From the AGA Journals

Mitochondrial DNA variant increases gallstone risk

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Gallstone disease is multifactorial

Cholesterol gallstone disease results from imbalances in cholesterol metabolism. Other than the well-known lifestyle risk factors, there is also a strong genetic predisposition to gallstone formation. This study by Sun and colleagues examined the possible association between mitochondrial DNA (mtDNA) variants and cholesterol gallstone development because of the importance of the mitochondria in cellular metabolism and the increased maternal transmission of gallstone disease.

Xiao Zhao, MD, is an assistant professor of medicine at Columbia University, New York. She reports having no conflicts of interest.

Dr. Xiao Zhao

The investigators compared sequencing data obtained from 104 patients with gallstones versus 300 controls in the Chinese population and identified 827A>G in the mitochondrial 12S ribosomal RNA as the most likely disease conferring variant. In order to functionally validate this polymorphism, the investigators generated cybrid cell lines. They found that, compared with the 827A cybrids, the 827G cybrids exhibited diminished mitochondrial function and increased production of reactive oxygen species. Moreover, there was activation of mitochondrial-nuclear signaling pathways in the 827G cybrids that increased the expression of the lithogenic genes ABCG5/8, which mediate hepatobiliary cholesterol export, especially in gallstone promoting conditions.

This study highlighted gallstone disease as a multifactorial condition that results from complex interaction between genetic and environmental factors. Interestingly, the allele frequency of the 827A>G mtDNA variant was noted to be higher in Native Americans, which may partially explain the high prevalence of gallstones in this population. Further studies are needed to identify additional genetic risk factors in ethnic groups that also have a significant burden of cholelithiasis.

Xiao Zhao, MD, is an assistant professor of medicine of division of digestive diseases in the department of medicine at Columbia University, New York. She reported having no conflicts of interest.



A mitochondrial DNA variant may increase the risk of gallstone disease more than fourfold, according to investigators.

Mitochondria - microbiology, cellular organelle 3d illustration wir0man/GettyImages

Mitochondrial DNA 827A>G disrupts mitochondrial function and leads to abnormal cholesterol transport, which increases gallstone development, reported Dayan Sun, of Fudan University, Shanghai, China, and colleagues.

The investigators noted that the findings add support to a genetic role in gallstone development, which could allow for identification of at-risk individuals and implementation of preventive measures.

“The etiology of gallstone disease is multifactorial; age, sex, pregnancy, diet (macronutrients, alcohol, and coffee), and other factors are involved,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Moreover, the significant familial predisposition and ethnic differences in prevalence of this disease indicate the potential influences of genetic factors.”

In 2002, Nakeeb and colleagues reported that at least 30% of gallstone disease cases stemmed from genetic factors. And genetics may play an even greater role in certain populations, such as Native Americans, among whom more than 70% of women have gallstone disease, based on a study by Everhart and colleagues.

According to Ms. Sun and colleagues, a variety of genetic drivers of gallstone disease have been identified, such as ABCG8, identified as the most common genetic risk factor by at least one study, along with a list of other rare mutations, such as one affecting CFTR that leads to altered bile composition.

Based on previous research that linked mitochondrial DNA variants with metabolic defects and, more specifically, aberrations in lipid metabolism, as well as an observed “maternal bias in the maternal transmission of gallstone disease” that suggest mitochondrial influence, the investigators looked for patterns specifically in mitochondrial DNA variants among patients with gallstones.

The study enrolled 104 probands with confirmed gallstone disease and 300 unrelated controls. After collecting DNA samples from all participants, the investigators sequenced mitochondrial DNA HVS1 regions. A comparison of haplogroups showed that B4b’d’e’j was more common among patients with gallstone disease than among controls (odds ratio, 4.428; P = .00012), and further analysis pinpointed 827A>G, a variant in 12S ribosomal RNA.

“During the evolutionary history of modern humans, haplogroup B4 might have originated in East Asia approximately 40,000 years ago,” the investigators wrote, noting that B2, a subhaplogroup of B4, “was a founder haplogroup and expanded in the Americas after the Last Glacial Maximum (approximately 20,000 years ago).”

According to the investigators, this may explain why Native Americans have a higher prevalence of gallstones than East Asians (14%-35% vs. 3%-12%) because they are more often carriers of B4 (14%-44% vs. 2%-8%).

The investigators sought to characterize the impact that the 827A>G variant has on mitochondrial function and found effects ranging from lower respiratory chain complex activity, diminished mitochondrial function, activated mitochondrial protein quality control and retrograde signaling pathways, abnormal lipid metabolism, and abnormal cholesterol transport processes.

For example, the investigators investigated respiratory chain complex activity by creating two sister branch haplogroup cell models, including six cybrids for 827A and six more for 827G, which is how they detected the lower activity. Another step the investigators took was corroborating this finding by detecting OXPHOS function in the 827A and 827G cybrids to determine mitochondrial function.

“In summary, our study demonstrates a potential link between mitochondrial DNA 827A>G and gallstone disease,” the investigators wrote. “Our findings provide a significant biological basis for the clinical diagnosis and prevention of gallstone disease in the future.”

The study was funded by the National Natural Science Foundation of China, the 111 Project, the Shanghai Municipal Science and Technology Major Project, the Scientific and Technology Committee of Shanghai Municipality, and the CAMS Innovation Fund for Medical Sciences. The investigators reported no conflicts of interest.

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