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A Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A With Implications for Glycemic Status in U.S. Hispanics/Latinos.

TitleA Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A With Implications for Glycemic Status in U.S. Hispanics/Latinos.
Publication TypePublication
Year2019
AuthorsMoon J-Y, Louie TL, Jain D, Sofer T, Schurmann C, Below JE, Lai C-Q, M Avilés-Santa L, Talavera GA, Smith CE, Petty LE, Bottinger EP, Chen Y-DIda, Taylor KD, Daviglus ML, Cai J, Wang T, Tucker KL, Ordovás JM, Hanis CL, Loos RJF, Schneiderman N, Rotter JI, Kaplan RC, Qi Q
JournalDiabetes Care
Volume42
Issue9
Pagination1784-1791
Date Published2019 09
ISSN1935-5548
KeywordsAdult, Alleles, Blood Glucose, Diabetes Mellitus, Fasting, Female, Genetic Variation, genome-wide association study, Glucose Tolerance Test, Glycated Hemoglobin A, Hematologic Diseases, Hispanic Americans, Humans, Hyperglycemia, Male, Middle Aged, Phenotype, Prediabetic State, Prevalence, United States
Abstract

OBJECTIVE: We aimed to identify hemoglobin A (HbA)-associated genetic variants and examine their implications for glycemic status evaluated by HbA in U.S. Hispanics/Latinos with diverse genetic ancestries.RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) of HbA in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies.RESULTS: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA at genome-wide significance levels ( < 5.0 × 10). In particular, two African ancestry-specific variants, rs334 and -rs1050828, which are causal mutations for sickle cell disease and deficiency, respectively, had ∼10 times larger effect sizes on HbA levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, -rs145546625, was associated with HbA and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of rs334 or -rs1050828 HbA-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, < 0.001). After recalibration of the HbA level taking -rs334 and -rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, = 0.28).CONCLUSIONS: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA test is performed.

DOI10.2337/dc19-0168
Alternate JournalDiabetes Care
PubMed ID31213470
PubMed Central IDPMC6702612
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
R01 DK120870 / DK / NIDDK NIH HHS / United States
R01 DK119268 / DK / NIDDK NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
R01 HL102830 / HL / NHLBI NIH HHS / United States
R01 DK073541 / DK / NIDDK NIH HHS / United States
R01 HL140976 / HL / NHLBI NIH HHS / United States
R01 AI085014 / AI / NIAID NIH HHS / United States
R01 HL060712 / HL / NHLBI NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States
P60 DK020595 / DK / NIDDK NIH HHS / United States
U01 DK085501 / DK / NIDDK NIH HHS / United States
P50 HL105185 / HL / NHLBI NIH HHS / United States
P01 AG023394 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
K01 HL129892 / HL / NHLBI NIH HHS / United States
P30 DK111022 / DK / NIDDK NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
U54 TR000123 / TR / NCATS NIH HHS / United States
MS#: 
0323B
Manuscript Lead/Corresponding Author Affiliation: 
Field Center: Bronx (Einstein College of Medicine)
ECI: 
Yes
Manuscript Status: 
Published