rs7566605 — INSIG2

INSIG2 and the Lipogenesis Brake: Why One Variant Quietly Redirects Fat Storage

Every time you eat, your body must decide how much cholesterol and fat to synthesize versus burn. That decision runs through a molecular checkpoint in the endoplasmic reticulum controlled by a family of proteins called Insigs. INSIG2 — insulin-induced gene 2 — is a membrane sensor that binds SCAP¹¹ SCAP
Sterol Cleavage-Activating Protein, the escort molecule for SREBP transcription factors when sterol levels are adequate, physically preventing SREBP transcription factors from reaching the Golgi for activation. When INSIG2 function is reduced or its expression changes, the brake weakens: SREBP enters the nucleus, and genes for cholesterol synthesis, fatty acid synthesis, and triglyceride assembly are upregulated. A common variant ~10 kb upstream of the INSIG2 transcription start site — rs7566605 — was the first genome-wide association study hit for body mass index²² first genome-wide association study hit for body mass index
Published in Science, April 2006, analyzing 86,604 SNPs in the Framingham Heart Study offspring cohort, predating the now-famous FTO GWAS discovery by a year.

The Mechanism

INSIG2 is an endoplasmic reticulum-resident protein that functions as a sterol sensor³³ sterol sensor
Activated by oxysterols and cholesterol to suppress lipid synthesis when levels are high. When intracellular sterol levels are adequate, INSIG2 binds SCAP and sequesters it in the ER, preventing SCAP from escorting the SREBP-SCAP complex to the Golgi. Without Golgi processing, SREBP is not cleaved into its active nuclear form — and without activated SREBP, transcription of genes encoding HMG-CoA reductase, fatty acid synthase, and other lipogenic enzymes is suppressed. Insig proteins also promote sterol-accelerated degradation of HMG-CoA reductase⁴⁴ sterol-accelerated degradation of HMG-CoA reductase
The rate-limiting enzyme in the mevalonate pathway for cholesterol synthesis, providing a second layer of lipogenesis control.

rs7566605 sits approximately 10 kb upstream of the INSIG2 transcription start site and is classified as an intron variant relative to a neighboring non-coding RNA (LOC107985940). Its exact molecular effect on INSIG2 expression has not been characterized in functional reporter studies, but the upstream location and consistent association with adiposity suggest it acts as a regulatory element⁵⁵ regulatory element
Likely affects INSIG2 promoter activity or enhancer function, modulating expression levels rather than protein structure. The CC genotype is hypothesized to reduce INSIG2 expression, weakening the brake on SREBP activity and increasing lipogenic gene transcription — particularly in adipose tissue and liver.

The Evidence

The original 2006 GWAS⁶⁶ original 2006 GWAS
Herbert et al., Science 312:279-283, PMID 16614226 analyzed 86,604 SNPs in 923 Framingham offspring and identified rs7566605 CC homozygosity as associated with obesity (OR 1.22 combined across five replication cohorts, p = 5×10⁻⁶). The CC genotype — present in approximately 10% of individuals — was the original signal. Subsequent replication has been inconsistent: a 2007 PLoS Genetics study⁷⁷ 2007 PLoS Genetics study
Lyon & Hirschhorn et al., analyzing ~17,000 individuals across nine cohorts found significant effects in five cohorts but not three others, and concluded that the effect is real but heterogeneous across populations.

The largest synthesis — a 2009 meta-analysis of 74,345 individuals across 34 studies⁸⁸ 2009 meta-analysis of 74,345 individuals across 34 studies
Loos et al., including 27 Caucasian adult cohorts — found no overall association with common obesity (OR 1.05, p=0.27), but detected a significant effect for extreme obesity (BMI ≥40 vs. <25: OR 1.27, p=0.003) and a nominal effect in general population studies (OR 1.10, p=0.015). A key insight from this meta-analysis: study design strongly influenced results, and family-based designs consistently showed stronger effects than population-based ones.

A critical piece of the puzzle came from a 2014 longitudinal analysis⁹⁹ 2014 longitudinal analysis
Cornes et al., European Journal of Human Genetics, in 6,926 participants from three cohorts followed for up to 31 years showing that rs7566605 CC carriers accumulate approximately 1.86 kg/m² excess BMI over 62 years — the variant's effect is age-dependent, with CC homozygotes diverging progressively from GG individuals starting in their 30s. This age interaction explains much of the prior non-replication: cross-sectional studies in young adults would underestimate the effect that only becomes apparent longitudinally.

Beyond BMI, the CC genotype was found to associate with greater baseline subcutaneous fat¹⁰¹⁰ greater baseline subcutaneous fat
In young adult women aged 18-40, p=0.0011, controlling for total body fat in women, and with a blunted fat-loss response to resistance training in men. In the Diabetes Prevention Program¹¹¹¹ Diabetes Prevention Program
3,234 participants with impaired glucose tolerance randomized to lifestyle intervention, metformin, or placebo, CC homozygotes lost approximately 1.7 kg more weight with intensive lifestyle intervention than G allele carriers — suggesting their higher baseline fat stores respond better to structured lifestyle change.

Practical Implications

The INSIG2 rs7566605 finding underscores a key principle in nutritional genetics: variants affecting lipogenesis regulation produce their strongest effects in environments with excess lipogenic substrate — namely, diets high in total fat and refined carbohydrates. The gene-diet interaction framework predicts that CC carriers who consume moderate rather than high dietary fat intakes may partially blunt the variant's effect on fat accumulation. Dietary patterns that reduce SREBP activation (lower saturated fat, lower refined carbohydrate) are mechanistically aligned with compensating for reduced INSIG2 braking activity.

The age-progressive nature of the BMI effect means young CC carriers may have little current phenotype but face increasing divergence from the population mean through midlife — making early dietary and lifestyle habits disproportionately important.

Interactions

rs7566605 shows documented interaction with MC4R rs2229616: in a longitudinal analysis, MC4R heterozygotes who also carry at least one INSIG2 C allele show a protective BMI effect three times larger than the MC4R main effect alone (−1.26 kg/m², p=0.009), compared to INSIG2 GG individuals. This suggests MC4R-driven appetite suppression may be particularly effective at counteracting INSIG2-mediated lipogenic tendency. If a user carries both INSIG2 CC/CG and MC4R rs2229616 variant genotypes, this interaction is worth noting — the MC4R variant may offer greater-than-expected protection.

The combined effect of INSIG2 CC and FTO AA genotypes was found to produce the lowest degree of overweight reduction in a lifestyle intervention in obese children, suggesting convergent pro-adipogenic signaling when both variants co-occur.