based calcium measures. Results: Aim 1: after adjustment for age,
sex, energy intake, body mass index (BMI), and behavioral risk factors, Mg (per 50 mg/d)
was inversely associated with FG (-0.0091 mmol/L, P<0.0001) and FI (-0.0204
ln-pmol/L, P<0.0001). No Mg-related SNP or interaction between any SNP and Mg reached
statistical significance after correction for multiple testing. However, rs2274924 in
TRPM6 (encoding an Mg transporter) showed nominal association (uncorrected P=0.03) with
FG, and 2 other SNPs showed nominal interaction (uncorrected both P=0.02) with Mg on FG.
Aim 2: after adjustment for age, sex, and energy intake, normal individuals in the
highest category of Mg intake had 37% lower risk of developing prediabetes/IR (P
trend=0.02), and impaired individuals had 32% lower risk of developing T2D (P trend =
0.05), compared to those with in the lowest category. Aim 3: after adjustment for age,
BMI, major CVD risk factors and treatment for CVD risk factors, as well as intakes of
calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy, higher Mg intake
(per 50 mg/d) was associated with 22% lower CAC (P<0.001) and non-significantly with
12% lower AAC (P=0.07). Compared to those with the lowest Mg intake, those with the
highest intake also had lower odds of having any CAC or AAC. Stronger inverse
associations were observed in women than in men. Summary and Conclusion: Consistent with
other studies, higher Mg intake was associated with lower FG and FI, generally
irrespective of genetic risk for elevated concentrations of these traits. Further,
higher Mg intake was associated not only with lower risk of developing metabolic
disorders, but also with lower risk of progressing to T2D from disordered states.
Finally, higher Mg intake was inversely associated with CAC and AAC. This research
provides epidemiologic evidence that increasing intake of Mg--a low-cost, widely
available nutrient--may improve health by reducing the burden of arterial calcification
and disordered glucose and insulin metabolism, and subsequently reduce risk of T2D and
CVD morbidity and mortality.
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Nutritional Epidemiology.
Advisor: Nicola McKeown.
Committee: Paul Jacques, Christopher O'Donnell, and James Meigs.
Keywords: Nutrition, Epidemiology, and Medicine.read less