A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption

During the Cardiovascular Risk Survey in western China, a Kazakh family with inherited low levels of LDL-C was identified. The Kazakhs are mainly descendent from the Turkic and medieval Mongol peoples, they live in isolated regions and usually marry within their own ethnic group. They exhibit often unique differences in single nucleotide variants (SNVs) across their genomes. To identify the causal SNV(s), samples from three subjects exhibiting low LDL-C (38-70 md/dl) and one exhibiting normal LDL-C were analyzed by whole-exome sequencing. A frameshift mutation in the LIMA1 gene was identified. Given that LDL-C is influenced by both endogenous cholesterol biosynthesis and intestinal cholesterol absorption, the campesterol to lathosterol ratio was measured. The LIMA1 mutation was associated with a significantly lower Ca:L ratio than in non-carriers, suggesting that LIMA1-mutation carriers have reduced intestinal cholesterol absorption.