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Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study.

TitleGenetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study.
Publication TypeJournal Article
Year of Publication2015
AuthorsTin A, Köttgen A, Folsom AR, Maruthur NM, Tajuddin SM, Nalls MA, Evans MK, Zonderman AB, Friedrich CA, Boerwinkle E, Coresh JJ
Secondary AuthorsKao W H L
JournalBMC Genet
Volume16
Pagination56
Date Published2015 May 29
ISSN1471-2156
KeywordsAfrican Americans, Atherosclerosis, European Continental Ancestry Group, Female, Gene-Environment Interaction, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin, Magnesium, Male, Middle Aged, Mucin-1, Polymorphism, Single Nucleotide, Progestins, Risk, TRPM Cation Channels
Abstract

BACKGROUND: Low serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression.

RESULTS: The GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta=-0.013, p=6.1x10(-9)). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta=-0.028, p=7.3x10(-5)) than in those without any hormone use (beta=-0.011, p=7.0x10(-8), p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (

CONCLUSIONS: We identified three loci that explained 2.8% of the variance in serum magnesium concentration in ARIC African-American participants. Following-up on functional studies of gene expression identified gene-environment interactions between progestin use and MUC1 and between insulin and TRPM6 on serum magnesium concentration in ARIC European-American participants. These results extend our understanding of the metabolism of serum magnesium.

DOI10.1186/s12863-015-0219-7
Alternate JournalBMC Genet
PubMed ID26058915
PubMed Central IDPMC4462077
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
T32 DK007732 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States