Sitosterolaemia in Switzerland: molecular genetics links the US Amish‐Mennonites to their European roots

Solcà, Curzio; Stanga, Zeno; Pandit, Bhaswati; Diem, Peter; Greeve, Jobst; Patel, Shailendra B.

doi:10.1111/j.1399-0004.2005.00472.x

Cited by 15 publications

(8 citation statements)

References 38 publications

(49 reference statements)

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“…The ABCG8 G574R variant present in the Lancaster Amish has been found in contemporary Switzerland. 23 Haplotype analyses have revealed that the initial Amish index cases and the contemporary case identified in Switzerland share a common haplotype, consistent with a common ancestral source for this variant that originated in Switzerland (or before) and was carried to Pennsylvania by ≥1 emigrants in the early 1700s.…”

Section: Discussionmentioning

confidence: 77%

The ABCG8 G574R Variant, Serum Plant Sterol Levels, and Cardiovascular Disease Risk in the Old Order Amish

Horenstein

Mitchell

Post

et al. 2013

ATVB

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Objective To determine whether long-term exposure to moderate elevations in plasma plant sterol levels increases risk for atherosclerosis. Methods and Results In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Carriers of a single 574R allele had increased plant sterol levels (eg, 35%–37% higher plasma levels of sitosterol, campesterol, and stigmasterol) and increased plant sterol/cholesterol ratios (P<0.001 for all). 574R carriers had significantly decreased levels of lathosterol and lanosterol, precursors in a pathway for endogenous cholesterol synthesis, suggesting that plant sterols may alter regulation of genes involved in cholesterol synthesis. The G574R variant was not associated with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol levels. Compared with noncarriers, 574R carriers had decreased carotid intima-media wall thickness (0.62 versus 0.66 mm; age- and sex-adjusted P=0.03). Adjustment for body weight, blood pressure, and standard lipid measures (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) did not alter this association. Conclusion Although the G574R variant is associated with moderately elevated plant sterol levels, carriers of the 574R allele had modestly lower levels of carotid wall thickness compared with noncarriers.

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Section: Discussionmentioning

confidence: 77%

The ABCG8 G574R Variant, Serum Plant Sterol Levels, and Cardiovascular Disease Risk in the Old Order Amish

Horenstein

Mitchell

Post

et al. 2013

ATVB

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“…The presence of the homozygous mutation Gly574Arg in the ABCG8 gene has been found previously in the Amish-Mennonite patients where a founder effect has been reported [73].…”

Section: Phytosterolemia or Sitosterolemia: Abcg5/g8 Mutationsmentioning

confidence: 85%

“…Solcà et al [73] performed an haplotype analyses using microsatellite markers spanning 4.9 cM on chromosome 2 and showed that a patient with sitosterolemia of SwissGerman origin and the two Amish-Mennonite probands were identical for markers D2S2174, D2S1761, D2S4009, D2S4014, D2S4015, and D2S4016 encompassing the STSL locus. Other studies reported the same observations [42], and mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and 2, respectively, are now known to be mutant in sitosterolemia.…”

Section: Phytosterolemia or Sitosterolemia: Abcg5/g8 Mutationsmentioning

confidence: 99%

Phytosterols and phytosterolemia: gene–diet interactions

et al. 2010

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Phytosterol intake is recommended as an adjunctive therapy for hypercholesterolemia, and plant sterols/stanols can reduce cholesterol absorption at the intestinal lumen through the Niemann-Pick C1 Like 1 (NPC1L1) transporter pathway by competitive solubilization in mixed micelles. Phytosterol absorption is of less magnitude than cholesterol and is preferably secreted in the intestinal lumen by ABCG5/G8 transporters. Therefore, plasma levels of plant sterols/stanols are negligible compared with cholesterol, under an ordinary diet. The mechanisms of cholesterol and plant sterols absorption and the whole-body pool of sterols are discussed in this chapter. There is controversy about treatment with statins inducing further increase in plasma non-cholesterol sterols raising concerns about the safety of supplementation of plant sterols to such drugs. In addition, increase in plant sterols has also been reported upon consumption of plant sterolenriched foods, regardless of other treatments. Rare mutations on ABCG5/G8 transporters affecting cholesterol/non-cholesterol extrusion, causing sitosterolemia with xanthomas and premature atheroslerotic disease are now known, and cholesterol/plant sterols absorption inhibitor, ezetimibe, emerges as the drug that reduces phytosterolemia and promotes xanthoma regression. On the other hand, common polymorphisms affecting the NPC1L1 transporter can interfere with the action of ezetimibe. Gene-diet interactions participate in this intricate network modulating the expression of genetic variants on specific phenotypes and can also affect the individual response to the hypolipidemic treatment. These very interesting aspects promoted a great deal of research in the field.

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“…Several mutations have been reported and provide important insights in to the nature of the inheritance. Founder effects for mutations underlie many of the cases, suggesting that this disease has been present for many generations, perhaps more than 4000 years 85 86. Caucasians seem to carry mutations in ABCG8, whereas Chinese, Japanese and Indian (20% of known cases) patients seem to have mutations in ABCG5 5.…”

Section: Genetic Aspects Of Sitosterolaemiamentioning

confidence: 99%

Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis

Kidambi¹,

Patel

2008

J Clin Pathol

101

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Sitosterolaemia is an extremely rare autosomal recessive disease, the key feature of which is the impairment of pathways that normally prevent absorption and retention of non-cholesterol sterols, for example plant sterols and shellfish sterols. The clinical manifestations are akin to familial hypercholesterolaemia (such as presence of tendon xanthomas and premature atherosclerosis), but with "normal to moderately elevated" cholesterol levels. The gene(s) causing sitosterolaemia was mapped to the STSL locus on human chromosome 2p21, and mutations in either of the two genes that comprise this locus, ABCG5 or ABCG8, cause this disease. Exact prevalence is unknown, but there are estimated to be 80-100 cases around the world. This rare disease has shed light into the molecular mechanisms that control sterol trafficking in the enterocyte and hepatocyte; ABCG5 and ABCG8 heterodimerise to form a sterol efflux transporter in the liver and intestine. In this review the pathophysiology, clinical manifestations and approach to clinical and laboratory diagnosis of this disease are described.

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Sitosterolaemia in Switzerland: molecular genetics links the US Amish‐Mennonites to their European roots

Cited by 15 publications

References 38 publications

The ABCG8 G574R Variant, Serum Plant Sterol Levels, and Cardiovascular Disease Risk in the Old Order Amish

The ABCG8 G574R Variant, Serum Plant Sterol Levels, and Cardiovascular Disease Risk in the Old Order Amish

Phytosterols and phytosterolemia: gene–diet interactions

Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis

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