Expressive

rs113812546 (CFTR): Lipids and Acute Pancreatitis

Key takeaways

  • Genetically predicted high triglycerides were associated with increased acute pancreatitis risk (OR 2.02), but pancreatitis did not appear to raise triglycerides in return.
  • HDL cholesterol and acute pancreatitis showed a bidirectional relationship in large-scale genetic analysis, each influencing the other.
  • The ALT allele is linked to increased expression of gene ENSG00000286390 in the hippocampus, amygdala, and spinal cord.
  • Evidence is drawn from a UK Biobank study of over 421,000 participants using bidirectional Mendelian randomization.

Key takeaways

  • Genetically predicted higher triglyceride levels were associated with increased acute pancreatitis risk (odds ratio 2.02), but pancreatitis did not appear to raise triglyceride levels in return.
  • HDL cholesterol and acute pancreatitis showed a bidirectional relationship in genetic analysis, each influencing the other.
  • The ALT allele of this variant is associated with increased expression of gene ENSG00000286390 in multiple brain regions, including the hippocampus and amygdala.
  • Evidence comes from a large bidirectional Mendelian randomization study (n=421,181) and tissue-specific expression data from GTEx.

What the research says A bidirectional Mendelian randomization study (Wang B et al., Scientific Reports 2024) using UK Biobank data with 421,181 participants and 2,281 incident acute pancreatitis cases examined causal relationships between lipid levels and acute pancreatitis. Genetically predicted triglyceride (TG) levels were positively associated with pancreatitis (OR 2.02, 95% CI 1.22-3.31), while the reverse pathway from pancreatitis to TG was not supported (mean difference 0.003, SE 0.002, p=0.138). A bidirectional relationship was observed for HDL cholesterol (HDL-C): a 1-standard-deviation increment in genetically predicted HDL-C was associated with lower pancreatitis risk (OR 0.84, 95% CI 0.76-0.92), and genetically predisposed pancreatitis was associated with 0.005 SD lower HDL-C (mean difference -0.005, SE 0.002, p=0.004).

Reported associations

  • Acute pancreatitis risk (triglycerides): Genetically predicted higher TG levels were associated with increased acute pancreatitis risk in univariable Mendelian randomization (OR 2.02, 95% CI 1.22-3.31).
  • Acute pancreatitis risk (HDL cholesterol): A 1-SD increment in genetically predicted HDL-C was associated with reduced acute pancreatitis risk (OR 0.84, 95% CI 0.76-0.92).
  • HDL cholesterol as a downstream consequence of pancreatitis: Genetic predisposition to acute pancreatitis was associated with 0.005 SD lower HDL-C (p=0.004), suggesting a bidirectional rather than purely one-directional relationship between HDL-C and the condition.

Evidence quality Evidence is drawn from a single bidirectional two-sample Mendelian randomization study (Wang B et al., Scientific Reports 2024) using UK Biobank data with 421,181 participants and 2,281 incident pancreatitis cases followed for a mean of 12.52 years. The study identified seven independent signals in its GWAS meta-analysis of acute pancreatitis and used two non-overlapping GWAS datasets to reduce sample-overlap bias. Effect sizes are notable for the TG association (OR 2.02) but more modest for HDL-C (OR 0.84); the bidirectional HDL-C finding has a small magnitude (0.005 SD) and should be considered preliminary. No conflicting findings were reported within this single study. Independent replication of variant-specific findings is not reported in the provided evidence, warranting caution. GTEx eQTL data (953 donors, FDR<0.05) add tissue-specific expression context, though the functional significance of the observed brain expression changes is not established by the provided study evidence.

Tissue-specific expression effects

  • ENSG00000286390: The ALT allele is associated with increased expression in the spinal cord (cervical c-1), hippocampus, and amygdala, all three showing substantial positive slopes in brain and central nervous system tissue GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Diet

  • Mediterranean-style diet with unsaturated fats Moderate

    Omega-3 and unsaturated fat sources lower triglycerides and raise HDL-C, reducing acute pancreatitis risk in rs113812546 carriers.

    Fish 2-3 times weekly, olive oil, nuts, seeds; limit saturated fat to less than 7 percent daily calories

Exercise

  • Regular aerobic exercise Moderate

    Aerobic activity improves triglyceride and HDL-C levels, reducing acute pancreatitis risk in carriers of this genetic risk variant.

    150 minutes moderate intensity aerobic activity per week

Lifestyle

  • Excessive alcohol consumption Moderate

    Alcohol raises triglycerides and independently increases acute pancreatitis risk; particularly important for rs113812546 carriers with elevated genetic predisposition.

    Limit to 1 drink per day for women, 2 drinks per day for men; abstinence recommended given genetic risk

Screening

  • Lipid panel triglycerides and HDL-cholesterol Moderate

    rs113812546 confers increased acute pancreatitis risk via lipid metabolism pathways; triglycerides and HDL-C are documented causal risk factors for pancreatitis in carriers.

    Baseline measurement; repeat every 2-3 years or annually if abnormality detected

Frequently asked questions

What is the CFTR gene?

CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a gene involved in regulating the movement of salt and fluids in cells. Variants in this gene have been examined in relation to conditions affecting the pancreas, including acute pancreatitis.

Is rs113812546 linked to pancreatitis risk?

This variant sits in the CFTR gene and appears in the context of a Mendelian randomization study that found genetically predicted high triglyceride levels were associated with increased acute pancreatitis risk (OR 2.02). The study identified seven independent signals in a genome-wide meta-analysis of pancreatitis.

What does bidirectional Mendelian randomization mean?

Bidirectional Mendelian randomization is a statistical method that uses genetic variants to test whether two traits influence each other in both directions. It uses the random nature of genetic inheritance to reduce confounding and help separate cause from effect.

What are the brain expression effects associated with rs113812546?

GTEx data shows the ALT allele is associated with increased expression of gene ENSG00000286390 in the hippocampus, amygdala, and spinal cord. These are tissue-specific expression effects and their clinical significance is not established by the available evidence.

How strong is the evidence for rs113812546?

Evidence comes from one large Mendelian randomization study with over 421,000 UK Biobank participants and 2,281 acute pancreatitis cases. While the sample size is substantial, independent replication of findings specific to this variant would strengthen the evidence base.