Gallstone Genes

Gallstones are not something you usually think about — until something goes wrong. And then you think about them a lot! Ouch!

Gallstones:

Your gallbladder is a small organ (~4 inches long) located on the upper right side of your abdomen, behind the liver. It stores bile, which your liver produces to break down fat in the foods you eat.

Gallstones (also called cholelithiasis) are hard ‘stones’ made of hardened bile. The composition of the stones can be either cholesterol or calcium bilirubinate. Cholesterol stones, the most common type, are thought to be formed if there is a lot of cholesterol in the bile. When the bile becomes supersaturated with cholesterol, the cholesterol can no longer be soluble in micelles (think oil droplets in water).[ref]

It is estimated that 10 – 40% of the population has gallstones, which are more common in women than in men. About 700,000 people each year in the US have their gallbladders removed.[ref]  That is a lot of people missing an organ…


Genetic Variants Linked to Gallstones:

Unsurprisingly, the genetic link to gallstones centers around the genes involved in regulating the absorption of cholesterol from plants and the excretion of cholesterol from the body.

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ABCG8 and ABCG5 genes:

The ABCG8 protein combines with ABCG5 protein to make a protein called sterolin. This protein helps transport dietary cholesterol. Plant sterols, which are unusable fatty components from plants, are eliminated by sterolin.

Check your genetic data for rs11887534 (23andMe v4 only):

  • C/C:   up to 7x risk of gallstones, increased cholesterol secretion[ref][ref]
  • C/G:  increased risk of gallstones
  • G/G: typical risk of gallstones.

Members: Your genotype for rs11887534 is .

Check your genetic data for rs6756629 (23andMe v4;AncestryDNA):

  • G/G: typical risk of gallstones
  • A/G: increased risk of gallstones
  • A/A: increased risk of gallstones[ref]

Members: Your genotype for rs6756629 is .

Check your genetic data for rs4299376 (23andMe v4, v5; AncestryDNA):

  • G/G: typical risk of gallstones
  • G/T: increased risk of gallstones (Caucasians)
  • T/T: increased risk of gallstones (Caucasians)[ref]

Members: Your genotype for rs4299376 is .

Check your genetic data for rs4245791 (23andMe v4, v5;AncestryDNA):

  • T/T: typical risk of gallstones
  • C/T: somewhat increased risk of gallstones
  • C/C: increased risk of gallstones[ref]

Members: Your genotype for rs4245791 is .

 

ABCB4 gene:

Check your genetic data for rs2230028 (23andMe v4, v5)

  • T/T: typical risk of gallstones
  • C/T: increased risk of gallstones
  • C/C: increased risk of gallstones[ref]

Members: Your genotype for rs2230028 is .

 


Lifehacks:

Plant Sterols:
Conflicting information exists for plant sterols (from margarine or other foods labeled as containing “cholesterol-lowering plant sterols”), gallstones,  as well as cardiovascular disease. The American Heart Association says plant sterols good for reducing cardiovascular disease. But the ABCG8 variants that increase the risk of gallstones due to increased absorption of sterols also increase the risk of cardiovascular disease.

Related article: Plant sterols and your genes.

Weight loss and alcohol:
Being overweight or obese increases the risk of gallstones, but strangely, high alcohol consumption decreases the risk.[ref]

Weight loss (and perhaps regaining weight) increases the risk of gallstones. One study of men who lost weight and regained it found that multiple rounds of weight loss/gain increased the risk of gallstones by about 50%.[ref]  Rapid weight loss (without regaining) has also increased the risk of gallstones.[ref]

Note: I’m not saying that you should drink a lot and stay overweight because it reduces your risk of gallstones… There are other, really good reasons to cut out the hard drinking and lose a little weight if needed.

Estrogens (natural or environmental):
Environmental factors thought to increase gallstones include estrogens (women have more gallstones), oral contraceptives, and hormone replacement therapy.[ref]

Diabetes and Pre-diabetes:
Insulin resistance and diabetes also increase the risk of gallstones.[ref] Insulin resistance specifically interacts with ABCG8 and ABCG5[ref], so if you carry the risk alleles for those genetic variants, you may want to focus on dietary ways to keep your insulin and glucose levels stable (e.g. stop eating a lot of junk food and drinking a lot of sodas).

Diet:
Studies show that your best bet, dietarily, for preventing gallstones is the usual recommendations of cutting out refined foods and fast food and eating more fruits and vegetables as well as including olive oil in your diet.[ref]

Gallstone problems not taken care of through the surgical removal of the gallbladder are sometimes treated with the prescription medication, ursodeoxycholic acid (UDCA).

TUDCA:
A naturally-occurring bile salt, tauroursodeoxycholic acid (TUDCA), is available as a supplement. Its main use as a supplement is for maintaining a healthy liver, but it has been used, along with a low cholesterol diet, to treat gallstones. Most of the studies on this are 20+ years old since gallbladder surgery is a much more common treatment these days.[ref]  There is a good Examine.com article on TUDCA.


Related Articles and Topics:

LDL Cholesterol Genes
Your genes combine with your diet to influence your LDL cholesterol level. Learn more about why LDL cholesterol levels may matter in heart disease and find out how your genes are important here.

Heart disease, cancer, diabetes: A gene that ties together the “Big 3”
When it comes to chronic diseases, the “Big 3” are heart disease, cancer, and type 2 diabetes. Heart disease is the number one killer in the US, with cancer a close second. Diabetes numbers are increasing at an alarming rate.

Genetics and Type 2 Diabetes
Not all type 2 diabetes risk is from what you eat… Genetics plays a big role in diabetes. Learn more about your genetic susceptibility.

Inflammation: Causes and Natural Solutions
Take a deep dive into the causes of chronic inflammation and learn how to target specific inflammatory pathways to reverse or prevent chronic disease.

References:

Buch, Stephan, et al. “A Genome-Wide Association Scan Identifies the Hepatic Cholesterol Transporter ABCG8 as a Susceptibility Factor for Human Gallstone Disease.” Nature Genetics, vol. 39, no. 8, Aug. 2007, pp. 995–99. PubMed, https://doi.org/10.1038/ng2101.

Di Ciaula, Agostino, et al. “The Role of Diet in the Pathogenesis of Cholesterol Gallstones.” Current Medicinal Chemistry, vol. 26, no. 19, 2019, pp. 3620–38. PubMed, https://doi.org/10.2174/0929867324666170530080636.

Di Ciaula, Agostino, and Piero Portincasa. “Recent Advances in Understanding and Managing Cholesterol Gallstones.” F1000Research, vol. 7, Sept. 2018, p. F1000 Faculty Rev-1529. PubMed Central, https://doi.org/10.12688/f1000research.15505.1.

Frank, Kurtis, et al. Tauroursodeoxycholic Acid Research Analysis. Jan. 2022. examine.com, https://examine.com/supplements/tauroursodeoxycholic-acid/.

Goodloe, Robert, et al. “Lipid Trait-Associated Genetic Variation Is Associated with Gallstone Disease in the Diverse Third National Health and Nutrition Examination Survey (NHANES III).” BMC Medical Genetics, vol. 14, no. 1, Dec. 2013, p. 120. DOI.org (Crossref), https://doi.org/10.1186/1471-2350-14-120.

Joshi, Amit D., et al. “Four Susceptibility Loci for Gallstone Disease Identified in a Meta-Analysis of Genome-Wide Association Studies.” Gastroenterology, vol. 151, no. 2, Aug. 2016, pp. 351-363.e28. PubMed, https://doi.org/10.1053/j.gastro.2016.04.007.

Njeze, Gabriel E. “Gallstones.” Nigerian Journal of Surgery : Official Publication of the Nigerian Surgical Research Society, vol. 19, no. 2, 2013, pp. 49–55. PubMed Central, https://doi.org/10.4103/1117-6806.119236.

Paumgartner, G., et al. “Ursodeoxycholic Acid Treatment of Cholesterol Gallstone Disease.” Scandinavian Journal of Gastroenterology. Supplement, vol. 204, 1994, pp. 27–31. PubMed, https://doi.org/10.3109/00365529409103622.

Rodriguez, Santiago, et al. “Lipids, Obesity and Gallbladder Disease in Women: Insights from Genetic Studies Using the Cardiovascular Gene-Centric 50K SNP Array.” European Journal of Human Genetics, vol. 24, no. 1, Jan. 2016, pp. 106–12. PubMed Central, https://doi.org/10.1038/ejhg.2015.63.

Tsai, Chung-Jyi, et al. “Weight Cycling and Risk of Gallstone Disease in Men.” Archives of Internal Medicine, vol. 166, no. 21, Nov. 2006, pp. 2369–74. Silverchair, https://doi.org/10.1001/archinte.166.21.2369.

Wang, Siqi, et al. “Is the Oral Contraceptive or Hormone Replacement Therapy a Risk Factor for Cholelithiasis: A Systematic Review and Meta-Analysis.” Medicine, vol. 96, no. 14, Apr. 2017, p. e6556. PubMed, https://doi.org/10.1097/MD.0000000000006556.

Zhan, Lei, et al. “Prevalence of ABCB4 Polymorphisms in Gallstone Disease in Han-Chinese Population.” American Journal of Translational Research, vol. 8, no. 2, Feb. 2016, pp. 1218–27. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846965/.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.