Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1)

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Abstract
Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both1,2, is observed in about 20% of individuals with premature coronary heart disease1. We previously identified a locus linked to FCHL on 1q21–q23 in Finnish families with the disease3. This region has also been linked to FCHL in families from other populations4,5,6 as well as to type 2 diabetes mellitus7,8,9,10,11,12. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice13, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism14,15,16,17.

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