Association of Rare Loss-Of-Function Alleles in HAL , Serum Histidine

Abstract

Background Histidine is a semi-essential amino acid with anti-oxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels and incident coronary heart disease (CHD) in a population-based sample. Methods and Results By conducting whole-exome sequencing on 1,152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified three novel rare LoF variants in HAL, a gene which encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β = 0.26, p = 1.2 × 10-13). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (MAF = 1%, p = 1.2 × 10-4). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years follow-up among African Americans (HR = 0.18, p = 1.9 × 10-4). This finding was validated in an independent sample of European-Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium. Conclusions Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African- and European-Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

Evaluation of mitochondrial DNA copy number estimation techniques

“…Sequence reads were aligned using Burrows-Wheeler Aligner (BWA) [16] to the hg19 reference genome. Variant calling, and quality control were performed as previously described [17]. mtDNA-CN was calculated using the mitoAnalyzer software package, which determines the observed ratios of sequence coverages between autosomal and mtDNA [18,19].…”

The Rotterdam Study: 2016 objectives and design update

“…We identified 3 genetic loci associated with uric acid concentration and gout [ 70 ]. Three loss-of-function variants in HAL gene were found to associate with histidine levels [ 71 ] but not with coronary heart disease. We also identified a significant association between the UMOD gene which encodes Tamm-Horsfall protein and chronic kidney disease [ 72 ].…”

Whole genome sequence analysis of serum amino acid levels

“…Genome-wide association studies (GWAS) have identified common variants associated with multiple amino acid levels [4–6]. Low-frequency variants that modulate amino acid levels independent of known GWAS loci have also been reported using exome arrays and a targeted analytical approach for exome sequence data [7, 8]. To date, no study has assessed the impact of rare and low-frequency variations captured by systematic and comprehensive sequencing of the protein-encoding exons and whole genomes on amino acid levels in a multi-ethnic population.…”