Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program

AbstractHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in patients with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K/FN3KRP in Europeans and G6PD in African-Americans and Hispanics) and discovered a new African-ancestry specific low-frequency variant (rs1039215 in HBG2/HBE1, minor allele frequency (MAF)=0.03). The most associated G6PD variant (p.Val98Met, rs1050828-T, MAF=12% in African-Americans, MAF=2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693 - p.Leu353Pro, MAF=0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African-American cohorts and replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

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A combined polygenic score of 21,293 rare and 22 common variants significantly improves diabetes diagnosis based on hemoglobin A1C levels

10.1101/2021.11.04.21265868 ◽

2021 ◽

Author(s):

Peter Dornbos ◽

Ryan Koesterer ◽

Andrew Ruttenburg ◽

Joanne B Cole ◽

Aaron Leong ◽

...

Keyword(s):

Rare Variant ◽

Genetic Variants ◽

Hemoglobin A1c ◽

Rare Variants ◽

Treatment Strategies ◽

Common Variant ◽

Common Disease ◽

Diabetes Diagnosis ◽

Common Variants ◽

Polygenic Scores

Polygenic scores (PS), constructed from the combined effects of many genetic variants, have been shown to predict risk or treatment strategies for certain common diseases. As most PS to date are based on common variants, the benefit of adding rare variation to PS remains largely unknown and methodically challenging. We developed and validated a novel method for constructing a rare variant PS and applied it to a previously identified clinical scenario, in which genetic variants modify the hemoglobin A1C (HbA1C) threshold recommended for type 2 diabetes (T2D) diagnosis. The resultant rare variant PS is highly polygenic (21,293 variants across 144 genes), depends on ultra-rare variants (72.7% of variants observed in <3 people), and identifies significantly more undiagnosed T2D cases than expected by chance (OR=2.71, p=1.51x10-6). A model combining the rare variant PS with a previously published common variant PS is expected to identify 4.9M misdiagnosed T2D cases in the USA, nearly 1.5-fold more than the common variant PS alone. These results provide a method for constructing complex phenotype PS from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.

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Genetic Variation: Impact on Folate (and Choline) Bioefficacy

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000040 ◽

2010 ◽

Vol 80 (45) ◽

pp. 319-329 ◽

Cited By ~ 9

Author(s):

Allyson A. West ◽

Marie A. Caudill

Keyword(s):

Carbon Metabolism ◽

Genetic Variants ◽

Plasma Homocysteine ◽

Water Soluble ◽

Gene Interactions ◽

Dietary Folate ◽

Methyl Donors ◽

Common Genetic Variants ◽

One Carbon Metabolism ◽

The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

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Common Genetic Variants and Risk of Brain Injury After Preterm Birth

PEDIATRICS ◽

10.1542/peds.2013-3011d ◽

2014 ◽

Vol 133 (6) ◽

pp. X35-X35

Keyword(s):

Preterm Birth ◽

Brain Injury ◽

Genetic Variants ◽

Common Genetic Variants

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Faculty Opinions recommendation of Common genetic variants account for differences in gene expression among ethnic groups.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1066847.519793 ◽

2007 ◽

Author(s):

Karin Schmitt

Keyword(s):

Gene Expression ◽

Ethnic Groups ◽

Genetic Variants ◽

Common Genetic Variants

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Faculty Opinions recommendation of Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717988248.793472522 ◽

2013 ◽

Author(s):

Zhao-Shen Li ◽

Zhuan Liao

Keyword(s):

Genetic Variants ◽

Common Genetic Variants

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Financial Resources and Biomarkers of Aging in the National Health and Aging Trends Study

Innovation in Aging ◽

10.1093/geroni/igaa057.1974 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 589-589

Author(s):

Laura Samuel ◽

Laken Roberts ◽

Danielle Boyce ◽

Melissa Hladek ◽

Sarah LaFave ◽

...

Keyword(s):

Hemoglobin A1c ◽

Income Group ◽

Cross Sectional Study ◽

Financial Strain ◽

Diabetes Diagnosis ◽

Lower Income ◽

Sampling Weights ◽

Cross Sectional ◽

Lower Income Group ◽

Biomarkers Of Aging

Abstract Lower income and financial strain (i.e. difficulty making ends meet) are associated with worse aging biomarkers, but evidence among nationally representative samples is limited. This cross-sectional study tested whether income to poverty ratio (analyzed separately for those <500% vs. ≥500% poverty threshold) and financial strain are associated with biomarkers of aging among NHATS participants aged ≥65 years (n=4,648), adjusting for age, race/ethnicity, gender, smoking, BMI, and diabetes diagnosis for hemoglobin A1c. Sampling weights were applied. Among those with incomes <500% poverty, higher income was associated with lower hemoglobin A1c (b= -0.0196, p=0.007), CMV (b= -0.0689, p<0.001) and CRP (b= -0.0428, p=0.012). Among those with incomes ≥500%, higher income was associated with lower IL-6 (b= -0.0001, p=0.023) and lower CMV (b= -0.0001, p<0.001). Financial strain was not associated with biomarkers. Income is more strongly associated with biomarkers among the lower income group, calling for special attention to this vulnerable population.

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Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins

Scientific Reports ◽

10.1038/s41598-021-86801-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sabrina Samad Shoily ◽

Tamim Ahsan ◽

Kaniz Fatema ◽

Abu Ashfaqur Sajib

Keyword(s):

Diabetes Mellitus ◽

Chronic Kidney Disease ◽

Genetic Variants ◽

Nucleotide Polymorphisms ◽

Differential Distribution ◽

East Asians ◽

Single Nucleotide ◽

Common Genetic Variants ◽

Haplotype Frequencies ◽

Variant Alleles

AbstractDiabetes mellitus is a complex and heterogeneous metabolic disorder which is often pre- or post-existent with complications such as cardiovascular disease, hypertension, inflammation, chronic kidney disease, diabetic retino- and nephropathies. However, the frequencies of these co-morbidities vary among individuals and across populations. It is, therefore, not unlikely that certain genetic variants might commonly contribute to these conditions. Here, we identified four single nucleotide polymorphisms (rs5186, rs1800795, rs1799983 and rs1800629 in AGTR1, IL6, NOS3 and TNFA genes, respectively) to be commonly associated with each of these conditions. We explored their possible interplay in diabetes and associated complications. The variant allele and haplotype frequencies at these polymorphic loci vary among different super-populations (African, European, admixed Americans, South and East Asians). The variant alleles are particularly highly prevalent in different European and admixed American populations. Differential distribution of these variants in different ethnic groups suggests that certain drugs might be more effective in selective populations rather than all. Therefore, population specific genetic architectures should be considered before considering a drug for these conditions.

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