Genetic variations in magnesium-related ion channels may affect diabetes risk among African American and Hispanic American women.
BACKGROUND
Prospective studies consistently link low magnesium intake to higher type 2 diabetes (T2D) risk.


OBJECTIVE
We examined the association of common genetic variants [single nucleotide polymorphisms (SNPs)] in genes related to magnesium homeostasis with T2D risk and potential interactions with magnesium intake.


METHODS
Using the Women's Health Initiative-SNP Health Association Resource (WHI-SHARe) study, we identified 17 magnesium-related ion channel genes (583 SNPs) and examined their associations with T2D risk in 7287 African-American (AA; n = 1949 T2D cases) and 3285 Hispanic-American (HA; n = 611 T2D cases) postmenopausal women. We performed both single- and multiple-locus haplotype analyses.


RESULTS
Among AA women, carriers of each additional copy of SNP rs6584273 in cyclin mediator 1 (CNNM1) had 16% lower T2D risk [OR: 0.84; false discovery rate (FDR)-adjusted P = 0.02]. Among HA women, several variants were significantly associated with T2D risk, including rs10861279 in solute carrier family 41 (anion exchanger), member 2 (SLC41A2) (OR: 0.54; FDR-adjusted P = 0.04), rs7174119 in nonimprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) (OR: 1.27; FDR-adjusted P = 0.04), and 2 SNPs in mitochondrial RNA splicing 2 (MRS2) (rs7738943: OR = 1.55, FDR-adjusted P = 0.01; rs1056285: OR = 1.48, FDR-adjusted P = 0.02). Even with the most conservative Bonferroni adjustment, two 2-SNP-haplotypes in SLC41A2 and MRS2 region were significantly associated with T2D risk (rs12582312-rs10861279: P = 0.0006; rs1056285-rs7738943: P = 0.002). Among women with magnesium intake in the lowest 30% (AA: ≤0.164 g/d; HA: ≤0.185 g/d), 4 SNP signals were strengthened [rs11590362 in claudin 19 (CLDN19), rs823154 in SLC41A1, rs5929706 and rs5930817 in membra; HA: ≥0.313 g/d), rs6584273 in CNNM1 (OR: 0.71; FDR-adjusted P = 0.04) and rs1800467 in potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) (OR: 2.50; FDR-adjusted P = 0.01) were significantly associated with T2D risk.


CONCLUSIONS
Our findings suggest important associations between genetic variations in magnesium-related ion channel genes and T2D risk in AA and HA women that vary by amount of magnesium intake.
Department of Epidemiology, and Departments of.
Kei Hang K
KH
Chan
Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA;
Sara A
SA
Chacko
Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN; Departments of.
Yiqing
Y
Song
Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA;
Michele
M
Cho
Family Medicine, Epidemiology, and Center for Primary Care and Prevention, Memorial Hospital of Rhode Island, Pawtucket, RI;
Charles B
CB
Eaton
Medicine, Warren Alpert Medical School, Brown University, Providence, RI; Vascular Research Laboratory, Providence US Department of Veterans Affairs Medical Center, Providence, RI; and.
Wen-Chih H
WC
Wu
Department of Epidemiology, and Departments of Medicine, Warren Alpert Medical School, Brown University, Providence, RI; Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; Division of Endocrinology, Rhode Island Hospital, Providence, RI simin_liu@brown.edu.
Simin
S
Liu
D001741:Black or African American / Q000235:genetics*; D000368:Aged; D015992:Body Mass Index; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics; D057167:Claudins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D019587:Dietary Supplements; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D016015:Logistic Models; D008274:Magnesium / Q000008:administration & dosage* / Q000097:blood; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors; D000099161:Kcnj11 Channel
D027682:Cation Transport Proteins; D057167:Claudins; D007473:Ion Channels; D008274:Magnesium; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C508912:CLDN19 protein, human; C476304:SLC41A1 protein, human
diabetes; genes; ion channel; magnesium intake; women