Complexity of a complex trait locus: HP, HPR, haemoglobin and cholesterol |
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Authors: | Guthrie Philip A I Rodriguez Santiago Gaunt Tom R Lawlor Debbie A Smith George Davey Day Ian N M |
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Affiliation: | Bristol Genetic Epidemiology Laboratory (BGEL), MRC Centre for Causal Analyses in Translational Epidemiology (MRC CAiTE), School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Clifton BS8 2BN, UK. philip.guthrie@bristol.ac.uk |
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Abstract: | HP and HPR are related and contiguous genes in strong linkage disequilibrium (LD), encoding haptoglobin and haptoglobin-related protein. These bind and chaperone free Hb for recycling, protecting against oxidation. A copy number variation (CNV) within HP (Hp1/Hp2) results in different possible haptoglobin complexes which have differing properties. HPR rs2000999 (G/A), identified in meta-GWAS, influences total cholesterol (TC) and LDL-cholesterol (LDL-C). We examined the relationship between HP CNV, HPR rs2000999, Hb, red cell count (RCC), LDL-C and TC in the British Women's Heart and Health Study (n=2779 for samples having CNV, rs2000999, and phenotypes). Analysing single markers by linear regression, rs2000999 was associated with LDL-C (β=0.040 mmol/L, p=0.023), TC (β=-0.040 mmol/L, p=0.019), Hb (β=-0.044 g/dL, p=0.028) and borderline with RCC (β=-0.032 × 10(12)/L, p=0.066). Analysis of CNV by linear regression revealed an association with Hb (Hp1 vs Hp2, β=0.057 g/dL, p=0.004), RCC (β=0.045 × 10(12)/L, p=0.014), and showed a trend with LDL-C and TC. There were 3 principal haplotypes (Hp1-G 36%; Hp2-G 45%; Hp2-A 18%). Haplotype comparisons showed that LDL-C and TC associations were from rs2000999; Hb and RCC associations derived largely from the CNV. Distinct genotype-phenotype effects are evident at the genetic epidemiological level once LD has been analysed, perhaps reflecting HP-HPR functional biology and evolutionary history. The derived Hp2 allele of the HP gene has apparently been subject to malaria-driven positive selection. Haptoglobin-related protein binds Hb and apolipoprotein-L, i.e. linking HPR to the cholesterol system; and the HPR/apo-L complex is specifically trypanolytic. Our analysis illustrates the complex interplay between functions and haplotypes of adjacent genes, environmental context and natural selection, and offers insights into potential use of haptoglobin or haptoglobin-related protein as therapeutic agents. |
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Keywords: | HP, haptoglobin gene HPR, haptoglobin-related protein gene LD, linkage disequilibrium Hb, haemoglobin CNV, copy number variant GWAS, genome-wide association study TC, total cholesterol LDL-C, low density lipoprotein cholesterol HDL-C, high density lipoprotein cholesterol RCC, red cell count Apo-L, apolipoprotein-L Apo-A, apolipoprotein-A SNP, single nucleotide polymorphism K-EDTA, potassium ethylene diamine tetraacetic acid ARCS, amplification ratiometry control system PCR, polymerase chain reaction HW, Hardy Weinberg HTR, haplotype trend regression EM, expectation maximization PASW, a statistical software package by the company SPSS Inc PLINK, open-source software for whole genome data analysis TLF-1, trypanosome lytic factor-1 TLF-2, trypanosome lytic factor-2 kD, kilo Daltons CHD, coronary heart disease |
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