rs692383 — ABCG1 ABCG1 HDL-c Variant

ABCG1 rs692383 — Your HDL Response to Calorie Restriction

When you lose weight through a calorie-restricted diet, your HDL-cholesterol levels can shift in complex ways — and your ABCG1 genotype at rs692383 appears to determine how much HDL-c you preserve during that process. ABCG1¹¹ ABCG1
ATP-binding cassette transporter G1, a membrane pump that moves cholesterol and phospholipids from macrophage cell membranes onto mature HDL particles — the second step in reverse cholesterol transport after ABCA1 initiates HDL loading is one of the body's primary cholesterol efflux transporters. Located on chromosome 21q22.3 and expressed in macrophages, liver, and many other tissues, ABCG1 loads surplus cellular cholesterol onto mature HDL particles, funneling it back to the liver — a central step in preventing foam cell accumulation and atherosclerotic plaque formation.

The rs692383 variant is an intronic variant in ABCG1 at chromosome 21, position 42,215,064 (GRCh38). It does not alter the ABCG1 protein sequence but sits within a region where intronic variants can influence gene expression, splicing efficiency, or regulatory element responsiveness to metabolic signals. What distinguishes rs692383 is its documented interaction with calorie-restricted dietary conditions: the G allele at this position is associated with better preservation of HDL-c levels during weight-loss dieting.

The Mechanism

The precise molecular mechanism by which rs692383 modifies ABCG1's response to calorie restriction is not yet established. However, ABCG1 transcription is regulated by liver X receptor (LXR)²² liver X receptor (LXR)
a nuclear receptor activated by oxysterols and dietary lipid signals; once activated, LXR drives expression of ABCG1, ABCA1, and other cholesterol homeostasis genes. During calorie restriction, circulating lipid profiles shift substantially: fatty acid mobilization increases, HDL remodeling accelerates, and ABCG1 activity modulates how efficiently cholesterol is transferred to and from HDL particles.

An intronic variant in this regulatory context could influence how strongly the ABCG1 gene responds to these dietary metabolic signals — for instance, by altering an enhancer element or splice site that controls expression levels under conditions of negative energy balance. AA homozygotes may have a less robust ABCG1 response during calorie restriction, resulting in less efficient cholesterol recycling through HDL and a net decline in circulating HDL-c. G allele carriers appear to maintain ABCG1 efflux activity more effectively under these conditions, preserving HDL-c levels even while losing weight.

The Evidence

The primary evidence comes from a study by Teixeira et al. (2020)³³ study by Teixeira et al. (2020)
Teixeira MD et al. Is it possible ABC transporters genetic variants influence the outcomes of a weight-loss diet in obese women? Genetics and Molecular Biology, 2020 examining 137 obese women following a nine-week calorie-restricted diet (−600 kcal/day). G allele carriers showed a significantly lower reduction in HDL-c compared to AA homozygotes (p=0.043), and this association remained significant after correction for multiple testing in the longitudinal analysis. A secondary finding — association between the AA genotype and lower BMI in the post-diet period — did not survive multiple-testing correction.

The evidence base for rs692383 is currently at the emerging level: a single study with a modest sample size (137 women), focused on one specific context (obese women undergoing calorie restriction), with no independent replication to date. The biological plausibility is solid — ABCG1 is a well-characterized HDL efflux transporter — but the specific effect of rs692383 on HDL-c during dieting requires confirmation in larger and more diverse populations.

The global G allele frequency is approximately 0.46, with substantial population stratification: ~31% in Europeans, ~76% in Africans, and ~46% in East Asians. This variation means the population-level relevance of this finding differs markedly by ancestry.

Practical Actions

For AA homozygotes (~29% of people globally, ~47% of Europeans): calorie-restricted dieting may reduce HDL-c more than expected. This does not mean weight loss should be avoided — the metabolic benefits of appropriate weight management outweigh a modest HDL-c dip in most cases. However, tracking HDL-c before, during, and after a weight-loss intervention gives personalized data on whether this genotype-specific response is occurring. If HDL-c falls substantially during dieting, specific interventions can offset this effect: regular aerobic activity is one of the most potent HDL-raising strategies, EPA/DHA supplementation modestly supports HDL remodeling, and niacin (extended-release) raises HDL-c specifically — though it should only be considered under medical supervision.

For G allele carriers (AG or GG): HDL-c appears more resilient during calorie restriction, which may provide a cardiovascular advantage during weight-loss periods. Standard dietary monitoring is appropriate.

Interactions

ABCG1 at rs692383 is one of three independent ABCG1 variants in this database. The rs4148102 variant modifies LDL-c response to high-PUFA diets, and the rs57137919 promoter variant alters ABCG1 expression in macrophages and is associated with altered HDL-c and LDL-c levels at baseline. Together, these three variants define distinct aspects of ABCG1 biology: promoter regulation, dietary PUFA response, and HDL-c dynamics during calorie restriction. Carrying risk alleles at multiple ABCG1 variants may compound impairment in reverse cholesterol transport, though no study has directly examined the rs692383 × rs4148102 or rs692383 × rs57137919 interaction.