What you carry at this position in your DNA and what research says about it.
Metabolic Health: 9/10 evidence, 47 publications.
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Sample genotype (not yours): C/C
Higher Body Fat but Lower Metabolic Risk
This profile links to a higher body mass index but a healthier metabolic distribution of fat. It helps maintain lower triglyceride levels and a lower risk of metabolic syndrome.
What this genotype means: Favorable body fat distribution; Lower risk of metabolic syndrome; Slightly higher risk of osteoarthritis.
Sample genotype (not yours): A/A
Lower Body Fat but Higher Metabolic Risk
This profile links to a lower body mass index but a less favorable, abdominal-heavy fat distribution. It is associated with higher triglycerides and metabolic syndrome risk.
What this genotype means: Abdominal-heavy fat distribution; Higher risk of metabolic syndrome; Lower risk of osteoarthritis.
Sample genotype (not yours): C/A
Typical Body Fat and Metabolic Profile
This intermediate profile is associated with average body mass index, typical fat distribution, and standard cardiovascular and metabolic risks.
What this genotype means: Typical body fat distribution; Average risk of metabolic syndrome; Standard risk of osteoarthritis.
Gene function and biological role
Gene Function: The POLR1C gene encodes a core subunit shared by RNA polymerases I and III, which are essential enzymes responsible for synthesizing ribosomal and transfer RNAs [1]. While fundamental to basic cellular transcription, genetic variation in this genomic region is strongly linked to systemic metabolic regulation and fat storage patterns [2]. Researchers have identified that variants near this locus can uncouple body mass index from its typical cardiovascular and metabolic complications [3]. This means the gene plays a role in determining whether excess energy is stored safely in subcutaneous fat tissue or ectopically in organs like the liver [4].
Variant Impact: The rs998584 variant is an intronic change located within the POLR1C gene, situated close to the VEGFA gene on chromosome 6. This genetic marker acts as a major regulator of body fat distribution and lipid metabolism. It influences whether fat is preferentially stored around the abdomen or in the hips and thighs, which has a profound impact on metabolic health. The variant is highly pleiotropic, meaning it simultaneously influences body mass index, circulating triglycerides, and blood sugar markers. Understanding this variant helps explain why some people can have a higher body weight while maintaining healthy blood lipid and insulin profiles.
Key Insight: This variant uncouples body weight from metabolic health, meaning a higher body mass index does not automatically translate to poor cholesterol or high blood sugar.
Location: POLR1C. Chromosome 6 · 6p21.1 · 43.8 Mb
Estimated prevalence by population
Global 36.0%; European 27.0%; African 64.4%; East Asian 20.3%; South Asian 10.6%; Americas 25.1%; Ashkenazi 21.9%; Finnish 24.6%; Middle Eastern 24.7%; Amish 12.4%.
Estimated CC genotype frequency.
Global 44.7%; European 49.9%; African 31.7%; East Asian 49.5%; South Asian 44.0%; Americas 50.0%; Ashkenazi 49.8%; Finnish 50.0%; Middle Eastern 50.0%; Amish 45.6%.
Estimated CA genotype frequency.
Global 19.4%; European 23.1%; African 3.9%; East Asian 30.2%; South Asian 45.4%; Americas 24.9%; Ashkenazi 28.3%; Finnish 25.4%; Middle Eastern 25.3%; Amish 41.9%.
Estimated AA genotype frequency.
Showing effects for C/C genotype
Cardiovascular & Metabolic
Metabolic Syndrome & Insulin Resistance
Metabolic Syndrome. Evidence: 9/10. Source: PMID 31589552. Lower Risk.
Lipids & Cholesterol
Triglycerides. Evidence: 10/10. Source: PMID 24097068. Lower Levels.
Obesity & Body Composition
Waist-to-Hip Ratio. Evidence: 10/10. Source: PMID 25673412. Lower Ratio.
Body Mass Index. Evidence: 10/10. Source: PMID 25673413. Higher BMI.
Body Fat Percentage. Evidence: 9/10. Source: PMID 33619380. Higher Body Fat.
Heart Rhythm & Conduction
Atrial Fibrillation. Evidence: 6/10. Source: PMID 40050429. ~1.06x Risk.
Diabetes & Glycemic Traits
HbA1c. Evidence: 9/10. Source: PMID 34594039. Lower HbA1c.
Organ Systems
Bone, Joint & Connective Tissue Health
Osteoarthritis. Evidence: 8/10. Source: PMID 36889626. ~1.06x Risk.
Showing effects for A/A genotype
Metabolic Syndrome. Evidence: 9/10. Source: PMID 31589552. Higher Risk.
Triglycerides. Evidence: 10/10. Source: PMID 24097068. Higher Levels.
Waist-to-Hip Ratio. Evidence: 10/10. Source: PMID 25673412. Higher Ratio.
Body Mass Index. Evidence: 10/10. Source: PMID 25673413. Lower BMI.
Body Fat Percentage. Evidence: 9/10. Source: PMID 33619380. Lower Body Fat.
Atrial Fibrillation. Evidence: 6/10. Source: PMID 40050429. Lower Risk.
HbA1c. Evidence: 9/10. Source: PMID 34594039. Higher HbA1c.
Osteoarthritis. Evidence: 8/10. Source: PMID 36889626. Lower Risk.
Showing effects for C/A genotype
Metabolic Syndrome. Evidence: 9/10. Source: PMID 31589552. Typical Risk.
Triglycerides. Evidence: 10/10. Source: PMID 24097068. Typical Levels.
Waist-to-Hip Ratio. Evidence: 10/10. Source: PMID 25673412. Typical Ratio.
Body Mass Index. Evidence: 10/10. Source: PMID 25673413. Typical BMI.
Body Fat Percentage. Evidence: 9/10. Source: PMID 33619380. Typical Body Fat.
Atrial Fibrillation. Evidence: 6/10. Source: PMID 40050429. Typical Risk.
HbA1c. Evidence: 9/10. Source: PMID 34594039. Typical HbA1c.
Osteoarthritis. Evidence: 8/10. Source: PMID 36889626. Typical Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Carrying two copies of the C allele is associated with a higher body mass index and an increased body fat percentage [1]. However, this genetic profile also promotes a highly favorable metabolic distribution of that fat, leading to a lower waist-to-hip ratio [2]. Because fat is stored safely in subcutaneous depots rather than around vital organs, circulating triglycerides and VLDL cholesterol levels remain lower [3]. This protective fat-distribution pattern significantly reduces the risk of developing metabolic syndrome and elevated blood sugar [4]. Conversely, the higher overall body weight associated with this genotype is linked to a slightly increased risk of osteoarthritis [5]. There is also a small associated increase in the risk of developing atrial fibrillation [6]. Overall, this profile represents a classic metabolic trade-off where higher adiposity does not translate to typical metabolic harm.
Favorable body fat distribution; Lower risk of metabolic syndrome; Slightly higher risk of osteoarthritis.
Sample genotype: AA (Homozygous)
Carrying two copies of the A allele is associated with a lower body mass index and a lower overall body fat percentage [1]. Despite having less total body fat, this genetic profile predisposes to an unfavorable, abdominal-heavy fat distribution, resulting in a higher waist-to-hip ratio [2]. This pattern of fat storage is linked to ectopic fat accumulation in organs like the liver, which is reflected in higher levels of the liver enzyme aspartate aminotransferase [3]. Consequently, circulating triglycerides and VLDL cholesterol levels are elevated [4]. This metabolic environment increases the risk of developing metabolic syndrome and higher HbA1c levels [5]. On the positive side, the lower overall body mass index associated with this genotype provides a protective effect against osteoarthritis [6]. It is also linked to a slightly lower risk of developing atrial fibrillation [7].
Abdominal-heavy fat distribution; Higher risk of metabolic syndrome; Lower risk of osteoarthritis.
Sample genotype: CA (Heterozygous)
Carrying one copy of each allele results in a balanced, intermediate metabolic and physical profile. Body mass index and overall body fat percentage tend to fall within the typical population average [1]. The distribution of body fat between abdominal and lower-body depots is also balanced, leading to a typical waist-to-hip ratio [2]. Circulating lipid levels, including triglycerides and VLDL cholesterol, generally remain within normal ranges [3]. This intermediate status means there is no genetically elevated risk for metabolic syndrome or high blood sugar markers [4]. Similarly, risks for weight-related joint issues like osteoarthritis and cardiovascular conditions like atrial fibrillation are typical [5] [6]. This genotype represents the most common baseline profile, avoiding both the metabolic risks of one extreme and the joint risks of the other.
Typical body fat distribution; Average risk of metabolic syndrome; Standard risk of osteoarthritis.
Variants with shared genetic architecture
rs1358980 · POLR1C Gene · Chr 6 · Body Fat Distribution
rs6905288 · POLR1C Gene · Chr 6 · Cardiometabolic Health Risk
rs6921438 · POLR1C Gene · Chr 6 · Heart Disease Risk
The Polygenic and Monogenic Basis of Blood Traits and Diseases.
Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities.
Genetic studies of body mass index yield new insights for obesity biology.
New genetic loci link adipose and insulin biology to body fat distribution.
Discovery and refinement of loci associated with lipid levels.
Genome-Wide Association Study of the Metabolic Syndrome in UK Biobank.
Content updated August 2026.
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