younger and middle-aged subjects.33–36 In a smaller prospec- tive European study of healthy middle-aged men, sCD14 lev- els did not differ between CHD cases and controls.37 Despite the association between sCD14 levels and CVD risk in CHS, we found little evidence of association between CD14 geno- type and risk of CHD or stroke, in samples totaling >4000 CHD cases and 3000 stroke cases. These results are consistent with those of a recent meta-analysis of previously published studies (11 813 CHD cases and 6196 controls) that showed no evidence of association between the CD14 C-159T promoter polymorphism and CHD in Europeans or subjects from India, though a possible association between -159 T and CHD was observed among East Asians.38

phosphatidylinositol glycan class A (PIGA) in hematopoietic stem cells cause paroxysmal nocturnal hemoglobinuria, which manifests as bone marrow failure, hemolytic anemia, and thrombosis. As a result of the GPI anchoring defect, paroxysmal nocturnal hemoglobinuria patients do not express mCD14 on their monocytes, yet have normal plasma levels of sCD14.6 Notably, the Pro266Ser amino acid substitution encoded by PIGC rs1063412 is predicted to be functionally deleterious by Condel.29 The association of higher sCD14 with a functional coding variant of PIGC suggests that defective GPI anchor synthesis may be a mechanism that results in increased release of intracellular CD14 into the circulation from myeloid cells. Although the association reached genomewide significance in EA and is certainly biologically plausible, verification of the association between PIGC rs1063412 and sCD14 in an independent EA population is necessary to authenticate the finding.

Several limitations of the current study should be noted. Replication in an independent sample of EA, and also studies including larger numbers of blacks, will be required to validate the PIGC association and to determine whether the finding is ethnicity specific. The remaining phenotypic variability in sCD14 not ascribed to heritable factors or loci identified in our analyses suggests a contribution of combined effects of rare variants not tagged by current genotyping arrays, nonaddi- tive genetic factors, as well environmental factors. Therefore, genotyping arrays of even greater density and targeted sequencing of the CD14 locus may ultimately be required to identify the full spectrum of trait-associated variants. Finally, further study of the inverse relationship of sCD14 with body mass, as well as generalization of these association findings to younger adults is needed.

Germline mutations in GPI anchor genes have been identified in congenital autosomal recessive disorders that are characterized by a diverse range of phenotypes. To our knowledge, this is the first report of a common, inherited variant of a gene involved in GPI anchor biosynthesis associated with a complex trait. A recent GWAS identified a SNP located ≈70 kb downstream of PIGC associated with waist- hip ratio.30 However, there is no LD between the waist-hip ratio-associated rs1011731 variant and the sCD14-associated PIGC coding variant. In the current study, we were unable to detect an association between the PIGC locus and sCD14 in blacks. Even though the variant is more common in blacks, our black sample size was considerably smaller than our EA sample; therefore, power was only 43% to detect an effect of similar magnitude in blacks. Other possible explanations for the lack of replication in blacks include (1) a false-positive result (type I error) or overestimation of the effect (winner’s curse) in EA; (2) effect modification by another genetic or environmental factor that is differentially expressed between EA and blacks; (3) rs1063412 may not be true causal variant and the frequency of the true causal variant differs between EA and blacks and is not well tagged in blacks.

In population studies of older adults, serum levels of CRP and IL-6 predict adverse health outcomes and mortality. Though sCD14 is an acute phase protein, and correlates with CRP and IL-6, we found that sCD14 and IL-6 were strong and independent risk factors for mortality in older adults. Accounting for IL-6 and sCD14, there was no association of CRP or fibrinogen with mor- tality. sCD14 levels are increased in a number of acute and chronic inflammatory conditions and higher levels have been associated with disease severity,39 including mortality in Gram-negative sep- sis.40 Conversely, in mouse models, CD14 deficiency has been associated with resistance to LPS-induced shock,41 whereas mice harboring toll-like receptor (TLR)-4 and CD14 mutations have increased bone mineral density, decreased body fat, greater insu- lin sensitivity, live long lives, and show no evidence of infection.32 Increasing evidence suggests that proinflammatory mediators play a direct role in aging-related chronic diseases such as ath- erosclerosis, diabetes mellitus, and cancer. Whether higher levels of sCD14 or other inflammatory mediators are directly causal, or indicative of chronic, low-level infection and other immune alterations in older adults, or simply reflect worsening subclini- cal and clinical disease, is difficult to distinguish. Nonetheless, sCD14 may have potential clinical utility as a marker of aging, disease risk, or disease progression in older adults.